Method of chemical reprogramming and pluripotent stem cells

Abstract

Provided herein in some aspects are methods and compositions for cell transformation. These methods can transform a population of cells comprising one cell type to another population of cells comprising another cell type. The transformed cell types may have increased cell differentiation potential. The transformed cell type may comprise pluripotent stem cells. Compositions provided herein may comprise chemical reprogramming factors for transforming cells. Compositions provided herein may comprise chemical reprogramming factors and cells. Also provided herein are agents for performing the methods of transforming cells. In addition, provided herein are methods and compositions for using various cell types obtained by the methods and / or compositions provided herein.

Description

BACKGROUND OF THE INVENTION

[0002] There remains a great demand for cellular resources for use in basic research, therapy, agriculture, and the food industry. Improved methods for the industrial-scale production of stem cells and cells of various differentiated states and cell types remain to be developed.

[0003] Cell identity can be established during development to acquire and maintain cell functions exclusive to somatic cells. Cell reprogramming can manipulate cell identity, enabling the generation of desired cell types that have a wide range of applications in disease modeling, drug discovery, and regenerative medicine. By using cytokines (including oocyte components and transcription factors), mouse and human somatic cells can be reprogrammed into pluripotent stem cells. Alternatively, chemical reprogramming can be utilized to induce somatic cells into pluripotent stem cells by simple exposure to small molecules. However, the efficiency and kinetics of the human chemical reprogramming system need to be improved to robustly induce pluripotent stem cells from human somatic cells. SUMMARY OF THE INVENTION

[0004] In some aspects, the present disclosure provides methods and compositions for cell transformation using chemical reprogramming factors. The methods and compositions can produce cells with enhanced differentiation potential. The methods and compositions can transform a cell population comprising at least one cell type into a cell population comprising another cell type, which exhibits increased differentiation potential. The various cells produced by the methods and / or compositions can include pluripotent stem cells or other intermediate cells that have an increased potential to become pluripotent stem cells relative to the untransformed cells. These intermediate cells can include epithelial-like cells, intermediate plastic state cells, their progeny, or their derivatives.

[0005] The methods and compositions can bypass the use of genetic modification to generate cells with enhanced differentiation potential. In some cases, not using genetic modification to generate stem cells or cells of various differentiated states can reduce the negative effects of genetic modification. Such negative effects can include the accidental induction of mutations in stem cells. In some cases, such negative effects can also be produced by exogenous nucleic acid molecules or sequences used for cell genetic modification. Cells containing accidental mutations can have various adverse characteristics, including but not limited to enhanced or unregulated cell proliferation potential (which can lead to tumor diseases such as cancer), unforeseen differentiation characteristics, and / or an adverse cell senescence stage. By utilizing chemical reprogramming factors, the methods and compositions provided herein can eliminate these negative effects caused by genetic modification. Additionally, when genetic modification is required for downstream purposes after generating the transformed cells, the methods and compositions provided herein can reduce the negative effects described herein.

[0006] By using the chemical programming factors described herein, the methods and compositions can also improve the scalability of producing stem cells and cells in various differentiation states. Compared with existing methods, these methods and compositions can generate stem cells or cells in various differentiation states in a shorter time. Thus, the methods and compositions can meet the demand for cell resources applied to basic research, therapies, agriculture, and the food industry.

[0007] In some aspects, provided herein are methods for producing pluripotent stem cells. In one aspect, a method for producing pluripotent stem cells includes: (a) obtaining epithelial-like cells that express LIN28A; (b) converting the epithelial-like cells or their progeny into intermediate plastic state cells that express LIN28A and SALL4, and one or more of MSX2, NMYC, SDC1, WNT4, FGF19, or TOP2A; and (c) converting the intermediate plastic state cells or their progeny into pluripotent stem cells.

[0008] In some embodiments, converting the epithelial-like cells or their progeny includes contacting the epithelial-like cells with a composition comprising a glycogen kinase inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor. In some embodiments, the composition further comprises a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor. In some embodiments, the composition further comprises a SAH hydrolase inhibitor or an adenosine kinase inhibitor.

[0009] In some aspects, provided herein are methods for producing pluripotent stem cells. In one aspect, a method for producing pluripotent stem cells includes: (a) obtaining epithelial-like cells that express LIN28A; (b) contacting the epithelial-like cells or their progeny with (i) a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor; (ii) a glycogen kinase inhibitor; (iii) a TGFβ receptor inhibitor; and (iv) a c-Jun kinase inhibitor, thereby converting the epithelial-like cells or their progeny into intermediate plastic state cells that express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A; and (c) converting the intermediate plastic state cells or their progeny into pluripotent stem cells.

[0010] In some embodiments, the epithelial-like cells express one or more of KRT18, KRT19, WT1, NMYC, WNT2B, PAX8, SMAD3, GLI3, or TBX2. In some embodiments, the epithelial-like cells express one or more of NMYC, WNT2B, PAX8, SMAD3, or GLI3. In some embodiments, the epithelial-like cells further express one or more of KRT18, KRT19, WT1, or TBX2. In some embodiments, the mesenchymal intermediate state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, the mesenchymal intermediate state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1. In some embodiments, the mesenchymal intermediate state cells further express one or more of FGF9, HOXA9, HOXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, the pluripotent stem cells express one or more of OCT4, SOX2, or NANOG. In some embodiments, the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DPPA5, DNMT3L, REX1, or UTF1. In some embodiments, the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, or REX1. In some embodiments, the pluripotent cells further express one or more of DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1.

[0011] In some embodiments, the method further comprises processing a population of somatic cells to convert at least a subset of the somatic cells in the population into epithelial-like cells. In some embodiments, the somatic cells include primary human adult adipose-derived mesenchymal stromal cells (hADSCs). In some embodiments, the somatic cells include fibroblasts. In some embodiments, the method converts somatic cells into pluripotent stem cells in less than about 50 days. In some embodiments, the method converts somatic cells into pluripotent stem cells in at most about 32 days. In some embodiments, the method converts somatic cells into pluripotent stem cells in at most about 24 days. In some embodiments, the method results in one pluripotent stem cell per at most 1,000 somatic cells in the population of somatic cells. In some embodiments, the method results in one pluripotent stem cell per at most 200 somatic cells in the population of somatic cells. In some embodiments, the method results in one pluripotent stem cell per at most 50 somatic cells in the population of somatic cells. In some embodiments, the method further comprises inoculating the somatic cells at a density of at most about 1 x 10^6 cells per square centimeter (cm^2) of cell growth area. In some embodiments, the somatic cells are inoculated at a density of at most about 5 x 10^5 cells per cm^2 of cell growth area. In some embodiments, the somatic cells are inoculated at a density of at most about 2.5 x 10^5 cells per cm^2 of cell growth area.

[0012] In some aspects, provided herein are methods of producing pluripotent stem cells. In one aspect, a method of producing pluripotent stem cells comprises: (a) obtaining a first population of cells comprising epithelial-like cells that express LIN28A; (b) contacting the first population of cells with a second composition comprising: (i) a glycogen kinase inhibitor; (ii) a TGFβ receptor inhibitor; and (iii) a c-Jun kinase inhibitor, thereby obtaining a second population of cells; and (c) contacting the second population of cells with a third composition comprising: (i) a MEK inhibitor; (ii) a B-Raf inhibitor; and (iii) a histone deacetylase inhibitor, thereby obtaining a third population of cells comprising pluripotent stem cells.

[0013] In some embodiments, the glycogen kinase inhibitor includes CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor includes CHIR99021. In some embodiments, the amount of CHIR99021 present in the second composition is from about 0.5 micromolar (μM) to about 50 μM. In some embodiments, the amount of CHIR99021 present in the second composition is from about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the second composition is from about 2 μM to about 12.5 μM. In some embodiments, the amount of CHIR99021 present in the second composition is about 5 μM. In some embodiments, the TGFβ receptor inhibitor is an ALK5 inhibitor. In some embodiments, the TGFβ receptor inhibitor includes E-616452, A83-01, SB431542, SB 505124, GW 788388, dorsomorphine, or SB 525334. Optionally, the TGFβ receptor inhibitor includes E-616452. In some embodiments, the amount of E-616452 present in the second composition is from about 1 μM to about 100 μM. In some embodiments, the amount of E-616452 present in the second composition is from about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the second composition is from about 4 μM to about 25 μM. In some embodiments, the amount of E-616452 present in the second composition is about 10 μM. In some embodiments, the c-Jun kinase inhibitor includes JNKIN8, JNKIN7, JNKIN5, or JNKIN12. In some embodiments, the c-Jun kinase inhibitor includes JNKIN8. In some embodiments, the amount of JNKIN8 present in the second composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of JNKIN8 present in the second composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of JNKIN8 present in the second composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of JNKIN8 present in the second composition is about 0.5 μM. In some embodiments, the MEK inhibitor includes PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor includes PD0325901. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.4 μM to about 2.5 μM.In some embodiments, the amount of PD0325901 present in the third composition is about 1 μM. In some embodiments, the B-Raf inhibitor includes SB590885, Vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor includes SB590885. In some embodiments, the amount of SB590885 present in the third composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SB590885 present in the third composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SB590885 present in the third composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SB590885 present in the third composition is about 0.5 μM. In some embodiments, the histone deacetylase inhibitor includes valproic acid (VPA), LMK235, MS275, or HDACi I. In some embodiments, the histone deacetylase inhibitor includes VPA. In some embodiments, the amount of VPA present in the third composition is from about 0.1 millimolar (mM) to about 10 mM. In some embodiments, the amount of VPA present in the third composition is from about 0.2 mM to about 5 mM. In some embodiments, the amount of VPA present in the third composition is from about 0.4 mM to about 2.5 mM. In some embodiments, the amount of VPA present in the third composition is about 1 mM. In some embodiments, the second composition further comprises a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor. In some embodiments, the second composition further comprises: (a) a retinoic acid receptor (RAR) agonist; (b) a CBP / p300 bromodomain inhibitor; and (c) an SAH hydrolase inhibitor or an adenosine kinase inhibitor. In some embodiments, the RAR agonist includes TTNPB, Ch55, or AM580. In some embodiments, the RAR agonist includes TTNPB. In some embodiments, the amount of TTNPB present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of TTNPB present in the second composition is about 2 μM. In some embodiments, the SAH hydrolase inhibitor includes DZNep, NepA, Adox, or DZA. In some embodiments, the SAH hydrolase inhibitor includes DZNep. In some embodiments, the amount of DZNep present in the second composition is from about 0.02 μM to about 2 μM. In some embodiments, the amount of DZNep present in the second composition is from about 0.04 μM to about 1 μM.In some embodiments, the amount of DZNep present in the second composition is from about 0.08 μM to about 0.5 μM. In some embodiments, the amount of DZNep present in the second composition is about 0.2 μM. In some embodiments, the CBP / p300 bromodomain inhibitor includes SGC-CBP30, I-CBP112, or GNE27. In some embodiments, the CBP / p300 bromodomain inhibitor includes SGC-CBP30. In some embodiments, the amount of SGC-CBP30 present in the second composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of SGC-CBP30 present in the second composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of SGC-CBP30 present in the second composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of SGC-CBP30 present in the second composition is about 2 μM. In some embodiments, the adenosine kinase inhibitor includes 5-iodotubercidin (5-ITU) or ABT 702. In some embodiments, the adenosine kinase inhibitor includes 5-ITU. In some embodiments, the amount of 5-ITU present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of 5-ITU present in the composition is from about 0.1 micromolar μM to about 2.5 μM. In some embodiments, the amount of 5-ITU present in the composition is from about 0.2 micromolar μM to about 1 μM. In some embodiments, the amount of 5-ITU present in the composition is about 0.5 μM.

[0014] In some embodiments, the method includes culturing a first cell population in the second composition for up to about 20 days. In some embodiments, the method includes culturing a first cell population in the second composition for up to about 16 days. In some embodiments, the method includes culturing a first cell population in the second composition for about 4 days to 16 days. In some embodiments, the method further includes removing the second composition from the second cell population. In some embodiments, the method includes culturing the second cell population in a third composition for up to about 20 days. In some embodiments, the method includes culturing the second cell population in a third composition for up to about 12 days. In some embodiments, the method includes culturing the second cell population in a third composition for about 4 days to 12 days. In some embodiments, the epithelial-like cells or their progeny comprise a genetic modification. In some embodiments, the pluripotent stem cells or their progeny comprise a genetic modification. In some embodiments, the genetic modification includes an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence includes a sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification includes altering a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the pluripotent stem cells or their progeny.

[0015] In some aspects, provided herein are methods for reprogramming epithelial-like cells that express LIN28A. In one aspect, a method for reprogramming epithelial-like cells that express LIN28A includes contacting a cell population comprising epithelial-like cells or progeny thereof with a composition comprising: (a) an SAH hydrolase inhibitor or an adenosine kinase inhibitor; (b) a glycogen kinase inhibitor; (c) a TGFβ receptor inhibitor; and (d) a c-Jun kinase inhibitor.

[0016] In some embodiments, during the contact, the cell population is incubated with about 21% atmospheric oxygen. In some embodiments, the composition comprises an adenosine kinase inhibitor. In some embodiments, the adenosine kinase inhibitor comprises 5-iodotubercidin (5-ITU) or ABT 702. In some embodiments, the adenosine kinase inhibitor comprises 5-ITU. In some embodiments, the amount of 5-ITU present in the composition is from about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of 5-ITU present in the composition is from about 0.1 micromolar μM to about 2.5 μM. In some embodiments, the amount of 5-ITU present in the composition is from about 0.2 micromolar μM to about 1 μM. In some embodiments, the amount of 5-ITU present in the composition is about 0.5 μM. In some embodiments, the composition comprises an SAH hydrolase inhibitor. In some embodiments, the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA. In some embodiments, the SAH hydrolase inhibitor comprises DZNep. In some embodiments, the amount of DZNep present in the second composition is from about 0.02 μM to about 2 μM. In some embodiments, the amount of DZNep present in the second composition is from about 0.04 μM to about 1 μM. In some embodiments, the amount of DZNep present in the second composition is from about 0.08 μM to about 0.5 μM. In some embodiments, the amount of DZNep present in the composition is about 0.2 micromolar (μM). In some embodiments, the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021. In some embodiments, the amount of CHIR99021 present in the composition is from about 0.5 micromolar (μM) to about 50 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 2 μM to about 12.5 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 5 μM. In some embodiments, the TGFβ receptor inhibitor is an ALK5 inhibitor. In some embodiments, the TGFβ receptor inhibitor comprises E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334, optionally, wherein the TGFβ receptor inhibitor comprises E-616452. In some embodiments, the amount of E-616452 present in the composition is from about 1 micromolar (μM) to about 100 μM. In some embodiments, the amount of E-616452 present in the composition is from about 2 μM to about 50 μM.In some embodiments, the amount of E-616452 present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of E-616452 present in the composition is about 10 μM. In some embodiments, the c-Jun kinase inhibitor includes JNKIN8, JNKIN7, JNKIN5, or JNKIN12. In some embodiments, the c-Jun kinase inhibitor includes JNKIN8. In some embodiments, the amount of JNKIN8 present in the composition is from about 0.05 micromolar (μM) to about 50 μM. In some embodiments, the amount of JNKIN8 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of JNKIN8 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of JNKIN8 present in the composition is about 0.5 μM. In some embodiments, the composition further comprises a CBP / p300 bromodomain inhibitor. In some embodiments, the CBP / p300 bromodomain inhibitor includes SGC-CBP30, I-CBP112, GNE272, or GNE409. In some embodiments, the CBP / p300 bromodomain inhibitor includes SGC-CBP30. In some embodiments, the amount of SGC-CBP30 present in the composition is from about 0.2 micromolar (μM) to about 20 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is about 2 μM. In some embodiments, the composition further comprises one or more of a SETD2 inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1, EPZ-719, or MMSET-IN-1. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is about 0.4 μM. In some embodiments, the Akt inhibitor includes an AKT kinase inhibitor. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is from about 0.2 μM to about 5 μM.In some embodiments, the AKT kinase inhibitor is present in the composition in an amount of from about 0.4 μM to about 2.5 μM. In some embodiments, the AKT kinase inhibitor is present in the composition in an amount of about 1 μM. In some embodiments, the casein kinase 2 inhibitor includes CX-4945, TPP 22, or ellagic acid. In some embodiments, the casein kinase 2 inhibitor includes CX-4945. In some embodiments, CX-4945 is present in the composition in an amount of from about 0.08 μM to about 8 μM. In some embodiments, CX-4945 is present in the composition in an amount of from about 0.16 μM to about 4 μM. In some embodiments, CX-4945 is present in the composition in an amount of from about 0.32 μM to about 2 μM. In some embodiments, CX-4945 is present in the composition in an amount of about 0.8 μM. In some embodiments, the composition further comprises one or more of a Menin-MLL interaction inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, or a BMP receptor / AMPK inhibitor. In some embodiments, the Menin-MLL interaction inhibitor includes VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the Menin-MLL interaction inhibitor includes VTP50469. In some embodiments, VTP50469 is present in the composition in an amount of from about 0.05 micromoles (μM) to about 5 μM. In some embodiments, VTP50469 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM. In some embodiments, VTP50469 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM. In some embodiments, VTP50469 is present in the composition in an amount of about 0.5 μM. In some embodiments, the agonist of the G protein-coupled receptor Smoothened includes SAG, Purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened includes SAG. In some embodiments, SAG is present in the composition in an amount of from about 0.05 micromoles (μM) to about 5 μM. In some embodiments, SAG is present in the composition in an amount of from about 0.1 μM to about 2.5 μM. In some embodiments, SAG is present in the composition in an amount of from about 0.2 μM to about 1.25 μM. In some embodiments, SAG is present in the composition in an amount of about 0.5 μM. In some embodiments, the ROCK inhibitor includes Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor includes Y-27632. In some embodiments, Y-27632 is present in the composition in an amount of from about 1 μM to about 100 μM.In some embodiments, the amount of Y-27632 present in the composition is from about 2 μM to about 50 μM. In some embodiments, the amount of Y-27632 present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of Y-27632 present in the composition is about 10 μM. In some embodiments, the BMP receptor / AMPK inhibitor includes Dorsomorphin. In some embodiments, the amount of Dorsomorphin present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of Dorsomorphin present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of Dorsomorphin present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of Dorsomorphin present in the composition is about 0.5 μM. In some embodiments, the composition further comprises a RAR agonist. In some embodiments, the RAR agonist includes TTNPB, Ch55, or AM580. In some embodiments, the RAR agonist includes TTNPB. In some embodiments, the amount of TTNPB present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of TTNPB present in the composition is about 2 μM. In some embodiments, the composition further comprises one or more of a Dot1L inhibitor, a Jak1 / Jak2 inhibitor, or a p38 MAPK inhibitor. In some embodiments, the Dot1L inhibitor includes EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor includes EPZ5676. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 2 μM. In some embodiments, the Jak1 / Jak2 inhibitor includes Ruxolitinib, Tofacitinib, AZD1480, Baricitinib, S-Ruxolitinib, or Fedratinib. In some embodiments, the Jak1 / Jak2 inhibitor includes Ruxolitinib. In some embodiments, the amount of Ruxolitinib present in the composition is from about 0.1 μM to about 10 μM.In some embodiments, ruxolitinib is present in the composition in an amount of from about 0.2 μM to about 5 μM. In some embodiments, ruxolitinib is present in the composition in an amount of from about 0.4 μM to about 2.5 μM. In some embodiments, ruxolitinib is present in the composition in an amount of about 1 μM. In some embodiments, the p38 MAPK inhibitor includes BIRB796, SB203580, or SB202190. In some embodiments, the p38 MAPK inhibitor includes BIRB796. In some embodiments, BIRB796 is present in the composition in an amount of from about 0.2 μM to about 20 μM. In some embodiments, BIRB796 is present in the composition in an amount of from about 0.4 μM to about 10 μM. In some embodiments, BIRB796 is present in the composition in an amount of from about 0.8 μM to about 5 μM. In some embodiments, BIRB796 is present in the composition in an amount of about 2 μM.

[0017] In some embodiments, the method includes culturing a cell population in the composition for up to about 20 days. In some embodiments, the method includes culturing a cell population in the composition for up to about 16 days. In some embodiments, the method includes culturing a cell population in the composition for from about 4 days to about 16 days.

[0018] In some embodiments, the method results in the transformation of epithelial cells into intermediate plastic state cells that express LIN28A and SALL4, and one or more of MSX2, NMYC, SDC1, WNT4, FGF19, or TOP2A. In some embodiments, the intermediate plastic state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, the intermediate plastic state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1. In some embodiments, the intermediate plastic state cells further express one or more of FGF9, HOXA9, HOXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2.

[0019] In some embodiments, the intermediate plastic state cells or their progeny contain a genetic modification. In some embodiments, the genetic modification includes an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence includes the sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification includes an alteration of the genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the intermediate plastic state cells or their progeny.

[0020] In some aspects, the present disclosure provides methods for reprogramming somatic cells. In one aspect, a method for reprogramming somatic cells includes contacting a cell population comprising somatic cells with a composition comprising: (a) a glycogen kinase inhibitor; (b) a TGFβ receptor inhibitor; (c) a RAR agonist; and (d) one or more of an Akt inhibitor or a SETD2 inhibitor.

[0021] In some embodiments, the somatic cells include primary human adult adipose-derived mesenchymal stromal cells (hADSCs). In some embodiments, the somatic cells include fibroblasts. In some embodiments, during the contact, the cell population is incubated with up to about 10% atmospheric oxygen. In some embodiments, during the contact, the cell population is incubated with up to about 5% atmospheric oxygen. In some embodiments, the glycogen kinase inhibitor includes CHIR99021. In some embodiments, the amount of CHIR99021 present in the composition is from about 0.5 μM to about 50 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 2 μM to about 12.5 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 5 μM. In some embodiments, the TGFβ receptor inhibitor is an ALK5 inhibitor. In some embodiments, the TGFβ receptor inhibitor includes E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334, optionally, wherein the TGFβ receptor inhibitor includes E-616452. In some embodiments, the amount of E-616452 present in the composition is from about 1 μM to about 100 μM. In some embodiments, the amount of E-616452 present in the composition is from about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of E-616452 present in the composition is about 10 μM. In some embodiments, the RAR agonist includes TTNPB, Ch55, or AM580. In some embodiments, the RAR agonist includes TTNPB. In some embodiments, the amount of TTNPB present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of TTNPB present in the composition is about 2 μM. In some embodiments, the composition comprises an Akt inhibitor. In some embodiments, the Akt inhibitor includes an AKT kinase inhibitor. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is about 1 μM.In some embodiments, the composition comprises a SETD2 inhibitor. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1, EPZ-719, or MMSET-IN-1. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is about 0.4 μM. In some embodiments, the composition does not contain serum. In some embodiments, the composition does not contain feeder cells. In some embodiments, the composition further comprises an agonist of the G protein-coupled receptor Smoothened or an inhibitor of the Menin-MLL interaction. In some embodiments, the agonist of the G protein-coupled receptor Smoothened includes SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened includes SAG. In some embodiments, the amount of SAG present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SAG present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SAG present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SAG present in the composition is about 0.5 μM. In some embodiments, the inhibitor of the Menin-MLL interaction includes VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the inhibitor of the Menin-MLL interaction includes VTP50469. In some embodiments, the amount of VTP50469 present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of VTP50469 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of VTP50469 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of VTP50469 present in the composition is about 0.5 μM. In some embodiments, the composition further comprises a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Dot1L inhibitor. In some embodiments, the Jak1 / Jak2 inhibitor includes ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib. In some embodiments, the Jak1 / Jak2 inhibitor includes ruxolitinib. In some embodiments, the amount of ruxolitinib present in the composition is from about 0.1 μM to about 10 μM.In some embodiments, ruxolitinib is present in the composition in an amount of from about 0.2 μM to about 5 μM. In some embodiments, ruxolitinib is present in the composition in an amount of from about 0.4 μM to about 2.5 μM. In some embodiments, ruxolitinib is present in the composition in an amount of about 1 μM. In some embodiments, the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA. In some embodiments, the SAH hydrolase inhibitor comprises DZNep. In some embodiments, DZNep is present in the second composition in an amount of from about 0.02 μM to about 2 μM. In some embodiments, DZNep is present in the second composition in an amount of from about 0.04 μM to about 1 μM. In some embodiments, DZNep is present in the second composition in an amount of from about 0.08 μM to about 0.5 μM. In some embodiments, DZNep is present in the second composition in an amount of about 0.2 μM. In some embodiments, the Dot1L inhibitor comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676. In some embodiments, EPZ5676 is present in the composition in an amount of from about 0.2 μM to about 20 μM. In some embodiments, EPZ5676 is present in the composition in an amount of from about 0.4 μM to about 10 μM. In some embodiments, EPZ5676 is present in the composition in an amount of from about 0.8 μM to about 5 μM. In some embodiments, EPZ5676 is present in the composition in an amount of about 2 μM.

[0022] In some embodiments, the method includes culturing a cell population in the composition for up to about 20 days. In some embodiments, the method includes culturing a cell population in the composition for up to about 12 days. In some embodiments, the method includes culturing a cell population in the composition for about 4 days to about 12 days. In some embodiments, the method results in the conversion of somatic cells into epithelial-like cells expressing LIN28A. In some embodiments, the epithelial-like cells express one or more of KRT18, KRT19, WT1, NMYC, WNT2B, PAX8, SMAD3, GLI3, or TBX2. In some embodiments, the epithelial-like cells express one or more of NMYC, WNT2B, PAX8, SMAD3, or GLI3. In some embodiments, the epithelial-like cells also express one or more of KRT18, KRT19, WT1, or TBX2. In some embodiments, the epithelial-like cells or their progeny contain a genetic modification. In some embodiments, the genetic modification includes an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence includes the sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification includes an alteration of a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the epithelial-like cells or their progeny.

[0023] In some aspects, provided herein are methods of generating pluripotent stem cells. In one aspect, a method of generating pluripotent stem cells includes contacting a cell population comprising intermediate plastic state cells or their progeny with a composition comprising: (a) a MEK inhibitor; (b) a B-Raf inhibitor; and (c) a histone deacetylase inhibitor; thereby generating pluripotent stem cells, wherein the intermediate plastic state cells express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A.

[0024] In some embodiments, during the contact, the cell population is incubated with approximately 21% atmospheric oxygen. In some embodiments, the MEK inhibitor includes PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor includes PD0325901. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of PD0325901 present in the third composition is about 1 μM. In some embodiments, the B-Raf inhibitor includes SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor includes SB590885. In some embodiments, the amount of SB590885 present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SB590885 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SB590885 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SB590885 present in the composition is about 0.5 μM. In some embodiments, the histone deacetylase inhibitor includes valproic acid (VPA), LMK235, MS275, or HDACi I. In some embodiments, the histone deacetylase inhibitor includes VPA. In some embodiments, the amount of VPA present in the composition is from about 0.1 millimolar (mM) to 10 mM. In some embodiments, the amount of VPA present in the composition is from about 0.2 mM to 5 mM. In some embodiments, the amount of VPA present in the composition is from about 0.4 mM to 2.5 mM. In some embodiments, the amount of VPA present in the composition is about 1 mM. In some embodiments, the composition further comprises one or more of a Wnt inhibitor, a glycogen kinase inhibitor, or a ROCK inhibitor. In some embodiments, the composition further comprises a Wnt inhibitor. In some embodiments, the Wnt inhibitor includes IWR-1 or IWP-2. In some embodiments, the Wnt inhibitor includes IWR-1. In some embodiments, the Wnt inhibitor includes IWP-2. In some embodiments, the amount of IWP-2 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of IWP-2 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of IWP-2 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of IWP-2 present in the composition is about 2 μM.In some embodiments, the composition further comprises a glycogen kinase inhibitor. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021. In some embodiments, CHIR99021 is present in the composition in an amount of from about 0.1 micromolar (μM) to about 10 μM. In some embodiments, CHIR99021 is present in the composition in an amount of from about 0.2 μM to about 5 μM. In some embodiments, CHIR99021 is present in the composition in an amount of from about 0.4 μM to about 2.5 μM. In some embodiments, CHIR99021 is present in the composition in an amount of about 1 μM. In some embodiments, the composition further comprises a ROCK inhibitor. In some embodiments, the ROCK inhibitor comprises Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor comprises Y-27632. In some embodiments, Y-27632 is present in the composition in an amount of from about 1 μM to about 100 μM. In some embodiments, Y-27632 is present in the composition in an amount of from about 2 μM to about 50 μM. In some embodiments, Y-27632 is present in the composition in an amount of from about 4 μM to about 25 μM. In some embodiments, Y-27632 is present in the composition in an amount of about 10 μM. In some embodiments, the composition further comprises one or more of a histone demethylation inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor. In some embodiments, the composition further comprises a histone demethylation inhibitor. In some embodiments, the histone demethylation inhibitor comprises tranylcypromine. In some embodiments, tranylcypromine is present in the composition in an amount of from about 1 μM to about 100 μM. In some embodiments, tranylcypromine is present in the composition in an amount of from about 2 μM to about 50 μM. In some embodiments, tranylcypromine is present in the composition in an amount of from about 4 μM to about 25 μM. In some embodiments, tranylcypromine is present in the composition in an amount of about 10 μM. In some embodiments, the composition further comprises a Dot1L inhibitor. In some embodiments, the Dot1L inhibitor comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676. In some embodiments, EPZ5676 is present in the composition in an amount of from about 0.2 μM to about 20 μM. In some embodiments, EPZ5676 is present in the composition in an amount of from about 0.4 μM to about 10 μM. In some embodiments, EPZ5676 is present in the composition in an amount of from about 0.8 μM to about 5 μM. In some embodiments, EPZ5676 is present in the composition in an amount of about 2 μM. In some embodiments, the composition further comprises a SAH hydrolase inhibitor.In some embodiments, the SAH hydrolase inhibitor includes DZNep, NepA, Adox, or DZA. In some embodiments, the SAH hydrolase inhibitor includes DZNep. In some embodiments, the amount of DZNep present in the composition is from about 0.02 μM to about 20 μM. In some embodiments, the amount of DZNep present in the composition is from about 0.04 μM to about 10 μM. In some embodiments, the amount of DZNep present in the composition is from about 0.08 μM to about 5 μM. In some embodiments, the amount of DZNep present in the composition is about 0.2 μM. In some embodiments, the contacting includes culturing a cell population in the composition. In some embodiments, the method further includes culturing for about 5 days and then replacing the composition with a second composition for culturing. In some embodiments, the second composition contains a histone deacetylase inhibitor. In some embodiments, the concentration of the histone deacetylase inhibitor in the second composition is about 50% of the concentration of the histone deacetylase inhibitor in the composition. In some embodiments, the method further includes culturing for about 5 days in the second composition and then replacing the second composition with a third composition for culturing. In some embodiments, the third composition does not contain a histone deacetylase inhibitor, a histone demethylation inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

[0025] In some embodiments, the method includes culturing a cell population in the composition for up to about 20 days. In some embodiments, the method includes culturing a cell population in the composition for up to about 12 days. In some embodiments, the method includes culturing a cell population in the composition for about 4 days to about 12 days. In some embodiments, the method results in the transformation of intermediate plastic state cells or their progeny into pluripotent stem cells. In some embodiments, the pluripotent stem cells express one or more of OCT4, SOX2, or NANOG. In some embodiments, the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DPPA5, DNMT3L, REX1, or UTF1. In some embodiments, the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, or REX1. In some embodiments, the pluripotent cells further express one or more of DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DPPA5, DNMT3L, REX1, or UTF1.

[0026] In some embodiments, the pluripotent stem cells or their progeny contain genetic modifications. In some embodiments, the genetic modifications include exogenous nucleic acid sequences. In some embodiments, the exogenous nucleic acid sequences encode polypeptides. In some embodiments, the exogenous nucleic acid sequences include sequences of non-coding nucleic acid molecules. In some embodiments, the genetic modifications include alterations of genomic sequences. In some embodiments, the genetic modifications reduce the immunogenicity of the pluripotent stem cells or their progeny.

[0027] In some aspects, the present disclosure provides isolated cell populations. In one aspect, the isolated cell population contains intermediate plastic state cells that express: (a) LIN28A and SALL4; (b) one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A; and (c) one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1.

[0028] In some embodiments, the intermediate plastic state cells further express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, the intermediate plastic state cells contain genetic modifications. In some embodiments, the genetic modifications include exogenous nucleic acid sequences. In some embodiments, the exogenous nucleic acid sequences encode polypeptides. In some embodiments, the exogenous nucleic acid sequences include sequences of non-coding nucleic acid molecules. In some embodiments, the genetic modifications include alterations of genomic sequences. In some embodiments, the genetic modifications reduce the immunogenicity of the intermediate plastic state cells.

[0029] In some aspects, the present disclosure provides compositions. In some aspects, the compositions provided herein are culture media for culturing cells. In one aspect, the compositions provided herein contain intermediate plastic state cells that express: LIN28A, SALL4, and one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A; and one or more of a glycogen kinase inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, or an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, a casein kinase 2 inhibitor.

[0030] In some embodiments, glycogen kinase inhibitors include CHIR99021 or CHIR98014. In some embodiments, glycogen kinase inhibitors include CHIR99021. In some embodiments, TGFβ receptor inhibitors include E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334. In some embodiments, TGFβ receptor inhibitors include E-616452. In some embodiments, RAR agonists include TTNPB, Ch55 or AM580. In some embodiments, RAR agonists include TTNPB. In some embodiments, c-Jun kinase inhibitors include JNKIN7, JNKIN5 or JNKIN12. In some embodiments, c-Jun kinase inhibitors include JNKIN8. In some embodiments, CBP / p300 bromodomain inhibitors include SGC-CBP30, I-CBP112, GNE272 or GNE409. In some embodiments, CBP / p300 bromodomain inhibitors include SGC-CBP30. In some embodiments, SAH hydrolase inhibitors include DZNep, NepA, Adox or DZA. In some embodiments, SAH hydrolase inhibitors include DZNep. In some embodiments, adenosine kinase inhibitors include 5-iodotubercidin or ABT 702. In some embodiments, adenosine kinase inhibitors include 5-iodotubercidin (5-ITU). In some embodiments, Dot1L inhibitors include EPZ004777 or EPZ5676. In some embodiments, Dot1L inhibitors include EPZ5676. In some embodiments, Menin-MLL interaction inhibitors include VTP50469, MI3454 or WDR5-IN-4. In some embodiments, Menin-MLL interaction inhibitors include VTP50469. In some embodiments, SETD2 inhibitors include SETD2-IN-1, EPZ-719 or MMSET-IN-1. In some embodiments, SETD2 inhibitors include SETD2-IN-1. In some embodiments, agonists of the G protein-coupled receptor Smoothened include SAG, purmorphamine, Hh-Ag1.5 or human SHH. In some embodiments, agonists of the G protein-coupled receptor Smoothened include SAG. In some embodiments, ROCK inhibitors include Y-27632 or thiazovivin. In some embodiments, ROCK inhibitors include Y-27632. In some embodiments, BMP receptor / AMPK inhibitors include dihydrodeoxymorphine.In some embodiments, the Jak1 / Jak2 inhibitors include ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib. In some embodiments, the Jak1 / Jak2 inhibitor includes ruxolitinib. In some embodiments, the p38MAPK inhibitors include BIRB796, SB203580, or SB202190. In some embodiments, the p38 MAPK inhibitor includes BIRB796. In some embodiments, the Akt inhibitor includes an AKT kinase inhibitor. In some embodiments, the casein kinase 2 inhibitors include CX-4945, TPP 22, or ellagic acid. In some embodiments, the casein kinase 2 inhibitor includes CX-4945.

[0031] In one aspect, the compositions provided herein comprise: epithelial-like cells that express LIN28A; and (a) a SAH hydrolase inhibitor or an adenosine kinase inhibitor; (b) a glycogen kinase inhibitor; (c) a TGFβ receptor inhibitor; and (d) a c-Jun kinase inhibitor.

[0032] In some embodiments, the composition further comprises a CBP / p300 bromodomain inhibitor.

[0033] In one aspect, the compositions provided herein comprise: (a) a SAH hydrolase inhibitor or an adenosine kinase inhibitor; (b) a glycogen kinase inhibitor; (c) a TGFβ receptor inhibitor; (d) a c-Jun kinase inhibitor; and (e) a CBP / p300 bromodomain inhibitor.

[0034] In some embodiments, the composition comprises an adenosine kinase inhibitor. In some embodiments, the adenosine kinase inhibitor comprises 5-iodotubercidin or ABT 702. In some embodiments, the adenosine kinase inhibitor comprises 5-iodotubercidin (5-ITU). In some embodiments, the amount of 5-ITU present in the composition is from about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of 5-ITU present in the composition is from about 0.1 micromolar μM to about 2.5 μM. In some embodiments, the amount of 5-ITU present in the composition is from about 0.2 micromolar μM to about 1 μM. In some embodiments, the amount of 5-ITU present in the composition is about 0.5 μM. In some embodiments, the composition comprises an SAH hydrolase inhibitor. In some embodiments, the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA. In some embodiments, the SAH hydrolase inhibitor comprises DZNep. In some embodiments, the amount of DZNep present in the composition is from about 0.02 μM to about 20 μM. In some embodiments, the amount of DZNep present in the composition is from about 0.04 μM to about 10 μM. In some embodiments, the amount of DZNep present in the composition is from about 0.08 μM to about 5 μM. In some embodiments, the amount of DZNep present in the composition is about 0.2 μM. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021. In some embodiments, the amount of CHIR99021 present in the composition is from about 0.5 micromolar (μM) to about 50 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 2 μM to about 12.5 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 5 μM. In some embodiments, the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW788388, dihydrodeoxymorphine or SB 525334. In some embodiments, the TGFβ receptor inhibitor comprises E-616452. In some embodiments, the amount of E-616452 present in the composition is from about 1 micromolar (μM) to about 100 μM. In some embodiments, the amount of E-616452 present in the composition is from about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of E-616452 present in the composition is about 10 μM.In some embodiments, the c-Jun kinase inhibitors include JNKIN8, JNKIN7, JNKIN5 or JNKIN12. In some embodiments, the c-Jun kinase inhibitor includes JNKIN8. In some embodiments, the amount of JNKIN present in the composition is from about 0.05 micromoles (μM) to about 50 μM. In some embodiments, the amount of JNKIN present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of JNKIN present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of JNKIN present in the composition is about 0.5 μM. In some embodiments, the CBP / p300 bromodomain inhibitors include SGC-CBP30, I-CBP112, GNE272 or GNE409. In some embodiments, the CBP / p300 bromodomain inhibitor includes SGC-CBP30. In some embodiments, the amount of SGC-CBP30 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is about 2 μM. In some embodiments, the composition further comprises one or more of a SETD2 inhibitor, an Akt inhibitor or a casein kinase 2 inhibitor. In some embodiments, the SETD2 inhibitors include SETD2-IN-1, EPZ-719 or MMSET-IN-1. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is about 0.4 μM. In some embodiments, the Akt inhibitors include AKT kinase inhibitors. In some embodiments, the amount of AKT kinase inhibitor present in the composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is about 1 μM. In some embodiments, the casein kinase 2 inhibitors include CX-4945, TPP 22 or ellagic acid.In some embodiments, the casein kinase 2 inhibitor includes CX-4945. In some embodiments, the amount of CX-4945 present in the composition is from about 0.08 μM to about 8 μM. In some embodiments, the amount of CX-4945 present in the composition is from about 0.16 μM to about 4 μM. In some embodiments, the amount of CX-4945 present in the composition is from about 0.32 μM to about 2 μM. In some embodiments, the amount of CX-4945 present in the composition is about 0.8 μM. In some embodiments, the composition further comprises one or more of a Menin-MLL interaction inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, or a BMP receptor / AMPK inhibitor. In some embodiments, the Menin-MLL interaction inhibitor includes VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the Menin-MLL interaction inhibitor includes VTP50469. In some embodiments, the amount of VTP50469 present in the composition is from about 0.05 micromoles (μM) to about 5 μM. In some embodiments, the amount of VTP50469 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of VTP50469 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of VTP50469 present in the composition is about 0.5 μM. In some embodiments, the agonist of the G protein-coupled receptor Smoothened includes SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened includes SAG. In some embodiments, the amount of SAG present in the composition is from about 0.05 micromoles (μM) to about 5 μM. In some embodiments, the amount of SAG present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SAG present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SAG present in the composition is about 0.5 μM. In some embodiments, the ROCK inhibitor includes Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor includes Y-27632. In some embodiments, the amount of Y27632 present in the composition is from about 1 μM to about 100 μM. In some embodiments, the amount of Y27632 present in the composition is from about 2 μM to about 50 μM. In some embodiments, the amount of Y27632 present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of Y27632 present in the composition is about 10 μM. In some embodiments, the BMP receptor / AMPK inhibitor includes dihydrodeoxymorphine.In some embodiments, the amount of dihydrodeoxymorphine present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of dihydrodeoxymorphine present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of dihydrodeoxymorphine present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of dihydrodeoxymorphine present in the composition is about 0.5 μM. In some embodiments, the method further comprises one or more of a Dot1L inhibitor, a Jak1 / Jak2 inhibitor, or a p38 MAPK inhibitor. In some embodiments, the Dot1L inhibitor comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 2 μM. In some embodiments, the Jak1 / Jak2 inhibitor comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib. In some embodiments, the Jak1 / Jak2 inhibitor comprises ruxolitinib. In some embodiments, the amount of ruxolitinib present in the composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of ruxolitinib present in the composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of ruxolitinib present in the composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of ruxolitinib present in the composition is about 1 μM. In some embodiments, the p38 MAPK inhibitor comprises BIRB796, SB203580, or SB202190. In some embodiments, the p38 MAPK inhibitor comprises BIRB796. In some embodiments, the amount of BIRB796 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of BIRB796 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of BIRB796 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of BIRB796 present in the composition is about 2 μM. In some embodiments, the composition further comprises an RAR agonist. In some embodiments, the RAR agonist comprises TTNPB, Ch55, or AM580. In some embodiments, the RAR agonist comprises TTNPB. In some embodiments, the amount of TTNPB present in the composition is from about 0.2 μM to about 20 μM.In some embodiments, the amount of TTNPB present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of TTNPB present in the composition is about 2 μM.

[0035] In some aspects, the present disclosure provides an isolated cell population. In one aspect, the isolated cell population comprises epithelial-like cells that express LIN28A and one or more of NMYC, WNT2B, PAX8, SMAD3, or GLI3.

[0036] In some embodiments, the isolated cell population comprising epithelial-like cells expresses one or more of KRT18, KRT19, WT1, or TBX2. In some embodiments, the isolated cell population comprising epithelial-like cells does not express any of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2.

[0037] In one aspect, the composition provided herein comprises epithelial-like cells that express LIN28A; and (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, (c) a RAR agonist, and (d) an Akt inhibitor or a SETD2 inhibitor.

[0038] In some embodiments, the composition comprises an Akt inhibitor. In some embodiments, the Akt inhibitor comprises an AKT kinase inhibitor. In some embodiments, the composition comprises a SETD2 inhibitor. In some embodiments, the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719, or MMSET-IN-1. In some embodiments, the SETD2 inhibitor comprises SETD2-IN-1.

[0039] In one aspect, the composition provided herein comprises epithelial-like cells that express LIN28A and one or more of NMYC, WNT2B, PAX8, SMAD3, or GLI3; and (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, and (c) a RAR agonist.

[0040] In some embodiments, the composition comprises an Akt inhibitor or a SETD2 inhibitor. In some embodiments, the composition comprises an Akt inhibitor. In some embodiments, the Akt inhibitor includes an AKT kinase inhibitor. In some embodiments, the composition comprises a SETD2 inhibitor. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1, EPZ-719, or MMSET-IN-1. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1. In some embodiments, the composition is serum-free. In some embodiments, the composition is feeder cell-free. In some embodiments, the glycogen kinase inhibitor includes CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor includes CHIR99021. In some embodiments, the TGFβ receptor inhibitor includes E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334. In some embodiments, the TGFβ receptor inhibitor includes E-616452. In some embodiments, the RAR agonist includes TTNPB, Ch55, or AM580. In some embodiments, the RAR agonist includes TTNPB. In some embodiments, the composition further comprises an agonist of G protein-coupled receptor Smoothened or a Menin-MLL interaction inhibitor. In some embodiments, the agonist of G protein-coupled receptor Smoothened includes SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of G protein-coupled receptor Smoothened includes SAG. In some embodiments, the Menin-MLL interaction inhibitor includes VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the Menin-MLL interaction inhibitor includes VTP50469. In some embodiments, the composition further comprises a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, a Dot1L inhibitor. In some embodiments, the Jak1 / Jak2 inhibitor includes ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib. In some embodiments, the Jak1 / Jak2 inhibitor includes ruxolitinib. In some embodiments, the SAH hydrolase inhibitor includes DZNep, NepA, Adox, or DZA. In some embodiments, the SAH hydrolase inhibitor includes DZNep. In some embodiments, the Dot1L inhibitor includes EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor includes EPZ5676.

[0041] In one aspect, the compositions provided herein comprise: (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, (c) a RAR agonist, and (d) an Akt inhibitor or a SETD2 inhibitor.

[0042] In some embodiments, the composition further comprises somatic cells. In some embodiments, the somatic cells comprise primary human adult adipose-derived mesenchymal stromal cells (hADSCs). In some embodiments, the somatic cells comprise fibroblasts. In some embodiments, the composition is serum-free. In some embodiments, the composition is feeder cell-free. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021. In some embodiments, the amount of CHIR99021 present in the composition is from about 0.5 micromolar (μM) to about 50 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 2 μM to about 12.5 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 5 μM. In some embodiments, the TGFβ receptor inhibitor is an ALK5 inhibitor. In some embodiments, the TGFβ receptor inhibitor comprises E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334, optionally, wherein the TGFβ receptor inhibitor comprises E-616452. In some embodiments, the amount of E-616452 present in the composition is from about 1 μM to about 100 μM. In some embodiments, the amount of E-616452 present in the composition is from about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of E-616452 present in the composition is about 10 μM. In some embodiments, the RAR agonist comprises TTNPB, Ch55, or AM580. In some embodiments, the RAR agonist comprises TTNPB. In some embodiments, the amount of TTNPB present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of TTNPB present in the composition is about 2 μM. In some embodiments, the composition comprises an Akt inhibitor. In some embodiments, the Akt inhibitor comprises an AKT kinase inhibitor. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is from about 0.2 μM to about 5 μM.In some embodiments, the amount of the AKT kinase inhibitor present in the composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is about 1 μM. In some embodiments, the composition comprises a SETD2 inhibitor. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1, EPZ-719 or MMSET-IN-1. In some embodiments, the SETD2 inhibitor includes SETD2-IN-1. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is about 0.4 μM. In some embodiments, the composition further comprises an agonist of the G protein-coupled receptor Smoothened or an inhibitor of the Menin-MLL interaction. In some embodiments, the agonist of the G protein-coupled receptor Smoothened includes SAG, purmorphamine, Hh-Ag1.5 or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened includes SAG. In some embodiments, the amount of SAG present in the composition is from about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of SAG present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SAG present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SAG present in the composition is about 0.5 μM. In some embodiments, the inhibitor of the Menin-MLL interaction includes VTP50469, MI3454 or WDR5-IN-4. In some embodiments, the inhibitor of the Menin-MLL interaction includes VTP50469. In some embodiments, the amount of VTP50469 present in the composition is from about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of VTP50469 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of VTP50469 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of VTP50469 present in the composition is about 0.5 μM. In some embodiments, the composition further comprises a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, a Dot1L inhibitor. In some embodiments, the Jak1 / Jak2 inhibitor includes ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib.In some embodiments, the Jak1 / Jak2 inhibitor includes ruxolitinib. In some embodiments, the amount of ruxolitinib present in the composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of ruxolitinib present in the composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of ruxolitinib present in the composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of ruxolitinib present in the composition is about 1 μM. In some embodiments, the SAH hydrolase inhibitor includes DZNep, NepA, Adox or DZA. In some embodiments, the SAH hydrolase inhibitor includes DZNep. In some embodiments, the amount of DZNep present in the composition is from about 0.002 μM to about 0.2 μM. In some embodiments, the amount of DZNep present in the composition is from about 0.004 μM to about 0.1 μM. In some embodiments, the amount of DZNep present in the composition is from about 0.008 μM to about 0.05 μM. In some embodiments, the amount of DZNep present in the composition is about 0.02 μM. In some embodiments, the Dot1L inhibitor includes EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor includes EPZ5676. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 2 μM.

[0043] In one aspect, the compositions provided herein comprise: intermediate plastic state cells that express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19 or TOP2A; and one or more of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a glycogen kinase inhibitor, a ROCK inhibitor, a histone demethylation inhibitor, a Dot1L inhibitor or a SAH hydrolase inhibitor.

[0044] In some embodiments, intermediate plastic state cells express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, MEK inhibitors include PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor includes PD0325901. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of PD0325901 present in the third composition is about 1 μM. In some embodiments, B-Raf inhibitors include SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor includes SB590885. In some embodiments, the amount of SB590885 present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SB590885 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SB590885 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SB590885 present in the composition is about 0.5 μM. In some embodiments, histone deacetylase inhibitors include valproic acid (VPA), LMK235, MS275, or HDACi IV. In some embodiments, the histone deacetylase inhibitor includes valproic acid (VPA). In some embodiments, the amount of VPA present in the composition is from about 0.1 millimolar (mM) to 10 mM. In some embodiments, the amount of VPA present in the composition is from about 0.2 mM to 5 mM. In some embodiments, the amount of VPA present in the composition is from about 0.4 mM to 2.5 mM. In some embodiments, the amount of VPA present in the composition is about 1 mM. In some embodiments, histone demethylation inhibitors include tranylcypromine. In some embodiments, the amount of tranylcypromine present in the composition is from about 1 μM to about 100 μM. In some embodiments, the amount of tranylcypromine present in the composition is from about 2 μM to about 50 μM. In some embodiments, the amount of tranylcypromine present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of tranylcypromine present in the composition is about 10 μM. In some embodiments, Dot1L inhibitors include EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor includes EPZ5676.In some embodiments, the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 2 μM. In some embodiments, the SAH hydrolase inhibitor includes DZNep, NepA, Adox, or DZA. In some embodiments, the SAH hydrolase inhibitor includes DZNep. In some embodiments, the amount of DZNep present in the composition is from about 0.02 μM to about 20 μM. In some embodiments, the amount of DZNep present in the composition is from about 0.04 μM to about 10 μM. In some embodiments, the amount of DZNep present in the composition is from about 0.08 μM to about 5 μM. In some embodiments, the amount of DZNep present in the composition is about 0.2 μM. In some embodiments, the Wnt inhibitor includes IWR-1 or IWP-2. In some embodiments, the Wnt inhibitor includes IWR-1. In some embodiments, the Wnt inhibitor includes IWP-2. In some embodiments, the amount of IWP-2 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of IWP-2 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of IWP-2 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of IWP-2 present in the composition is about 2 μM. In some embodiments, the glycogen kinase inhibitor includes CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor includes CHIR99021. In some embodiments, the amount of CHIR99021 present in the composition is from about 0.1 micromole (μM) to about 10 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of CHIR99021 present in the composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 1 μM. In some embodiments, the ROCK inhibitor includes Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor includes Y-27632. In some embodiments, the amount of Y-27632 present in the composition is from about 1 μM to about 100 μM. In some embodiments, the amount of Y-27632 present in the composition is from about 2 μM to about 50 μM. In some embodiments, the amount of Y-27632 present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of Y-27632 present in the composition is about 10 μM.

[0045] In one aspect, the compositions provided herein comprise: (a) a MEK inhibitor, a B-Raf inhibitor, and a histone deacetylase inhibitor; and (b) a histone demethylation inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

[0046] In some embodiments, the composition further comprises pluripotent stem cells that express OCT4, SOX2, and NANOG. In some embodiments, the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, or REX1. In some embodiments, the pluripotent cells express one or more of DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1.

[0047] In some embodiments, the MEK inhibitors include PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor includes PD0325901. In some embodiments, the B-Raf inhibitors include SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor includes SB590885. In some embodiments, the histone deacetylase inhibitors include valproic acid (VPA), LMK235, MS275, or HDACi IV. In some embodiments, the histone deacetylase inhibitor includes VPA. In some embodiments, the composition comprises a histone demethylation inhibitor. In some embodiments, the histone demethylation inhibitor includes tranylcypromine. In some embodiments, the composition comprises a Dot1L inhibitor. In some embodiments, the Dot1L inhibitors include EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor includes EPZ5676. In some embodiments, the SAH hydrolase inhibitors include DZNep, NepA, Adox, or DZA. In some embodiments, the SAH hydrolase inhibitor includes DZNep. In some embodiments, the composition further comprises a Wnt inhibitor, a glycogen kinase inhibitor, or a ROCK inhibitor. In some embodiments, the composition comprises a Wnt inhibitor. In some embodiments, the Wnt inhibitors include IWR-1 or IWP-2. In some embodiments, the Wnt inhibitor includes IWR-1. In some embodiments, the Wnt inhibitor includes IWP-2. In some embodiments, the composition comprises a glycogen kinase inhibitor. In some embodiments, the glycogen kinase inhibitors include CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor includes CHIR99021. In some embodiments, the glycogen kinase inhibitor includes CHIR98014. In some embodiments, the composition comprises a ROCK inhibitor. In some embodiments, the ROCK inhibitors include Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor includes Y-27632. In some embodiments, pluripotent stem cells protect genetic modifications. In some embodiments, the genetic modification includes an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence includes a sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification includes an alteration of a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of pluripotent stem cells. In some embodiments, the MEK inhibitors include PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor includes PD0325901.In some embodiments, the amount of PD0325901 present in the third composition is from about 0.1 μM to about 10 μM. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.2 μM to about 5 μM. In some embodiments, the amount of PD0325901 present in the third composition is from about 0.4 μM to about 2.5 μM. In some embodiments, the amount of PD0325901 present in the third composition is about 1 μM. In some embodiments, the B-Raf inhibitor includes SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor includes SB590885. In some embodiments, the amount of SB590885 present in the composition is from about 0.05 μM to about 5 μM. In some embodiments, the amount of SB590885 present in the composition is from about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SB590885 present in the composition is from about 0.2 μM to about 1.25 μM. In some embodiments, the amount of SB590885 present in the composition is about 0.5 μM. In some embodiments, the histone deacetylase inhibitor includes valproic acid (VPA), LMK235, MS275, or HDACi IV. In some embodiments, the histone deacetylase inhibitor includes valproic acid (VPA). In some embodiments, the amount of VPA present in the composition is from about 0.1 millimolar (mM) to 10 mM. In some embodiments, the amount of VPA present in the composition is from about 0.2 mM to 5 mM. In some embodiments, the amount of VPA present in the composition is from about 0.4 mM to 2.5 mM. In some embodiments, the amount of VPA present in the composition is about 1 mM. In some embodiments, the histone demethylation inhibitor includes tranylcypromine. In some embodiments, the amount of tranylcypromine present in the composition is from about 1 μM to about 100 μM. In some embodiments, the amount of tranylcypromine present in the composition is from about 2 μM to about 50 μM. In some embodiments, the amount of tranylcypromine present in the composition is from about 4 μM to about 25 μM. In some embodiments, the amount of tranylcypromine present in the composition is about 10 μM. In some embodiments, the Dot1L inhibitor includes EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor includes EPZ5676. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 2 μM.In some embodiments, the SAH hydrolase inhibitors include DZNep, NepA, Adox, or DZA. In some embodiments, the SAH hydrolase inhibitor includes DZNep. In some embodiments, DZNep is present in the composition in an amount of from about 0.02 μM to about 20 μM. In some embodiments, DZNep is present in the composition in an amount of from about 0.04 μM to about 10 μM. In some embodiments, DZNep is present in the composition in an amount of from about 0.08 μM to about 5 μM. In some embodiments, DZNep is present in the composition in an amount of about 0.2 μM. In some embodiments, the Wnt inhibitors include IWR-1 or IWP-2. In some embodiments, the Wnt inhibitor includes IWR-1. In some embodiments, the Wnt inhibitor includes IWP-2. In some embodiments, IWP-2 is present in the composition in an amount of from about 0.2 μM to about 20 μM. In some embodiments, IWP-2 is present in the composition in an amount of from about 0.4 μM to about 10 μM. In some embodiments, IWP-2 is present in the composition in an amount of from about 0.8 μM to about 5 μM. In some embodiments, IWP-2 is present in the composition in an amount of about 2 μM. In some embodiments, the glycogen kinase inhibitors include CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor includes CHIR99021. In some embodiments, CHIR99021 is present in the composition in an amount of from about 0.1 micromolar (μM) to about 10 μM. In some embodiments, CHIR99021 is present in the composition in an amount of from about 0.2 μM to about 5 μM. In some embodiments, CHIR99021 is present in the composition in an amount of from about 0.4 μM to about 2.5 μM. In some embodiments, CHIR99021 is present in the composition in an amount of about 1 μM. In some embodiments, the ROCK inhibitors include Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor includes Y-27632. In some embodiments, Y-27632 is present in the composition in an amount of from about 1 μM to about 100 μM. In some embodiments, Y-27632 is present in the composition in an amount of from about 2 μM to about 50 μM. In some embodiments, Y-27632 is present in the composition in an amount of from about 4 μM to about 25 μM. In some embodiments, Y-27632 is present in the composition in an amount of about 10 μM.

[0048] Those skilled in the art will readily appreciate other aspects and advantages of the present disclosure from the following detailed description of the invention, in which only exemplary embodiments of the present disclosure are shown and described. As will be recognized, the present disclosure is capable of covering other different embodiments, and several details thereof can be modified in various obvious aspects, all of which do not depart from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative rather than restrictive.

[0049] Incorporation by reference

[0050] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference, as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. If a publication, patent, or patent application incorporated by reference conflicts with the disclosure in the specification, the specification is intended to supersede and / or take precedence over any such conflicting material.

[0051] Brief description of the drawings

[0052] The novel features of the present disclosure are set forth in detail in the appended claims. The features and advantages of the present disclosure will be better understood by reference to the following detailed description of the invention and the accompanying drawings (also referred to herein as "figures"), in which exemplary embodiments utilizing the principles of the present disclosure are illustrated, wherein:

[0053] Figure 1 A schematic diagram showing the conversion of somatic cells into chemically induced human pluripotent stem cells (hCiPSCs) is shown.

[0054] Figure 2 Another schematic diagram showing the conversion of somatic cells into hCiPSCs is shown.

[0055] Figure 3 Representative images of cells at the end of the first stage of the first-stage conversion process using various culture media are shown.

[0056] Figure 4 The number of hCiPSC colonies generated during the first-stage conversion process using various culture media is shown.

[0057] Figure 5 The number of hCiPSC colonies generated during the first-stage conversion process using another set of various culture media is shown.

[0058] Figure 6 The number of hCiPSC colonies generated using the first-stage conversion medium with or without a SETD2 inhibitor is shown.

[0059] Figure 7A The number of hCiPSC colonies generated using the second-stage conversion medium with or without an adenosine kinase inhibitor is shown.

[0060] Figure 7B Shows the number of hCiPSC colonies generated using a stage 2 conversion medium with or without a Menin-MLL interaction inhibitor.

[0061] Figure 8 Shows representative images of immunofluorescence analysis of a set of pluripotency markers in hCiPSCs derived from human adipose-derived stromal cells (hADSCs).

[0062] Figure 9 Shows representative images of morphological analysis of hCiPSCs derived from hADSCs.

[0063] Figure 10 Shows the reprogramming efficiency of generating hCiPS cells from different donors.

[0064] Figure 11 Shows a comparison of the number of hCiPSC colonies generated using the method described herein and another method.

[0065] Figure 12 Shows representative images of immunofluorescence analysis of another set of pluripotency markers in hCiPSCs derived from hADSCs.

[0066] Figure 13 Shows reverse transcription (RT)-quantitative PCR (qPCR) analysis of pluripotency markers in the indicated hCiPSCs and controls.

[0067] Figure 14 Shows representative images of hematoxylin and eosin staining of endoderm (respiratory epithelium), mesoderm (cartilage), and ectoderm (pigmented retinal epithelium and neural tissue) of a single teratoma from the indicated hCiPSC clone.

[0068] Figure 15A Shows immunofluorescence analysis of regeneration-related genes at the end of stage 1 and stage 2. Figure 15B Shows analysis of somatic cell-related genes and regeneration-related gene expression in hADSCs and cells at the end of stage 2.

[0069] Figure 16 Shows GO term enrichment analysis of upregulated genes in hADSCs and cells at the end of stage 2.

[0070] Figure 17 Shows the number of hCiPSC colonies using various stage 2 conversion media.

[0071] Figure 18Shows the number of hCiPSC colonies produced using a stage 2 conversion medium with or without a serine - threonine kinase Akt inhibitor and a casein kinase 2 inhibitor.

[0072] Figure 19 Shows the number of hCiPSC colonies using various stage 3 conversion media.

[0073] Figure 20 Shows exemplary epithelial - like cells expressing LIN28A in stage 1 or stage 2 as shown in the heatmap.

[0074] Figure 21 Shows an exemplary composition comprising chemical reprogramming factors and optional cells in stage 1.

[0075] Figure 22 Shows the gene expression profile of exemplary intermediate plastic state cells in stage 2.

[0076] Figure 23 Shows an exemplary composition comprising chemical reprogramming factors and optional cells in stage 2.

[0077] Figure 24 Shows exemplary CiPSCs expressing OCT4, SOX2, and NANOG as shown in the heatmap.

[0078] Figure 25 Shows an exemplary composition comprising chemical reprogramming factors and optional cells in stage 3. DETAILED DESCRIPTION OF THE INVENTION

[0080] Definition

[0081] As used herein, the terms "conversion" or "reprogramming" and their grammatical equivalents, when referring to a cell, refer to the process of changing or reversing the differentiation state of a cell (e.g., a somatic cell). The conversion process as used herein, when referring to converting a cell of a first cell type into a cell of a second cell type, refers to the process of converting a cell of a first cell type into a cell of a second cell type, or refers to the process of converting one or more progeny of a cell of a first cell type into a cell of a second cell type.

[0082] As used herein, the term "differentiation" and its grammatical equivalents can refer to the process by which a less - specialized cell (e.g., a more naive cell with higher cell potential) becomes a more - specialized cell type (e.g., a less naive cell with lower cell potential); and the term "dedifferentiation" can refer to the process by which a more - specialized cell becomes a less - specialized cell type (e.g., a more naive cell with higher cell potential).

[0083] As used herein, the term "cellular potency" can refer to the ability of a cell to differentiate into cells of different lineages. For example, without being bound by a particular theory, a pluripotent cell (e.g., a stem cell) has the potential to differentiate into cells of any one of the three germ layers or cells derived from any one of the three germ layers, which are the endoderm (e.g., the inner lining of the stomach, the gastrointestinal tract, the lungs), the mesoderm (e.g., muscle, bone, blood, the urogenital system), or the ectoderm (e.g., epidermal tissue and the nervous system), and thus has high cellular potency; a multipotent cell (e.g., a certain type of stem cell, such as a hematopoietic stem cell, a cardiac stem cell, or a neural stem cell, etc.) has the ability to give rise to cells from multiple but a limited number of lineages (such as the blood cell lineage, the cardiac cell lineage, the neural cell lineage), and in comparison, its cellular potency is lower than that of a pluripotent cell. A cell committed to a specific lineage or terminally differentiated may have lower cellular potency.

[0084] As used herein, the term "isolated cell population" refers to a group of cells that do not occur in nature.

[0085] As used herein, the term "cell population" or its grammatical equivalents refer to a group of cells, their progeny, and / or cells derived therefrom. For example, a first cell population may comprise a first cell or the progeny of a first cell.

[0086] As used herein, the term "progeny" when referring to a cell can refer to any daughter cell derived from the mitosis of that cell or the mitosis of any progeny of that cell.

[0087] Whenever the terms "at least", "greater than", or "greater than or equal to" are placed before the first value in a series of two or more numerical values, the term "at least" or "greater than" applies to each value in that series.

[0088] Whenever the terms "at most", "not exceeding", "less than", or "less than or equal to" are placed before the first value in a series of two or more numerical values, the term "not exceeding" or "less than" applies to each value in that series.

[0089] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0090] As used herein, the term "and / or" as used in phrases such as "A and / or B" is intended to include both A and B; A or B; A alone; B alone. Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; C alone.

[0091] As used herein, the term "about" or "approximately" when referring to a measurable value (such as an amount or concentration, etc.) is intended to cover variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. For example, according to the practice in the art, "about" can represent plus or minus 10%. Alternatively, "about" can represent a range of plus or minus 20%, plus or minus 10%, plus or minus 5%, or plus or minus 1% of a given value. Alternatively, especially for biological systems or processes, the term can represent within an order of magnitude of the numerical value, up to 5-fold or up to 2-fold. When a specific value can be described in the application and claims, unless otherwise stated, it should be assumed that the term "about" represents an acceptable error range of the specific value. In addition, when a range, sub-range, or both of numerical values can be provided, the range or sub-range can include the endpoints of the range or sub-range. The terms "substantially", "substantially free", "substantially without", and "about" when describing a magnitude, position, or both can be used to indicate that the stated value can be up to a reasonably expected range of the value. For example, a numerical value can have a value of + / - 0.1%, + / - 1%, + / - 2%, + / - 5%, + / - 10%, etc. of the specified value (or numerical range). Any numerical range described herein can be intended to include all sub-ranges contained therein.

[0092] Method

[0093] In some aspects, the present disclosure provides methods and compositions for cell transformation. In some cases, the method can include contacting a first cell population with a composition comprising one or more reprogramming factors. In some cases, the contacting can include incubating the first cell population with the composition comprising one or more reprogramming factors for a period of time. After the contacting, at least one subset of the first cell population can be transformed into a different cell type. The cell population after transformation can include a second cell population. During or after the transformation, the first cell population and the second cell population can have different biological properties. The different biological properties can include different gene expression, different protein expression, different cell proliferation properties (such as cell division or cell growth / cell mass increase), different cell sizes, different cell numbers, different cell genomic modifications (such as epigenetic modifications), different cell cycle stages, different senescence stages, or different differentiation stages or types, or any combination thereof. The difference between the first cell population and the second cell population can be that they have at least two cells with at least different cell activities. The difference between the first cell population and the second cell population can be that they have different cell types. The different cell types can have different cell activities as described herein.

[0094] In some aspects, provided herein are methods and compositions for transforming cells in multiple stages. The methods and compositions for transforming cells can include at least 2, 3, 4, 5, or more stages. The methods and compositions for transforming cells can include at most 2, 3, 4, or more stages. The methods and compositions for transforming cells can include at most 2 stages. The methods and compositions for transforming cells can include at most 3 stages. The methods and compositions for transforming cells can include at least 3 stages. The 3 stages can include a first stage (or stage I), a second stage (or stage II), and / or a third stage (or stage III). The methods and compositions described herein can include a first stage that involves transforming somatic cells into cells with higher cellular potential (e.g., less specialized cells), such as epiblast-like cells. The methods and compositions described herein can include a second stage that involves transforming epiblast-like cells into cells with higher cellular potential (e.g., less specialized cells), such as intermediate plastic state cells. The methods and compositions described herein can include a third stage that involves transforming intermediate plastic state cells into cells with higher cellular potential (e.g., less specialized cells), such as pluripotent stem cells. The methods and compositions described herein can include the first stage, the second stage, and the third stage. One stage in the multiple stages can include contacting a first cell population with a first composition and transforming at least one subset of the first cell population into different cells. The transformed cell population can include a second cell population.

[0095] In some cases, the method can include (1) contacting a first cell population with a first composition; (2) transforming at least one subset of the first cell population into different cells and generating a second cell population comprising the transformed cells; (3) contacting the second cell population with a second composition; (4) transforming at least one subset of the second cell population into different cells and generating a third cell population comprising the transformed cells; (5) contacting the third cell population with a third composition; (6) transforming at least one subset of the third cell population into different cells and generating a fourth cell population comprising the transformed cells. The first, second, and third compositions can each comprise one or more reprogramming factors. Any one of the first, second, or third compositions can comprise one or more reprogramming factors. The first, second, and third compositions can be different. The first, second, third, and fourth cell populations can be different. In some cases, at least one cell in the cell population contacted with the composition can be cultured before, during, or after each contact. In some cases, the cell population contacted with the composition can be cultured before, during, or after each transformation. When culturing the cells, the cells can undergo cell proliferation.

[0096] It should be understood that the ordinal numbering of a cell population or composition may not limit the cell population or composition to a particular cell population or composition relative to other cell populations or compositions. In some cases, the ordinal numbering of a cell population or composition should be understood to distinguish the cell population or composition from other cell populations or compositions.

[0097] In some cases, the method may include: (1) contacting a first cell population comprising somatic cells with a first composition; (2) transforming at least one subset of the somatic cells or their progeny into different cells and generating a second cell population comprising transformed cells containing epithelial-like cells; (3) contacting the second cell population comprising epithelial-like cells with a second composition; (4) transforming at least one subset of the second cell population into different cells and generating a third cell population comprising transformed cells containing cells in an intermediate plastic state; (5) contacting the third cell population comprising cells in an intermediate plastic state with a third composition; (6) transforming at least one subset of the third cell population comprising cells in an intermediate plastic state into different cells and generating a fourth cell population comprising transformed cells containing pluripotent stem cells.

[0098] In some cases, the method can transform a cell population comprising somatic cells into a different cell population comprising pluripotent stem cells during a pluripotent stem cell conversion time period. The pluripotent stem cell conversion time period can include the time period from contacting the cell population comprising somatic cells to generating at least one pluripotent stem cell. The pluripotent stem cell conversion time period can be less than about 100 days, 90 days, 80 days, 70 days, 60 days, 59 days, 58 days, 57 days, 56 days, 55 days, 54 days, 53 days, 52 days, 51 days, 50 days, 49 days, 48 days, 47 days, 46 days, 45 days, 44 days, 43 days, 42 days, 41 days, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 34 days, 33 days, 32 days, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days or less. The pluripotent stem cell conversion time period can be less than about 55 days. The pluripotent stem cell conversion time period can be less than about 54 days. The pluripotent stem cell conversion time period can be less than about 53 days. The pluripotent stem cell conversion time period can be less than about 52 days. The pluripotent stem cell conversion time period can be less than about 51 days. The pluripotent stem cell conversion time period can be less than about 50 days. The pluripotent stem cell conversion time period can be less than about 49 days. The pluripotent stem cell conversion time period can be less than about 48 days. The pluripotent stem cell conversion time period can be less than about 47 days. The pluripotent stem cell conversion time period can be less than about 46 days. The pluripotent stem cell conversion time period can be less than about 45 days. The pluripotent stem cell conversion time period can be less than about 44 days. The pluripotent stem cell conversion time period can be less than about 43 days. The pluripotent stem cell conversion time period can be less than about 42 days. The pluripotent stem cell conversion time period can be less than about 41 days. The pluripotent stem cell conversion time period can be less than about 40 days. The pluripotent stem cell conversion time period can be less than about 39 days. The pluripotent stem cell conversion time period can be less than about 38 days. The pluripotent stem cell conversion time period can be less than about 37 days. The pluripotent stem cell conversion time period can be less than about 36 days. The pluripotent stem cell conversion time period can be less than about 35 days. The pluripotent stem cell conversion time period can be less than about 34 days. The pluripotent stem cell conversion time period can be less than about 33 days. The pluripotent stem cell conversion time period can be less than about 32 days. The pluripotent stem cell conversion time period can be less than about 31 days. The pluripotent stem cell conversion time period can be less than about 30 days. The pluripotent stem cell conversion time period can be less than about 29 days. The pluripotent stem cell conversion time period can be less than about 28 days. The pluripotent stem cell conversion time period can be less than about 27 days. The pluripotent stem cell conversion time period can be less than about 26 days. The pluripotent stem cell conversion time period can be less than about 25 days. The pluripotent stem cell conversion time period can be less than about 24 days. The pluripotent stem cell conversion time period can be less than about 23 days. The pluripotent stem cell conversion time period can be less than about 22 days. The pluripotent stem cell conversion time period can be less than about 21 days.The pluripotent stem cell conversion time period can be less than about 20 days. The pluripotent stem cell conversion time period can be less than about 19 days. The pluripotent stem cell conversion time period can be less than about 18 days. The pluripotent stem cell conversion time period can be less than about 17 days. The pluripotent stem cell conversion time period can be less than about 16 days. The pluripotent stem cell conversion time period can be less than about 15 days.

[0099] In some cases, the method can convert a cell population comprising somatic cells into a different cell population comprising pluripotent stem cells with a pluripotent stem cell conversion efficiency. The pluripotent stem cell conversion efficiency can be measured as the ratio (e.g., percentage) of the number of pluripotent stem cells produced relative to the number of somatic cells, where the methods disclosed herein are applied to produce the number of pluripotent stem cells. For example, if the method produces one pluripotent stem cell from 1000 somatic cells, the pluripotent stem cell conversion efficiency of the method is 0.1%. In some cases, the pluripotent stem cell conversion efficiency of the method can be at least about 0.0001%, 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.5% or more. In some cases, the pluripotent stem cell conversion efficiency of the method can be about 0.0001%, 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2% or 0.5%. The pluripotent stem cell conversion efficiency of the method can be about 0.0005%. The pluripotent stem cell conversion efficiency of the method can be about 0.0006%. The pluripotent stem cell conversion efficiency of the method can be about 0.0007%. The pluripotent stem cell conversion efficiency of the method can be about 0.0008%. The pluripotent stem cell conversion efficiency of the method can be about 0.0009%. The pluripotent stem cell conversion efficiency of the method can be about 0.001%. The pluripotent stem cell conversion efficiency of the method can be about 0.002%. The pluripotent stem cell conversion efficiency of the method can be about 0.003%. The pluripotent stem cell conversion efficiency of the method can be about 0.004%. The pluripotent stem cell conversion efficiency of the method can be about 0.005%. The pluripotent stem cell conversion efficiency of the method can be about 0.006%. The pluripotent stem cell conversion efficiency of the method can be about 0.007%. The pluripotent stem cell conversion efficiency of the method can be about 0.008%. The pluripotent stem cell conversion efficiency of the method can be about 0.009%.The conversion efficiency of pluripotent stem cells of the method can be about 0.01%. The conversion efficiency of pluripotent stem cells of the method can be about 0.02%. The conversion efficiency of pluripotent stem cells of the method can be about 0.03%. The conversion efficiency of pluripotent stem cells of the method can be about 0.04%. The conversion efficiency of pluripotent stem cells of the method can be about 0.05%. The conversion efficiency of pluripotent stem cells of the method can be about 0.06%. The conversion efficiency of pluripotent stem cells of the method can be about 0.07%. The conversion efficiency of pluripotent stem cells of the method can be about 0.08%. The conversion efficiency of pluripotent stem cells of the method can be about 0.09%. The conversion efficiency of pluripotent stem cells of the method can be about 0.1%.

[0100] In some cases, provided herein is a method for producing pluripotent stem cells. In some cases, the method includes obtaining epithelial-like cells expressing LIN28A for conversion. In some cases, the method includes converting the epithelial-like cells or their progeny into intermediate plastic state cells for further conversion. In some cases, the intermediate plastic state cells express LIN28A and SALL4, and one or more of MSX2, NMYC, SDC1, WNT4, FGF19, or TOP2A. In some cases, the method includes converting the intermediate plastic state cells into pluripotent stem cells. In some cases, the conversion of epithelial-like cells includes contacting the epithelial-like cells with a composition comprising a glycogen kinase inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor. In some cases, the composition contacting the epithelial-like cells further comprises a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor. In some cases, the composition contacting the epithelial-like cells further comprises a SAH hydrolase inhibitor or an adenosine kinase inhibitor.

[0101] In some cases, the method for producing pluripotent stem cells includes obtaining a first cell population comprising epithelial-like cells expressing LIN28A. In some cases, the method further includes contacting the first cell population with a second composition to obtain a second cell population. The second composition may comprise (i) a glycogen kinase inhibitor; (ii) a TGFβ receptor inhibitor; and (iii) a c-Jun kinase inhibitor. In some cases, the method further includes contacting the second cell population with a third composition to obtain a third cell population comprising pluripotent stem cells. The third composition may comprise: (1) a MEK inhibitor; (2) a B-Raf inhibitor; and (3) a histone deacetylase inhibitor.

[0102] In some cases, the epithelial-like cells expressing LIN28A are obtained by reprogramming somatic cells. In some cases, the methods disclosed herein include contacting a cell population comprising somatic cells with a composition comprising one or more reprogramming factors. In some cases, the composition contacting the somatic cells comprises one or more of a glycogen kinase inhibitor, a TGFβ receptor inhibitor, and a RAR agonist. In some cases, the composition contacting the somatic cells further comprises an Akt inhibitor or a SETD2 inhibitor.

[0103] In some cases, the epithelial-like cells expressing LIN28A are obtained by reprogramming a cell population comprising epithelial cells. By contacting the epithelial cells with a composition comprising one or more reprogramming factors, the epithelial cells can be transformed into epithelial-like cells expressing LIN28A. In some cases, the composition contacting the epithelial cells comprises one or more of a glycogen kinase inhibitor, a TGFβ receptor inhibitor, and a RAR agonist. In some cases, the composition contacting the epithelial cells further comprises an Akt inhibitor or a SETD2 inhibitor. In other cases, the composition contacting the epithelial cells comprises one or more of a CBP / p300 bromodomain inhibitor, an adenosine kinase inhibitor, a glycogen kinase inhibitor, a TGFβ receptor inhibitor, or a c-Jun kinase inhibitor. In some cases, the composition contacting the epithelial cells comprises a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor, a glycogen kinase inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor. In some cases, the composition contacting the epithelial cells further comprises a RAR agonist, a CBP / p300 bromodomain inhibitor, and a SAH hydrolase inhibitor or an adenosine kinase inhibitor.

[0104] The cells in any of the cell populations described herein may include mammalian cells. The cells may include mouse cells, hamster cells, rat cells, or rodent cells. The cells may include mouse cells. The cells may include hamster cells. The cells may include rat cells. The cells may include rodent cells. In some cases, the cells may include primate cells. The cells may include strepsirrhine cells or haplorrhine cells. The cells may include monkey cells, ape cells, or human cells. In some cases, the cells may include human cells. The cells may include monkey cells. The cells may include ape cells.

[0105] The first stage

[0106] In some aspects, provided herein are methods and compositions for converting somatic cells into cells with higher cellular potential (e.g., less specialized cells) such as epiblast-like cells - the conversion process is also referred to herein as "Phase 1". The Phase 1 method can be part of a conversion process for reprogramming somatic cells into pluripotent stem cells. The Phase 1 method can be the first phase of a conversion process for reprogramming somatic cells into pluripotent stem cells.

[0107] The Phase 1 method can include contacting a first cell population with a first composition. The Phase 1 method can include converting a subset of the first cell population into different cells after or during the contacting. The cell population containing the different cells can include a second cell population. The Phase 1 method can include incubating the first cell population with the first composition for a period of time. The subset of the first cell population can be converted into different cells before, during, or after the incubation. In some cases, the Phase 1 method can include removing the first composition from the second cell population. In other cases, the Phase 1 method can include removing the first composition from the first cell population.

[0108] The first cell population of the stage 1 cells may include somatic cells. The somatic cells may include skin cells, nerve cells, muscle cells, or blood cells. The somatic cells may not include germ cells. The somatic cells may not include undifferentiated cells. The somatic cells may not include gametes (sperm or egg). The somatic cells may not include gametophytes. In some cases, the somatic cells may also include muscle cells, fat cells, connective tissue cells, vascular cells, neurons, bone cells, or skin cells. The first cell population of the stage 1 cells may include fibroblasts, primary human adult adipose-derived mesenchymal stromal cells (hADSCs), smooth muscle cells, cardiomyocytes, skeletal muscle cells, neurons, red blood cells, white blood cells, platelets, osteoblasts, osteoclasts, squamous cells, basal cells, or melanocytes, or any combination thereof. The first cell population of the stage 1 cells may comprise fibroblasts or hADSCs. The first cell population of the stage 1 cells may comprise fibroblasts. The first cell population of the stage 1 cells may comprise primary human adult adipose-derived mesenchymal stromal cells (hADSCs). The first cell population of the stage 1 cells may comprise smooth muscle cells. The first cell population of the stage 1 cells may comprise cardiomyocytes. The first cell population of the stage 1 cells may comprise skeletal muscle cells. The first cell population of the stage 1 cells may comprise neurons. The first cell population of the stage 1 cells may comprise red blood cells. The first cell population of the stage 1 cells may comprise white blood cells. The first cell population of the stage 1 cells may comprise platelets. The first cell population of the stage 1 cells may comprise osteoblasts. The first cell population of the stage 1 cells may comprise osteoclasts. The first cell population of the stage 1 cells may comprise squamous cells. The first cell population of the stage 1 cells may comprise basal cells. The first cell population of the stage 1 cells may comprise melanocytes. The first cell population of the stage 1 cells may comprise cells from the intestinal epithelium. The first cell population of the stage 1 cells may comprise neonatal (e.g., foreskin) or adult fibroblasts. The first cell population of the stage 1 cells may include epithelial cells, endothelial cells, mesenchyme-derived cells, parenchymal cells (e.g., hepatocytes), nerve cells, or connective tissue cells, or any combination thereof. The first cell population of the stage 1 cells may not contain cells that are not somatic cells. In some cases, the first cell population of the stage 1 cells may include germ cells.

[0109] The first cell population of the stage 1 cells can be isolated by dissociating a suitable organ or tissue. For example, the tissue or organ can be mechanically dissociated and / or treated with digestive enzymes and / or chelating agents that weaken the connections between adjacent cells, so that the tissue can be dispersed to form a suspension of single cells without significant cell rupture. Enzymatic digestion can be achieved by chopping the tissue and treating the chopped tissue with one or more enzymes (such as trypsin, chymotrypsin, collagenase, elastase, and / or hyaluronidase, DNase, pronase, dispase, etc.). Mechanical disruption can also be achieved by a variety of methods, including but not limited to using a grinder, blender, sieve, homogenizer, pressure chamber, or ultrasonic generator.

[0110] The second cell population of the stage 1 cells may include epitheloid cells. The epitheloid cells may not be naturally occurring cells. The epitheloid cells may express a gene combination not expressed by naturally occurring cells. The epitheloid cells may express at least one gene at a level that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 5-fold, 100-fold, or higher than that of naturally occurring cells. The epitheloid cells may express at least one gene at a level that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% lower than that of naturally occurring cells. The second cell population of the stage 1 cells may include somatic cells or epitheloid cells. The second cell population of the stage 1 cells may include somatic cells and epitheloid cells. The second cell population of the stage 1 cells may not include somatic cells. In some cases, the second cell population of the stage 1 cells may include fewer somatic cells than the first cell population of the stage 1 cells. For example, the second cell population of the stage 1 cells may have 0.001%, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 99% fewer somatic cells than the first cell population of the stage 1 cells. In some cases, the second cell population of the stage 1 cells may include more epitheloid cells than the first cell population of the stage 1 cells. For example, the second cell population of the stage 1 cells may have 0.001%, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 100-fold, or more epitheloid cells than the first cell population of the stage 1 cells.

[0111] Epithelial cells can express LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. Epithelial cells can express LIN28A. Epithelial cells can express NMYC. Epithelial cells can express WNT2B. Epithelial cells can express PAX8. Epithelial cells can express SMAD3. Epithelial cells can express GLI3. Epithelial cells can express KRT18. Epithelial cells can express KRT19. Epithelial cells can express WT1. Epithelial cells can express TBX2. Epithelial cells can express LIN28A and one or more of NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2. Epithelial cells can express LIN28A and NMYC. Epithelial cells can express LIN28A and WNT2B. Epithelial cells can express LIN28A and PAX8. Epithelial cells can express LIN28A and SMAD3. Epithelial cells can express LIN28A and GLI3. Epithelial cells can express LIN28A and KRT18. Epithelial cells can express LIN28A and KRT19. Epithelial cells can express LIN28A and WT1. Epithelial cells can express LIN28A and TBX2. Epithelial cells may not express MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof. Epithelial cells may not express MMP1. Epithelial cells may not express ZEB1. Epithelial cells may not express VIM. Epithelial cells may not express COL1A1. Epithelial cells may not express COL5A1. Epithelial cells may not express COL6A2. Epithelial cells may not express PRRX1. Epithelial cells may not express SNAI2. Epithelial cells may not express TWIST1. Epithelial cells may not express TWIST2. Epithelial cells can express LIN28A but not express MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof. Epithelial cells can express LIN28A but not express VIM. Epithelial cells can express LIN28A but not express COL1A1. Epithelial cells can express LIN28A but not express COL5A1. Epithelial cells can express LIN28A but not express COL6A2. Epithelial cells can express LIN28A but not express PRRX1. Epithelial cells can express LIN28A but not express SNAI2. Epithelial cells can express LIN28A but not express TWIST1. Epithelial cells can express LIN28A but not express TWIST2.Epithelial-like cells can express LIN28A; one or more of NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2; but do not express MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof.

[0112] The first cell population of the stage 1 cells may not contain the epithelial-like cells described herein. The somatic cells of the first cell population of the stage 1 cells may not express LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. The somatic cells may not express LIN28A. The somatic cells may not express NMYC. The somatic cells may not express WNT2B. The somatic cells may not express PAX8. The somatic cells may not express SMAD3. The somatic cells may not express GLI3. The somatic cells may not express KRT18. The somatic cells may not express KRT19. The somatic cells may not express WT1. The somatic cells may not express TBX2. The somatic cells may not express LIN28A and may not express one or more of NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2. The somatic cells may not express LIN28A or NMYC. The somatic cells may not express LIN28A or WNT2B. The somatic cells may not express LIN28A or PAX8. The somatic cells may not express LIN28A or SMAD3. The somatic cells may not express LIN28A or GLI3. The somatic cells may not express LIN28A or KRT18. The somatic cells may not express LIN28A or KRT19. The somatic cells may not express LIN28A or WT1. The somatic cells may not express LIN28A or TBX2. The somatic cells can express MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof. The somatic cells can express MMP1. The somatic cells can express ZEB1. The somatic cells can express VIM. The somatic cells can express COL1A1. The somatic cells can express COL5A1. The somatic cells can express COL6A2. The somatic cells can express PRRX1. The somatic cells can express SNAI2. The somatic cells can express TWIST1. The somatic cells can express TWIST2.

[0113] Epithelial cells can express LIN28A and a second gene, but do not express a third gene. Epithelial cells can express LIN28A and one or more second genes, but do not express one or more third genes. The second genes expressed by epithelial cells can include NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. Somatic cells may not express LIN28A or the second gene, but express the third gene. Somatic cells may not express LIN28A or one or more second genes, but express one or more third genes. The second genes expressed by epithelial cells but not by somatic cells can include NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. Its second gene can include NMYC. Its second gene can include WNT2B. Its second gene can include PAX8. Its second gene can include SMAD3. Its second gene can include GLI3. Its second gene can include KRT18. Its second gene can include KRT19. Its second gene can include WT1. Its second gene can include TBX2. The third genes not expressed by epithelial cells can include MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof. Its third gene can include MMP1. Its third gene can include ZEB1. Its third gene can include VIM. Its third gene can include COL1A1. Its third gene can include COL5A1. Its third gene can include COL6A2. Its third gene can include PRRX1. Its third gene can include SNAI2. Its third gene can include TWIST1. Its third gene can include TWIST2. Figure 20 Exemplary epithelial cells expressing LIN28A in stage 1 or stage 2 as shown in the heat map are shown. The y-axis and x-axis of the heat map show the second and third genes, respectively. Each pixel of the heat map represents a cell population. For example, cell 201 expresses LIN28A and GLI3 but does not express COL6A2. Cell 202 expresses LIN28A and any combination of second genes (such as NYMC and WNT2B) but does not express TWIST1. Cell 203 expresses LIN28A and KRT19 but does not express any combination of third genes (such as MMP1 and VIM).

[0114] Cells of the second cell population of stage 1 cells may express higher levels of LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof, relative to cells of the first cell population of stage 1 cells. The higher expression level of any one of LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2 in cells of the second cell population of stage 1 cells, relative to cells of the first cell population of stage 1 cells, can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 5-fold, 100-fold, or more higher. Cells of the second cell population of stage 1 cells may express lower levels of any one of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2 relative to cells of the first cell population of stage 1 cells. The lower expression level of any one of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2 in cells of the second cell population of stage 1 cells, relative to cells of the first cell population of stage 1 cells, is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% lower. Expression levels can be measured by any method described herein. For example, gene expression can be measured by the method described in Example 2. Gene expression can be measured using any one of SEQ ID NO:1-83 (including controls).

[0115] In some aspects, the present disclosure provides a composition comprising reprogramming factors for stage 1 transformation, or comprising stage 1 cells (the first cell population or the second cell population), or comprising stage 1 cells (the first cell population or the second cell population) and reprogramming factors for stage 1 transformation. In some cases, the composition comprises a culture medium containing reprogramming factors for stage 1 transformation.

[0116] In some cases, the composition can include a separated cell population of a second cell population of stage 1 cells. In some cases, the composition can include a separated cell population of a first cell population of stage 1 cells. The separated cell population of stage 1 cells can include at least about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more cells. The separated cell population of stage 1 cells can include at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 cells. The separated cell population of stage 1 cells can include at least one epithelioid cell. In some cases, the separated cell population of stage 1 cells can include at least about 1, 1x10^1, 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more epithelioid cells. The separated cell population can include at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 epithelioid cells. In some cases, the separated cell population of stage 1 cells can include at least about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more somatic cells. The separated cell population can include at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 somatic cells. In some cases, the separated cell population of stage 1 cells can include at least about 1x10^1, 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more somatic cells, epithelioid cells or a combination thereof. The separated cell population of stage 1 cells can include at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 epithelioid cells, somatic cells or a combination thereof.

[0117] The composition may comprise chemical reprogramming factors. The composition may comprise a plurality of chemical reprogramming factors. The composition may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more chemical reprogramming factors. The composition may comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more chemical reprogramming factors. The composition may comprise 1 chemical reprogramming factor. The composition may comprise 2 chemical reprogramming factors. The composition may comprise 3 chemical reprogramming factors. The composition may comprise 4 chemical reprogramming factors. The composition may comprise 5 chemical reprogramming factors. The composition may comprise 6 chemical reprogramming factors. The composition may comprise 7 chemical reprogramming factors. The composition may comprise 8 chemical reprogramming factors. The composition may comprise 9 chemical reprogramming factors. The composition may comprise 10 chemical reprogramming factors. The composition may comprise 11 chemical reprogramming factors. The composition may comprise 12 chemical reprogramming factors. The composition may comprise 13 chemical reprogramming factors. The composition may comprise 14 chemical reprogramming factors. The composition may comprise 15 chemical reprogramming factors. The composition may comprise 16 chemical reprogramming factors. The composition may comprise 17 chemical reprogramming factors. The composition may comprise 18 chemical reprogramming factors. The composition may comprise 19 chemical reprogramming factors. The composition may comprise 20 chemical reprogramming factors. The chemical reprogramming factors in the composition may include any of the chemical reprogramming factors described herein.

[0118] The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor, or any combination thereof. The composition may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor. The composition may comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor.

[0119] The composition may comprise a GSK inhibitor. The composition may comprise a TGFβ receptor inhibitor. The composition may comprise a RAR agonist. The composition may comprise an Akt inhibitor. The composition may comprise a SETD2 inhibitor. The composition may comprise a Dot1L inhibitor. The composition may comprise an agonist of the G protein-coupled receptor Smoothened. The composition may comprise a Jak1 / Jak2 inhibitor. The composition may comprise a SAH hydrolase inhibitor. The composition may comprise a Menin-MLL interaction inhibitor. The composition may comprise a GSK inhibitor and a TGFβ receptor inhibitor. The composition may comprise a TGFβ receptor inhibitor and a RAR agonist. The composition may comprise a GSK inhibitor and a RAR agonist.

[0120] The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, or a RAR agonist, or any combination thereof. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, and a RAR agonist. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, or a SETD2 inhibitor, or any combination thereof. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, and a SETD2 inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, and a SETD2 inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or an Akt inhibitor, or any combination thereof. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or an Akt inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, and an Akt inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or a SETD2 inhibitor, or any combination thereof. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or a SETD2 inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, and a SETD2 inhibitor. The composition may further comprise a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor, or any combination thereof.

[0121] The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor, or any combination thereof. The composition may comprise somatic cells; and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor. The composition may comprise somatic cells; and at most 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, and a Menin-MLL interaction inhibitor. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, and a Menin-MLL interaction inhibitor.

[0122] The composition may comprise somatic cells; a GSK inhibitor and a TGFβ receptor inhibitor. The composition may comprise somatic cells; a TGFβ receptor inhibitor and a RAR agonist. The composition may comprise somatic cells; a GSK inhibitor and a RAR agonist. The composition may comprise somatic cells; and a GSK inhibitor. The composition may comprise somatic cells; and a TGFβ receptor inhibitor. The composition may comprise somatic cells; and a RAR agonist. The composition may comprise somatic cells; and an Akt inhibitor. The composition may comprise somatic cells; and a SETD2 inhibitor. The composition may comprise somatic cells; and a Dot1L inhibitor. The composition may comprise somatic cells; and an agonist of the G protein-coupled receptor Smoothened. The composition may comprise somatic cells; and a Jak1 / Jak2 inhibitor. The composition may comprise somatic cells; and a SAH hydrolase inhibitor. The composition may comprise somatic cells; and a Menin-MLL interaction inhibitor.

[0123] The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, or a RAR agonist, or any combination thereof. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, or a RAR agonist. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, and a RAR agonist. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, or a SETD2 inhibitor, or any combination thereof. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, or a SETD2 inhibitor. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, or a SETD2 inhibitor. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or an Akt inhibitor, or any combination thereof. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or an Akt inhibitor. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, and an Akt inhibitor. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or a SETD2 inhibitor, or any combination thereof. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or a SETD2 inhibitor. The composition may comprise somatic cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or a SETD2 inhibitor. The somatic cells may include any somatic cells described herein. For example, the somatic cells may include fibroblasts or hADSCs.

[0124] The composition may comprise epithelioid cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor, or any combination thereof. The composition may comprise epithelioid cells; and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor. The composition may comprise epithelioid cells; and at most 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor. The composition may comprise epithelioid cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, and a Menin-MLL interaction inhibitor.

[0125] The composition may comprise epithelioid cells; a GSK inhibitor and a TGFβ receptor inhibitor. The composition may comprise epithelioid cells; a TGFβ receptor inhibitor and a RAR agonist. The composition may comprise epithelioid cells; a GSK inhibitor and a RAR agonist. The composition may comprise epithelioid cells; and a GSK inhibitor. The composition may comprise epithelioid cells; and a TGFβ receptor inhibitor. The composition may comprise epithelioid cells; and a RAR agonist. The composition may comprise epithelioid cells; and an Akt inhibitor. The composition may comprise epithelioid cells; and a SETD2 inhibitor. The composition may comprise epithelioid cells; and a Dot1L inhibitor. The composition may comprise epithelioid cells; and an agonist of the G protein-coupled receptor Smoothened. The composition may comprise epithelioid cells; and a Jak1 / Jak2 inhibitor. The composition may comprise epithelioid cells; and a SAH hydrolase inhibitor. The composition may comprise epithelioid cells; and a Menin-MLL interaction inhibitor.

[0126] The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, or a RAR agonist, or any combination thereof. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, or a RAR agonist. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, and a RAR agonist. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, or a SETD2 inhibitor, or any combination thereof. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, or a SETD2 inhibitor. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, and a SETD2 inhibitor. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or an Akt inhibitor, or any combination thereof. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or an Akt inhibitor. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, and an Akt inhibitor. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or a SETD2 inhibitor, or any combination thereof. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, or a SETD2 inhibitor. The composition may comprise epithelial-like cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, and a SETD2 inhibitor. The epithelial-like cells may express LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. The epithelial-like cells may express LIN28A. The epithelial-like cells may further express NMYC, WNT2B, PAX8, SMAD3, or GLI3, or any combination thereof. The epithelial-like cells may express LIN28A and NMYC. The epithelial-like cells may express LIN28A and WNT2B. The epithelial-like cells may express LIN28A and PAX8. The epithelial-like cells may express LIN28A and SMAD3. The epithelial-like cells may express LIN28A and GLI3. The epithelial-like cells may not express any one of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2.

[0127] Figure 21 Exemplary compositions comprising chemical reprogramming factors and optionally stage 1 cells are shown. In Figure 21In it, "A" represents a combination of a GSK inhibitor, a TGFβ receptor inhibitor, and a RAR agonist; "B" represents an Akt inhibitor in the composition, and the composition may or may not contain an Akt inhibitor; "C" represents a SETD2 inhibitor, a Dot1L inhibitor, an agonist of the G protein-coupled receptor Smoothened, a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Menin-MLL interaction inhibitor, or any combination thereof, and the composition may or may not have any compound in group C; "D" represents somatic cells, epitheloid cells, or a combination of somatic cells and epitheloid cells, and the composition may or may not have any one of these cells. For example, ABC1C2 represents a composition that contains a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, an Akt inhibitor, an agonist of the G protein-coupled receptor Smoothened, and a Jak1 / Jak2 inhibitor.

[0128] The composition may contain CHIR99021 or CHIR98014. The composition may contain E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334. The composition may contain TTNPB, Ch55, or AM580. The composition may contain SETD2-IN-1, EPZ-719, or MMSET-IN-1. The composition may contain EPZ004777 or EPZ5676. The composition may contain SAG, purmorphamine, Hh-Ag1.5, or human SHH. The composition may contain ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib. The composition may contain DZNep, NepA, Adox, or DZA. The composition may contain VTP50469, MI3454, or WDR5-IN-4.

[0129] The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; an Akt inhibitor; SETD2-IN-1, EPZ-719 or MMSET-IN-1; EPZ004777 or EPZ5676; SAG, purmorphamine, Hh-Ag1.5 or human SHH; ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib; DZNep, NepA, Adox or DZA; VTP50469, MI3454 or WDR5-IN-4; or any combination thereof. The composition may comprise CHIR99021 or CHIR98014; E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; an Akt inhibitor; SETD2-IN-1, EPZ-719 or MMSET-IN-1; EPZ004777 or EPZ5676; SAG, purmorphamine, Hh-Ag1.5 or human SHH; ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib; DZNep, NepA, Adox or DZA; and VTP50469, MI3454 or WDR5-IN-4.

[0130] The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; or any combination thereof. The composition may comprise CHIR99021 or CHIR98014; E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; or TTNPB, Ch55 or AM580. The composition may comprise CHIR99021 or CHIR98014; E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; and TTNPB, Ch55 or AM580. The composition may comprise CHIR99021 or CHIR98014; E-616452, A83-01, SB431542, SB 505124, GW788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; an Akt inhibitor; SETD2-IN-1, EPZ-719 or MMSET-IN-1; or any combination thereof. The composition may comprise CHIR99021 or CHIR98014; E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; an Akt inhibitor; or SETD2-IN-1, EPZ-719 or MMSET-IN-1. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; an Akt inhibitor; and SETD2-IN-1, EPZ-719 or MMSET-IN-1. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; or an Akt inhibitor; or any combination thereof. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; or an Akt inhibitor.The composition may comprise CHIR99021 or CHIR98014; E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; and an Akt inhibitor. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; or a SETD2 inhibitor; or any combination thereof. The composition may comprise CHIR99021 or CHIR98014; E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; or a SETD2 inhibitor. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; and a SETD2 inhibitor.

[0131] The composition may comprise CHIR99021. The composition may comprise E-616452. The composition may comprise TTNPB. The composition may comprise AKTi. The composition may comprise SETD2-IN-1. The composition may comprise EPZ5676. The composition may comprise SAG. The composition may comprise ruxolitinib. The composition may comprise DZNep. The composition may comprise VTP50469.

[0132] The composition may comprise CHIR99021, E-616452, TTNPB, AKTi, SETD2-IN-1, EPZ5676, SAG, ruxolitinib, DZNep or VTP50469, or any combination thereof. The composition may comprise CHIR99021, E-616452, TTNPB, AKTi, SETD2-IN-1, EPZ5676, SAG, ruxolitinib, DZNep and VTP50469.

[0133] The composition may comprise CHIR99021, E-616452 or TTNPB, or any combination thereof. The composition may comprise CHIR99021, E-616452 or TTNPB. The composition may comprise CHIR99021, E-616452 and TTNPB. The composition may comprise CHIR99021, E-616452, TTNPB, AKTi or SETD2-IN-1, or any combination thereof. The composition may comprise CHIR99021, E-616452, TTNPB, AKTi or SETD2-IN-1. The composition may comprise CHIR99021, E-616452, TTNPB, AKTi and SETD2-IN-1. The composition may comprise CHIR99021, E-616452, TTNPB or AKTi, or any combination thereof. The composition may comprise CHIR99021, E-616452, TTNPB or AKTi. The composition may comprise CHIR99021, E-616452, TTNPB and AKTi. The composition may comprise CHIR99021, E-616452, TTNPB or SETD2-IN-1, or any combination thereof. The composition may comprise CHIR99021, E-616452, TTNPB or SETD2-IN-1. The composition may comprise CHIR99021, E-616452, TTNPB and SETD2-IN-1.

[0134] The composition may contain at least about 0.1 micromole (μM), 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 10.5 μM, 11 μM, 11.5 μM, 12 μM, 12.5 μM, 13 μM, 13.5 μM, 14 μM, 14.5 μM, 15 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, 43 μM, 44 μM, 45 μM, 46 μM, 47 μM, 48 μM, 49 μM, 50 μM, 100 μM, 150 μM, 200 μM, 250 μM or more of CHIR99021 in the composition. The composition may contain at most about 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 10.5 μM, 11 μM, 11.5 μM, 12 μM, 12.5 μM, 13 μM, 13.5 μM, 14 μM, 14.5 μM, 15 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, 43 μM, 44 μM, 45 μM, 46 μM, 47 μM, 48 μM, 49 μM, 50 μM, 100 μM, 150 μM, 200 μM or 250 μM of CHIR99021 in the composition. The composition may contain about 0.5 μM of CHIR99021 in the composition. The composition may contain about 1 μM of CHIR99021 in the composition. The composition contains about 2 μM of CHIR99021 in the composition. The composition may contain about 3 μM of CHIR99021 in the composition. The composition may contain about 4 μM of CHIR99021 in the composition. The composition may contain about 5 μM of CHIR99021 in the composition. The composition may contain about 6 μM of CHIR99021 in the composition. The composition may contain about 7 μM of CHIR99021 in the composition.The composition may contain about 8 μM CHIR99021 within the composition. The composition may contain about 9 μM CHIR99021 within the composition. The composition may contain about 10 μM CHIR99021 within the composition. The composition may contain about 15 μM CHIR99021 within the composition. The composition may contain about 20 μM CHIR99021 within the composition. The composition may contain about 30 μM CHIR99021 within the composition. The composition may contain about 40 μM CHIR99021 within the composition. The composition may contain about 50 μM CHIR99021 within the composition. The composition may contain from about 0.1 μM to about 100 μM CHIR99021 within the composition. The composition may contain from about 0.2 μM to about 75 μM CHIR99021 within the composition. The composition may contain from about 0.5 μM to about 50 μM CHIR99021 within the composition. The composition may contain from about 1 μM to about 25 μM CHIR99021 within the composition. The composition may contain from about 2 μM to about 12.5 μM CHIR99021 within the composition. The composition may contain from about 4 μM to about 6.25 μM CHIR99021 within the composition.

[0135] The composition may comprise at least about 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, 500 μM or more of E-616452 within the composition. The composition may comprise at most about 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, 500 μM of E-616452 within the composition. The composition may comprise about 1 μM of E-616452 within the composition. The composition may comprise about 2 μM of E-616452 within the composition. The composition may comprise about 3 μM of E-616452 within the composition. The composition may comprise about 4 μM of E-616452 within the composition. The composition may comprise about 5 μM of E-616452 within the composition. The composition may comprise about 6 μM of E-616452 within the composition. The composition may comprise about 7 μM of E-616452 within the composition. The composition may comprise about 8 μM of E-616452 within the composition. The composition may comprise about 9 μM of E-616452 within the composition. The composition may comprise about 10 μM of E-616452 within the composition. The composition may comprise about 15 μM of E-616452 within the composition. The composition may comprise about 20 μM of E-616452 within the composition. The composition may comprise about 30 μM of E-616452 within the composition. The composition may comprise about 40 μM of E-616452 within the composition. The composition may comprise about 50 μM of E-616452 within the composition. The composition may comprise about 60 μM of E-616452 within the composition. The composition may comprise about 70 μM of E-616452 within the composition. The composition may comprise about 80 μM of E-616452 within the composition. The composition may comprise about 90 μM of E-616452 within the composition. The composition may comprise about 100 μM of E-616452 within the composition. The composition may comprise from about 1 μM to about 100 μM of E-616452 within the composition.The composition may comprise from about 2 μM to about 75 μM of E-616452 within the composition. The composition may comprise from about 3 μM to about 50 μM of E-616452 within the composition. The composition may comprise from about 4 μM to about 40 μM of E-616452 within the composition. The composition may comprise from about 5 μM to about 30 μM of E-616452 within the composition. The composition may comprise from about 7.5 μM to about 20 μM of E-616452 within the composition.

[0136] The composition may comprise at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM or more of TTNPB within the composition. The composition may comprise at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM or 100 μM of TTNPB within the composition. The composition may comprise about 0.2 μM of TTNPB within the composition. The composition may comprise about 0.4 μM of TTNPB within the composition. The composition may comprise about 0.6 μM of TTNPB within the composition. The composition may comprise about 0.8 μM of TTNPB within the composition. The composition may comprise about 1 μM of TTNPB within the composition. The composition may comprise about 1.2 μM of TTNPB within the composition. The composition may comprise about 1.4 μM of TTNPB within the composition. The composition may comprise about 1.6 μM of TTNPB within the composition. The composition may comprise about 1.8 μM of TTNPB within the composition. The composition may comprise about 2 μM of TTNPB within the composition. The composition may comprise about 4 μM of TTNPB within the composition. The composition may comprise about 6 μM of TTNPB within the composition. The composition may comprise about 8 μM of TTNPB within the composition. The composition may comprise about 10 μM of TTNPB within the composition. The composition may comprise about 12 μM of TTNPB within the composition. The composition may comprise about 14 μM of TTNPB within the composition. The composition may comprise about 16 μM of TTNPB within the composition. The composition may comprise about 18 μM of TTNPB within the composition. The composition may comprise about 20 μM of TTNPB within the composition. The composition may comprise from about 0.2 μM to about 20 μM of TTNPB within the composition. The composition may comprise from about 0.4 μM to about 15 μM of TTNPB within the composition. The composition may comprise from about 0.6 μM to about 10 μM of TTNPB within the composition.The composition may comprise from about 0.8 μM to about 8 μM of TTNPB within the composition. The composition may comprise from about 1 μM to about 6 μM of TTNPB within the composition. The composition may comprise from about 1.5 μM to about 4 μM of TTNPB within the composition.

[0137] The composition may comprise at least about 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM, 50 μM or more of AKTi within the composition. The composition may comprise at most about 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM or 50 μM of AKTi within the composition. The composition may comprise about 0.1 μM of AKTi within the composition. The composition may comprise about 0.2 μM of AKTi within the composition. The composition may comprise about 0.3 μM of AKTi within the composition. The composition may comprise about 0.4 μM of AKTi within the composition. The composition may comprise about 0.5 μM of AKTi within the composition. The composition may comprise about 0.6 μM of AKTi within the composition. The composition may comprise about 0.7 μM of AKTi within the composition. The composition may comprise about 0.8 μM of AKTi within the composition. The composition may comprise about 0.9 μM of AKTi within the composition. The composition may comprise about 1 μM of AKTi within the composition. The composition may comprise about 2 μM of AKTi within the composition. The composition may comprise about 3 μM of AKTi within the composition. The composition may comprise about 4 μM of AKTi within the composition. The composition may comprise about 5 μM of AKTi within the composition. The composition may comprise about 6 μM of AKTi within the composition. The composition may comprise about 7 μM of AKTi within the composition. The composition may comprise about 8 μM of AKTi within the composition. The composition may comprise about 9 μM of AKTi within the composition. The composition may comprise about 10 μM of AKTi within the composition. The composition may comprise from about 0.1 μM to about 10 μM of AKTi within the composition. The composition may comprise from about 0.2 μM to about 7.5 μM of AKTi within the composition. The composition may comprise from about 0.3 μM to about 5 μM of AKTi within the composition.The composition may comprise from about 0.4 μM to about 4 μM of AKTi within the composition. The composition may comprise from about 0.5 μM to about 3 μM of AKTi within the composition. The composition may comprise from about 0.75 μM to about 2 μM of AKTi within the composition.

[0138] The composition may comprise at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of SETD2-IN-1 within the composition. The composition may comprise at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.05 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.1 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.15 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.2 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.25 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.3 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.35 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.4 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.45 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.5 μM of SETD2-IN-1 within the composition. The composition may comprise about 1 μM of SETD2-IN-1. The composition may comprise about 1.5 μM of SETD2-IN-1 within the composition. The composition may comprise about 2 μM of SETD2-IN-1 within the composition. The composition may comprise about 2.5 μM of SETD2-IN-1 within the composition. The composition may comprise about 3 μM of SETD2-IN-1 within the composition.The composition may comprise about 3.5 μM of SETD2-IN-1 in the composition. The composition may comprise about 4 μM of SETD2-IN-1 in the composition. The composition may comprise about 4.5 μM of SETD2-IN-1 in the composition. The composition may comprise about 5 μM of SETD2-IN-1 in the composition. The composition may comprise about 0.05 μM to about 2.5 μM of SETD2-IN-1 in the composition. The composition may comprise about 0.1 μM to about 1.875 μM of SETD2-IN-1 in the composition. The composition may comprise about 0.15 μM to about 1.25 μM of SETD2-IN-1 in the composition. The composition may comprise about 0.2 μM to about 1 μM of SETD2-IN-1 in the composition. The composition may comprise about 0.25 μM to about 0.75 μM of SETD2-IN-1 in the composition. The composition may comprise about 0.375 μM to about 0.5 μM of SETD2-IN-1 in the composition.

[0139] The composition may contain at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of SAG in the composition. The composition may contain at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of SAG in the composition. The composition may contain about 0.05 μM of SAG in the composition. The composition may contain about 0.1 μM of SAG in the composition. The composition may contain about 0.15 μM of SAG in the composition. The composition may contain about 0.2 μM of SAG in the composition. The composition may contain about 0.25 μM of SAG in the composition. The composition may contain about 0.3 μM of SAG in the composition. The composition may contain about 0.35 μM of SAG in the composition. The composition may contain about 0.4 μM of SAG in the composition. The composition may contain about 0.45 μM of SAG in the composition. The composition may contain about 0.5 μM of SAG in the composition. The composition may contain about 1 μM of SAG in the composition. The composition may contain about 1.5 μM of SAG in the composition. The composition may contain about 2 μM of SAG in the composition. The composition may contain about 2.5 μM of SAG in the composition. The composition may contain about 3 μM of SAG in the composition. The composition may contain about 3.5 μM of SAG in the composition. The composition may contain about 4 μM of SAG in the composition. The composition may contain about 4.5 μM of SAG in the composition. The composition may contain about 5 μM of SAG in the composition. The composition may contain about 0.05 μM to about 2.5 μM of SAG in the composition.The composition may comprise from about 0.1 μM to about 1.875 μM SAG within the composition. The composition may comprise from about 0.15 μM to about 1.25 μM SAG within the composition. The composition may comprise from about 0.2 μM to about 1 μM SAG within the composition. The composition may comprise from about 0.25 μM to about 0.75 μM SAG within the composition. The composition may comprise from about 0.375 μM to about 0.5 μM SAG within the composition.

[0140] The composition may comprise at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of VTP50469 within the composition. The composition may comprise at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of VTP50469 within the composition. The composition may comprise about 0.05 μM of VTP50469 within the composition. The composition may comprise about 0.1 μM of VTP50469 within the composition. The composition may comprise about 0.15 μM of VTP50469 within the composition. The composition may comprise about 0.2 μM of VTP50469 within the composition. The composition may comprise about 0.25 μM of VTP50469 within the composition. The composition may comprise about 0.3 μM of VTP50469 within the composition. The composition may comprise about 0.35 μM of VTP50469 within the composition. The composition may comprise about 0.4 μM of VTP50469 within the composition. The composition may comprise about 0.45 μM of VTP50469 within the composition. The composition may comprise about 0.5 μM of VTP50469 within the composition. The composition may comprise about 1 μM of VTP50469 within the composition. The composition may comprise about 1.5 μM of VTP50469 within the composition. The composition may comprise about 2 μM of VTP50469 within the composition. The composition may comprise about 2.5 μM of VTP50469 within the composition. The composition may comprise about 3 μM of VTP50469 within the composition. The composition may comprise about 3.5 μM of VTP50469 within the composition. The composition may comprise about 4 μM of VTP50469 within the composition.The composition may comprise about 4.5 μM of VTP50469 within the composition. The composition may comprise about 5 μM of VTP50469 within the composition. The composition may comprise from about 0.05 μM to about 2.5 μM of VTP50469 within the composition. The composition may comprise from about 0.1 μM to about 1.875 μM of VTP50469 within the composition. The composition may comprise from about 0.15 μM to about 1.25 μM of VTP50469 within the composition. The composition may comprise from about 0.2 μM to about 1 μM of VTP50469 within the composition. The composition may comprise from about 0.25 μM to about 0.75 μM of VTP50469 within the composition. The composition may comprise from about 0.375 μM to about 0.5 μM of VTP50469 within the composition.

[0141] The composition may comprise at least about 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM, 50 μM or more of ruxolitinib within the composition. The composition may comprise at most about 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM or 50 μM of ruxolitinib within the composition. The composition may comprise about 0.1 μM of ruxolitinib within the composition. The composition may comprise about 0.2 μM of ruxolitinib within the composition. The composition may comprise about 0.3 μM of ruxolitinib within the composition. The composition may comprise about 0.4 μM of ruxolitinib within the composition. The composition may comprise about 0.5 μM of ruxolitinib within the composition. The composition may comprise about 0.6 μM of ruxolitinib within the composition. The composition may comprise about 0.7 μM of ruxolitinib within the composition. The composition may comprise about 0.8 μM of ruxolitinib within the composition. The composition may comprise about 0.9 μM of ruxolitinib within the composition. The composition may comprise about 1 μM of ruxolitinib within the composition. The composition may comprise about 2 μM of ruxolitinib within the composition. The composition may comprise about 3 μM of ruxolitinib within the composition. The composition may comprise about 4 μM of ruxolitinib within the composition. The composition may comprise about 5 μM of ruxolitinib within the composition. The composition may comprise about 6 μM of ruxolitinib within the composition. The composition may comprise about 7 μM of ruxolitinib within the composition. The composition may comprise about 8 μM of ruxolitinib within the composition. The composition may comprise about 9 μM of ruxolitinib within the composition. The composition may comprise about 10 μM of ruxolitinib within the composition. The composition may comprise from about 0.1 μM to about 10 μM of ruxolitinib within the composition. The composition may comprise from about 0.2 μM to about 7.5 μM of ruxolitinib within the composition. The composition may comprise from about 0.3 μM to about 5 μM of ruxolitinib within the composition. The composition may comprise from about 0.4 μM to about 4 μM of ruxolitinib within the composition.The composition may comprise from about 0.5 μM to about 3 μM of ruxolitinib within the composition. The composition may comprise from about 0.75 μM to about 2 μM of ruxolitinib within the composition.

[0142] The composition may contain at least about 0.0004 μM, 0.0008 μM, 0.0012 μM, 0.0016 μM, 0.002 μM, 0.004 μM, 0.006 μM, 0.008 μM, 0.01 μM, 0.012 μM, 0.014 μM, 0.016 μM, 0.018 μM, 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.12 μM, 0.14 μM, 0.16 μM, 0.18 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.55 μM, 0.6 μM, 0.65 μM, 0.7 μM, 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM, 1 μM or more of DZNep within the composition. The composition may contain at most about 0.0004 μM, 0.0008 μM, 0.0012 μM, 0.0016 μM, 0.002 μM, 0.004 μM, 0.006 μM, 0.008 μM, 0.01 μM, 0.012 μM, 0.014 μM, 0.016 μM, 0.018 μM, 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.12 μM, 0.14 μM, 0.16 μM, 0.18 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.55 μM, 0.6 μM, 0.65 μM, 0.7 μM, 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM or 1 μM of DZNep within the composition. The composition may contain about 0.002 μM of DZNep within the composition. The composition may contain about 0.004 μM of DZNep within the composition. The composition may contain about 0.006 μM of DZNep within the composition. The composition may contain about 0.008 μM of DZNep within the composition. The composition may contain about 0.01 μM of DZNep within the composition. The composition may contain about 0.012 μM of DZNep within the composition. The composition may contain about 0.014 μM of DZNep within the composition. The composition may contain about 0.016 μM of DZNep within the composition. The composition may contain about 0.018 μM of DZNep within the composition. The composition may contain about 0.02 μM of DZNep within the composition. The composition may contain about 0.04 μM of DZNep within the composition. The composition may contain about 0.06 μM of DZNep within the composition. The composition may contain about 0.08 μM of DZNep within the composition. The composition may contain about 0.1 μM of DZNep within the composition. The composition may contain about 0.12 μM of DZNep within the composition. The composition may contain about 0.14 μM of DZNep within the composition.The composition may comprise about 0.16 μM DZNep within the composition. The composition may comprise about 0.18 μM DZNep within the composition. The composition may comprise about 0.2 μM DZNep within the composition. The composition may comprise from about 0.002 μM to about 0.2 μM DZNep within the composition. The composition may comprise from about 0.0025 μM to about 0.15 μM DZNep within the composition. The composition may comprise from about 0.005 μM to about 0.1 μM DZNep within the composition. The composition may comprise from about 0.0075 μM to about 0.75 μM DZNep within the composition. The composition may comprise from about 0.01 μM to about 0.5 μM DZNep within the composition. The composition may comprise from about 0.015 μM to about 0.4 μM DZNep within the composition.

[0143] The composition may comprise at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM or more of EPZ5676 within the composition. The composition may comprise at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM or 100 μM of EPZ5676 within the composition. The composition may comprise about 0.2 μM of EPZ5676 within the composition. The composition may comprise about 0.4 μM of EPZ5676 within the composition. The composition may comprise about 0.6 μM of EPZ5676 within the composition. The composition may comprise about 0.8 μM of EPZ5676 within the composition. The composition may comprise about 1 μM of EPZ5676 within the composition. The composition may comprise about 1.2 μM of EPZ5676 within the composition. The composition may comprise about 1.4 μM of EPZ5676 within the composition. The composition may comprise about 1.6 μM of EPZ5676 within the composition. The composition may comprise about 1.8 μM of EPZ5676 within the composition. The composition may comprise about 2 μM of EPZ5676 within the composition. The composition may comprise about 4 μM of EPZ5676 within the composition. The composition may comprise about 6 μM of EPZ5676 within the composition. The composition may comprise about 8 μM of EPZ5676 within the composition. The composition may comprise about 10 μM of EPZ5676 within the composition. The composition may comprise about 12 μM of EPZ5676 within the composition. The composition may comprise about 14 μM of EPZ5676 within the composition. The composition may comprise about 16 μM of EPZ5676 within the composition. The composition may comprise about 18 μM of EPZ5676 within the composition. The composition may comprise about 20 μM of EPZ5676 within the composition. The composition may comprise from about 0.2 μM to about 20 μM of EPZ5676 within the composition.The composition may comprise from about 0.4 μM to about 15 μM of EPZ5676 within the composition. The composition may comprise from about 0.6 μM to about 10 μM of EPZ5676 within the composition. The composition may comprise from about 0.8 μM to about 8 μM of EPZ5676 within the composition. The composition may comprise from about 1 μM to about 6 μM of EPZ5676 within the composition. The composition may comprise from about 1.5 μM to about 4 μM of EPZ5676 within the composition.

[0144] After contacting any cell population of the stage 1 cells with any of the compositions described herein, the cells may be incubated under hypoxic conditions. For example, the stage 1 cells may be incubated with up to 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less atmospheric oxygen. The hypoxic conditions may include about 10% atmospheric oxygen. The hypoxic conditions may include about 9% atmospheric oxygen. The hypoxic conditions may include about 8% atmospheric oxygen. The hypoxic conditions may include about 7% atmospheric oxygen. The hypoxic conditions may include about 6% atmospheric oxygen. The hypoxic conditions may include about 5% atmospheric oxygen. The hypoxic conditions may include about 4% atmospheric oxygen. The hypoxic conditions may include about 3% atmospheric oxygen. The hypoxic conditions may include about 2% atmospheric oxygen. The hypoxic conditions may include about 1% atmospheric oxygen.

[0145] After contacting any cell population of the first stage with any of the compositions described herein, the cell population of the first stage cells can be incubated with the composition for at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 25 days, or 30 days. The cell population of the first stage cells can be incubated with the composition for at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 25 days, or 30 days. The cell population of the first stage cells can be incubated with the composition for about 1 day. The cell population of the first stage cells can be incubated with the composition for about 2 days. The cell population of the first stage cells can be incubated with the composition for about 3 days. The cell population of the first stage cells can be incubated with the composition for about 4 days. The cell population of the first stage cells can be incubated with the composition for about 5 days. The cell population of the first stage cells can be incubated with the composition for about 6 days. The cell population of the first stage cells can be incubated with the composition for about 7 days. The cell population of the first stage cells can be incubated with the composition for about 8 days. The cell population of the first stage cells can be incubated with the composition for about 9 days. The cell population of the first stage cells can be incubated with the composition for about 10 days. The cell population of the first stage cells can be incubated with the composition for about 11 days. The cell population of the first stage cells can be incubated with the composition for about 12 days. The cell population of the first stage cells can be incubated with the composition for about 13 days. The cell population of the first stage cells can be incubated with the composition for about 14 days. The cell population of the first stage cells can be incubated with the composition for about 15 days. The cell population of the first stage cells can be incubated with the composition for about 16 days. The cell population of the first stage cells can be incubated with the composition for about 17 days. The cell population of the first stage cells can be incubated with the composition for about 18 days. The cell population of the first stage cells can be incubated with the composition for about 19 days. The cell population of the first stage cells can be incubated with the composition for about 20 days. The cell population of the first stage cells can be incubated with the composition for about 25 days.

[0146] Any composition may not contain feeder cells or serum. Any composition may not contain feeder cells and serum. Any composition may not contain feeder cells. Any composition may be serum-free. Any composition may contain feeder cells. Any composition may contain serum.

[0147] The second stage

[0148] In some aspects, provided herein are Phase 2 methods and compositions for converting epithelial-like cells into cells with higher cellular potential (e.g., less specialized cells), such as cells in an intermediate plastic state - this conversion process is also referred to herein as "Phase 2". The Phase 2 method can be part of a conversion process for reprogramming somatic cells or epithelial-like cells into pluripotent stem cells. The Phase 2 method can be the second phase of a conversion process for reprogramming somatic cells into pluripotent stem cells.

[0149] The Phase 2 method can include contacting a first cell population with a first composition. The Phase 2 method can include converting a subset of the first cell population into different cells after or during the contacting. The cell population containing the different cells can include a second cell population. The Phase 2 method can include incubating the first cell population with the first composition for a period of time. The subset of the first cell population can be converted into different cells before, during, or after the incubation. In some cases, the Phase 2 method can include removing the first composition from the second cell population. In other cases, the Phase 2 method can include removing the first composition from the first cell population.

[0150] The cell population of Phase 2 cells can include at least one subset of Phase 1 cells. The cell population of Phase 2 cells can include at most one subset of Phase 1 cells. The cell population of Phase 2 cells can include epithelial-like cells or somatic cells. The cell population of Phase 2 cells can include epithelial-like cells. The cell population of Phase 2 cells can include somatic cells. The cell population of Phase 2 cells can include epithelial-like cells and somatic cells.

[0151] The first cell population of Phase 2 cells can include any cell population of Phase 1 cells. In some cases, the first cell population of Phase 2 cells can include a second cell population of Phase 1 cells.

[0152] The second cell population of the stage 2 cells may include intermediate plastic state cells. The first cell population of the stage 2 cells may not include intermediate plastic state cells. Intermediate plastic state cells may not be naturally occurring cells. Intermediate plastic state cells may express a gene combination not expressed by naturally occurring cells. Intermediate plastic state cells may express at least one gene at a level that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 5-fold, 100-fold or higher relative to that of naturally occurring cells. Intermediate plastic state cells may express at least one gene at a level that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or 100% lower relative to that of naturally occurring cells. The second cell population of the stage 2 cells may include somatic cells, epitheloid cells or intermediate plastic state cells. The second cell population of the stage 2 cells may include somatic cells, epitheloid cells and intermediate plastic state cells. The second cell population of the stage 2 cells may not include somatic cells or epitheloid cells. In some cases, the second cell population of the stage 2 cells may include fewer somatic cells or epitheloid cells than the first cell population of the stage 2 cells. For example, the second cell population of the stage 2 cells may have 0.001%, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or 99% fewer somatic cells or epitheloid cells than the first cell population of the stage 2 cells. In some cases, the second cell population of the stage 2 cells may include more intermediate plastic state cells than the first cell population of the stage 2 cells. For example, the second cell population of the stage 2 cells may have 0.001%, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 100-fold or more intermediate plastic state cells than the first cell population of the stage 2 cells.

[0153] Intermediate plastic state cells may exhibit reduced expression of genes expressed by somatic cells. Intermediate plastic state cells may exhibit increased expression of genes related to embryonic development, increased cell proliferation, and a reduced epigenetic state of methylation. The promoter regions of genes related to embryonic development, the cell cycle, and stem cell proliferation may be demethylated in intermediate plastic state cells. Relative to somatic cells or epithelial-like cells, intermediate plastic state cells may undergo dedifferentiation. Genes upregulated in intermediate plastic state cells may include Figure 16 the genes described in. In some cases, genes related to limb and appendage development may be upregulated and have an open chromatin structure in intermediate plastic state cells. Intermediate plastic state cells can be reprogrammed to acquire the characteristics of developing human limb bud cells, similar to the case of salamander limb regeneration, in which genes controlling embryonic limb development are reactivated during dedifferentiation. However, according to Guan 2002, dedifferentiation was not found in frogs and mice, and their limb tissues did not show a significant activation of the embryonic gene expression program after injury.

[0154] Intermediate plastic state cells can express LIN28A, SALL4, MSX2, NMYC, WNT4, FGF19, TOP2A, MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2, or any combination thereof. Intermediate plastic state cells can express LIN28A. Intermediate plastic state cells can express SALL4. Intermediate plastic state cells can express MSX2. Intermediate plastic state cells can express NMYC. Intermediate plastic state cells can express WNT4. Intermediate plastic state cells can express FGF19. Intermediate plastic state cells can express TOP2A. Intermediate plastic state cells can express MSX1. Intermediate plastic state cells can express HOXB9. Intermediate plastic state cells can express WT1. Intermediate plastic state cells can express GATA2. Intermediate plastic state cells can express HMGA2. Intermediate plastic state cells can express LEF1. Intermediate plastic state cells can express FGF9. Intermediate plastic state cells can express HOXA9. Intermediate plastic state cells can express HOZXA1. Intermediate plastic state cells can express PTCH1. Intermediate plastic state cells can express HOXA5. Intermediate plastic state cells can express CCND2. Intermediate plastic state cells can express SDC1. Intermediate plastic state cells can express TBX3. Intermediate plastic state cells can express BMP4. Intermediate plastic state cells can express IGF2. Intermediate plastic state cells can express one or more of LIN28A, SALL4, MSX2, NMYC, WNT4, FGF19, TOP2A, MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2.

[0155] Intermediate plastic state cells can express LIN28A or SALL4. Intermediate plastic state cells can express LIN28A and SALL4. Intermediate plastic state cells can express LIN28A and SALL4; and MSX2, NMYC, WNT4, FGF19, TOP2A, MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2, or any combination thereof. Intermediate plastic state cells can express LIN28A and SALL4; and MSX2. Intermediate plastic state cells can express LIN28A and SALL4; and NMYC. Intermediate plastic state cells can express LIN28A and SALL4; and WNT4. Intermediate plastic state cells can express LIN28A and SALL4; and FGF19. Intermediate plastic state cells can express LIN28A and SALL4; and TOP2A. Intermediate plastic state cells can express LIN28A and SALL4; and MSX1. Intermediate plastic state cells can express LIN28A and SALL4; and HOXB9. Intermediate plastic state cells can express LIN28A and SALL4; and WT1. Intermediate plastic state cells can express LIN28A and SALL4; and GATA2. Intermediate plastic state cells can express LIN28A and SALL4; and HMGA2. Intermediate plastic state cells can express LIN28A and SALL4; and LEF1. Intermediate plastic state cells can express LIN28A and SALL4; and FGF9. Intermediate plastic state cells can express LIN28A and SALL4; and HOXA9. Intermediate plastic state cells can express LIN28A and SALL4; and HOZXA1. Intermediate plastic state cells can express LIN28A and SALL4; and PTCH1. Intermediate plastic state cells can express LIN28A and SALL4; and HOXA5. Intermediate plastic state cells can express LIN28A and SALL4; and CCND2. Intermediate plastic state cells can express LIN28A and SALL4; and SDC1. Intermediate plastic state cells can express LIN28A and SALL4; and TBX3. Intermediate plastic state cells can express LIN28A and SALL4; and BMP4. Intermediate plastic state cells can express LIN28A and SALL4; and IGF2.Intermediate plastic state cells can express LIN28A and SALL4; and one or more of MSX2, NMYC, WNT4, FGF19, TOP2A, MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2.

[0156] Intermediate plastic state cells can express LIN28A and SALL4; a second gene; and a third gene. Epithelial-like cells can express LIN28A and SALL4; one or more second genes; and one or more third genes. The second genes expressed by intermediate plastic state cells can include MSX2, NMYC, WNT4, FGF19 or TOP2A, or any combination thereof. Somatic cells or epithelial-like cells may not express SALL4. Somatic cells or epithelial-like cells may not express SALL4 and LIN28A. Somatic cells or epithelial-like cells may not express SALL4; the second gene; or the third gene. Somatic cells or epithelial-like cells may not express the second gene. Somatic cells or epithelial-like cells may not express the third gene. Somatic cells or epithelial-like cells may not express LIN28A or SALL4; may not express one or more second genes; and may not express one or more third genes. The second gene can include MSX2, NMYC, WNT4, FGF19 or TOP2A, or any combination thereof. The second gene can include MSX2. Its second gene can include NMYC. The second gene can include WNT4. Its second gene can include FGF19. The second gene can include TOP2A. The third gene can include MSX1, HOXB9, WT1, GATA2, HMGA2 or LEF1, or any combination thereof. The third gene can include MSX1. The third gene can include HOXB9. Its third gene can include WT1. The third gene can include GATA2. The third gene can include HMGA2. The third gene can include LEF1. Intermediate plastic state cells can express LIN28A and SALL4; the second gene; the third gene; and a fourth gene. Somatic cells or epithelial-like cells may not express the fourth gene. The fourth gene can include FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2, or any combination thereof. The fourth gene can include FGF9. The fourth gene can include HOXA9. The fourth gene can include HOZXA1. The fourth gene can include PTCH1. The fourth gene can include HOXA5. The fourth gene can include CCND2. The fourth gene can include SDC1. The fourth gene can include TBX3. The fourth gene can include BMP4. The fourth gene can include IGF2.

[0157] Figure 22shows the gene expression profiles of exemplary intermediate plastic state cells in the second stage. In Figure 22 , "A" represents the expression of LIN28A and SALL4; "B" represents the expression of a second gene, which includes the expression of MSX2, NMYC, WNT4, FGF19, or TOP2A, or any combination thereof; "C" represents the expression of a third gene, which includes the expression of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1, or any combination thereof; "D" represents the expression of a fourth gene, which includes the expression of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2, or any combination thereof. For example, AB1C1D1 represents an intermediate plastic state cell expressing LIN28A, SALL4, MSX2, and MSX1; AB1C1 represents an intermediate plastic state cell expressing LIN28A, SALL4, MSX2, MSX1, and FGF9. These cells can express more than one of B, C, or D. For example, AB1B2C1C2D1D2 represents an intermediate plastic state cell expressing LIN28A, SALL4, MSX2, NMYC, MSX1, HOXB9, FGF9, and HOXA9.

[0158] Cells of the second cell population of stage 2 cells may express higher levels of LIN28A, SALL4, MSX2, NMYC, WNT4, FGF19, TOP2A, MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2, or any combination thereof, compared to cells of the first cell population of stage 2 cells or any cell population of stage 1 cells. The higher expression level of any one of LIN28A, SALL4, MSX2, NMYC, WNT4, FGF19, TOP2A, MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2 in cells of the second cell population of stage 2 cells can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 5-fold, 100-fold, or more compared to cells of the first cell population of stage 2 cells or any cell population of stage 1 cells. Cells of the first cell population of stage 2 cells or any cell population of stage 1 cells may express lower levels of any one of LIN28A, SALL4, MSX2, NMYC, WNT4, FGF19, TOP2A, MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2 compared to cells of the second cell population of stage 2 cells. The lower expression level of any one of LIN28A, SALL4, MSX2, NMYC, WNT4, FGF19, TOP2A, MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2 in cells of the first cell population of stage 2 cells or any cell population of stage 1 cells can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% compared to cells of the second cell population of stage 2 cells. The expression level can be measured by any method described herein. For example, gene expression can be measured by the method described in Example 2.Gene expression can be measured by using any one of SEQ ID NO: 1-83 (including controls).

[0159] In some aspects, the present disclosure provides a composition comprising reprogramming factors for stage 2 transformation, or comprising stage 2 cells (first cell population or second cell population), or comprising stage 2 cells (first cell population or second cell population) and reprogramming factors for stage 2 transformation. In some cases, the composition comprises a culture medium containing reprogramming factors for stage 2 transformation.

[0160] In some cases, the composition comprises an isolated cell population of the second cell population of stage 2 cells. In some cases, the composition comprises an isolated cell population of the first cell population of stage 2 cells. The isolated cell population of stage 2 cells can comprise at least about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more cells. The isolated cell population of stage 2 cells can comprise at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 cells. The isolated cell population of stage 2 cells can comprise at least one intermediate plastic state cell. In some cases, the isolated cell population of stage 2 cells can comprise at least about 1, 1x10^1, 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more intermediate plastic state cells. The isolated cell population can comprise at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 intermediate plastic state cells. In some cases, the isolated cell population of stage 3 cells can comprise at least about 1x10^1, 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more intermediate plastic state cells, epithelial-like cells or somatic cells, or any combination thereof. The isolated cell population of stage 3 cells can comprise at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 intermediate plastic state cells, epithelial-like cells or somatic cells, or any combination thereof.

[0161] The composition may comprise chemical reprogramming factors. The composition may comprise a plurality of chemical reprogramming factors. The composition may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more chemical reprogramming factors. The composition may comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 chemical reprogramming factors. The composition may comprise 1 chemical reprogramming factor. The composition may comprise 2 chemical reprogramming factors. The composition may comprise 3 chemical reprogramming factors. The composition may comprise 4 chemical reprogramming factors. The composition may comprise 5 chemical reprogramming factors. The composition may comprise 6 chemical reprogramming factors. The composition may comprise 7 chemical reprogramming factors. The composition may comprise 8 chemical reprogramming factors. The composition may comprise 9 chemical reprogramming factors. The composition may comprise 10 chemical reprogramming factors. The composition may comprise 11 chemical reprogramming factors. The composition may comprise 12 chemical reprogramming factors. The composition may comprise 13 chemical reprogramming factors. The composition may comprise 14 chemical reprogramming factors. The composition may comprise 15 chemical reprogramming factors. The composition may comprise 16 chemical reprogramming factors. The composition may comprise 17 chemical reprogramming factors. The composition may comprise 18 chemical reprogramming factors. The composition may comprise 19 chemical reprogramming factors. The composition may comprise 20 chemical reprogramming factors. The composition may comprise 21 chemical reprogramming factors. The composition may comprise 22 chemical reprogramming factors. The composition may comprise 23 chemical reprogramming factors. The composition may comprise 24 chemical reprogramming factors. The composition may comprise 25 chemical reprogramming factors. The chemical reprogramming factors in the composition may comprise any of the chemical reprogramming factors described herein.

[0162] The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, a BMP receptor / AMPK inhibitor, or a casein kinase 2 inhibitor, or any combination thereof. The composition may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor. The composition may comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38MAPK inhibitor, an Akt inhibitor, and a casein kinase 2 inhibitor.

[0163] The composition may comprise a GSK inhibitor. The composition may comprise a TGFβ receptor inhibitor. The composition may comprise a RAR agonist. The composition may comprise a c-Jun kinase inhibitor. The composition may comprise a CBP / p300 bromodomain inhibitor. The composition may comprise a SAH hydrolase inhibitor. The composition may comprise an adenosine kinase inhibitor. The composition may comprise a Dot1L inhibitor. The composition may comprise a Menin-MLL interaction inhibitor. The composition may comprise a SETD2 inhibitor. The composition may comprise an agonist of the G protein-coupled receptor Smoothened. The composition may comprise a ROCK inhibitor. The composition may comprise a BMP receptor / AMPK inhibitor. The composition may comprise a Jak1 / Jak2 inhibitor. The composition may comprise a p38 MAPK inhibitor. The composition may comprise an Akt inhibitor. The composition may comprise a casein kinase 2 inhibitor.

[0164] The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, or a c-Jun kinase inhibitor, or any combination thereof. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, or an adenosine kinase inhibitor, or any combination thereof. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, and a SAH hydrolase inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, and an adenosine kinase inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and a SAH hydrolase inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and an adenosine kinase inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, and an adenosine kinase inhibitor. The composition may further comprise a RAR agonist, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor.

[0165] The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor, or any combination thereof. The composition may comprise epithelial-like cells expressing LIN28A; and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, and a casein kinase 2 inhibitor.

[0166] The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a TGFβ receptor inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a RAR agonist. The composition may comprise epithelial-like cells expressing LIN28A; and a c-Jun kinase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a CBP / p300 bromodomain inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a SAH hydrolase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and an adenosine kinase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a Dot1L inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a Menin-MLL interaction inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a SETD2 inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and an agonist of the G protein-coupled receptor Smoothened. The composition may comprise epithelial-like cells expressing LIN28A; and a ROCK inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a BMP receptor / AMPK inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a Jak1 / Jak2 inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a p38MAPK inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and an Akt inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a casein kinase 2 inhibitor.

[0167] The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, or a c-Jun kinase inhibitor, or any combination thereof. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, or an adenosine kinase inhibitor, or any combination thereof. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, and a SAH hydrolase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, and an adenosine kinase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and a SAH hydrolase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and an adenosine kinase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise epithelial-like cells expressing LIN28A; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, and an adenosine kinase inhibitor. The composition may further comprise a RAR agonist, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor. The epithelial-like cells may express LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. The epithelial-like cells may express LIN28A. The epithelial-like cells may further express NMYC, WNT2B, PAX8, SMAD3, or GLI3, or any combination thereof.Epithelial cells can express LIN28A and NMYC. Epithelial cells can express LIN28A and WNT2B. Epithelial cells can express LIN28A and PAX8. Epithelial cells can express LIN28A and SMAD3. Epithelial cells can express LIN28A and GLI3. Epithelial cells may not express any one of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1 or TWIST2.

[0168] The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor, or any combination thereof. The composition may comprise cells in an intermediate plastic state; and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor. The composition may comprise cells in an intermediate plastic state; and at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, and a casein kinase 2 inhibitor.

[0169] The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor. The composition may comprise cells in an intermediate plastic state; and a TGFβ receptor inhibitor. The composition may comprise cells in an intermediate plastic state; and a RAR agonist. The composition may comprise cells in an intermediate plastic state; and a c-Jun kinase inhibitor. The composition may comprise cells in an intermediate plastic state; and a CBP / p300 bromodomain inhibitor. The composition may comprise cells in an intermediate plastic state; and a SAH hydrolase inhibitor. The composition may comprise cells in an intermediate plastic state; and an adenosine kinase inhibitor. The composition may comprise cells in an intermediate plastic state; and a Dot1L inhibitor. The composition may comprise cells in an intermediate plastic state; and a Menin-MLL interaction inhibitor. The composition may comprise cells in an intermediate plastic state; and a SETD2 inhibitor. The composition may comprise cells in an intermediate plastic state; and an agonist of the G protein-coupled receptor Smoothened. The composition may comprise cells in an intermediate plastic state; and a ROCK inhibitor. The composition may comprise cells in an intermediate plastic state; and a BMP receptor / AMPK inhibitor. The composition may comprise cells in an intermediate plastic state; and a Jak1 / Jak2 inhibitor. The composition may comprise cells in an intermediate plastic state; and a p38MAPK inhibitor. The composition may comprise cells in an intermediate plastic state; and an Akt inhibitor. The composition may comprise cells in an intermediate plastic state; and a casein kinase 2 inhibitor.

[0170] The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, or a c-Jun kinase inhibitor, or any combination thereof. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, or an adenosine kinase inhibitor, or any combination thereof. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, and a SAH hydrolase inhibitor. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, and an adenosine kinase inhibitor. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and a SAH hydrolase inhibitor. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and an adenosine kinase inhibitor. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise cells in an intermediate plastic state; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, and an adenosine kinase inhibitor. The composition may further comprise a RAR agonist, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor.

[0171] Intermediate plastic state cells of the composition can express LIN28A, SALL4, MSX2, NMYC, WNT4, FGF19, or TOP2A, or any combination thereof. Intermediate plastic state cells of the composition can express LIN28A and SALL4. Intermediate plastic state cells of the composition can also express MSX2, NMYC, WNT4, FGF19, TOP2A, or a combination thereof. Intermediate plastic state cells of the composition can express LIN28A, SALL4, and MSX2. Intermediate plastic state cells of the composition can express LIN28A, SALL4, and NMYC. Intermediate plastic state cells of the composition can express LIN28A, SALL4, and WNT4. Intermediate plastic state cells of the composition can express LIN28A, SALL4, and FGF19. Intermediate plastic state cells of the composition can express LIN28A, SALL4, and TOP2A. Intermediate plastic state cells of the composition can also express any one or any combination of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1. In addition, intermediate plastic state cells of the composition can also express any one or any combination of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2.

[0172] Figure 23 Exemplary compositions containing chemical reprogramming factors and optionally stage 2 cells are shown. In Figure 23 wherein, "A" represents a combination of a GSK inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor; "B" represents a combination of a CBP / p300 bromodomain inhibitor or without a CBP / p300 bromodomain inhibitor; "C" represents a SAH hydrolase inhibitor or an adenosine kinase inhibitor or a combination thereof, and the composition may or may not contain a compound in group C; "D" represents a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, a casein kinase 2 inhibitor, or any combination thereof, and the composition may or may not contain a compound in group D; "E" represents epithelial-like cells, intermediate plastic state cells, or somatic cells, or any combination thereof, and the composition may or may not contain any one of these cells. For example, ABC1D1D2E2 represents a composition containing a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, a SAH hydrolase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, and intermediate plastic state cells.

[0173] The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; SGC-CBP30, I-CBP112, GNE272 or GNE409; DZNep, NepA, Adox or DZA; 5-ITU or ABT702; EPZ004777 or EPZ5676; VTP50469, MI3454 or WDR5-IN-4; SETD2-IN-1, EPZ-719 or MMSET-IN-1; SAG, purinomorphamine, Hh-Ag1.5 or human SHH; Y-27632 or thiazovivin; dihydrodeoxymorphine; ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib; BIRB796, SB203580 or SB202190; AKTi; CX-4945, TPP 22 or ellagic acid, or any combination thereof. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; SGC-CBP30, I-CBP112, GNE272 or GNE409; DZNep, NepA, Adox or DZA; 5-ITU or ABT 702; EPZ004777 or EPZ5676; VTP50469, MI3454 or WDR5-IN-4; SETD2-IN-1, EPZ-719 or MMSET-IN-1; SAG, purinomorphamine, Hh-Ag1.5 or human SHH; Y-27632 or thiazovivin; dihydrodeoxymorphine; ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib; BIRB796, SB203580 or SB202190; AKTi; or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 of CX-4945, TPP 22 or ellagic acid.The composition may comprise up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 of CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; SGC-CBP30, I-CBP112, GNE272 or GNE409; DZNep, NepA, Adox or DZA; 5-ITU or ABT 702; EPZ004777 or EPZ5676; VTP50469, MI3454 or WDR5-IN-4; SETD2-IN-1, EPZ-719 or MMSET-IN-1; SAG, puromycin aminonucleoside, Hh-Ag1.5 or human SHH; Y-27632 or thiazovivin; dihydrodeoxymorphine; ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib; BIRB796, SB203580 or SB202190; AKTi; or CX-4945, TPP 22 or ellagic acid. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; SGC-CBP30, I-CBP112, GNE272 or GNE409; DZNep, NepA, Adox or DZA; 5-ITU or ABT 702; EPZ004777 or EPZ5676; VTP50469, MI3454 or WDR5-IN-4; SETD2-IN-1, EPZ-719 or MMSET-IN-1; SAG, puromycin aminonucleoside, Hh-Ag1.5 or human SHH; Y-27632 or thiazovivin; dihydrodeoxymorphine; ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib; BIRB796, SB203580 or SB202190; AKTi; and CX-4945, TPP 22 or ellagic acid.

[0174] The composition may comprise CHIR99021 or CHIR98014. The composition may comprise E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334. The composition may comprise TTNPB, Ch55 or AM580. The composition may comprise JNKIN8, JNKIN7, JNKIN5 or JNKIN12. The composition may comprise SGC-CBP30, I-CBP112, GNE272 or GNE409. The composition may comprise DZNep, NepA, Adox or DZA. The composition may comprise 5-ITU or ABT702. The composition may comprise EPZ004777 or EPZ5676. The composition may comprise VTP50469, MI3454 or WDR5-IN-4. The composition may comprise SETD2-IN-1, EPZ-719 or MMSET-IN-1. The composition may comprise SAG, purinomorphamine, Hh-Ag1.5 or human SHH. The composition may comprise Y-27632 or thiazovivin. The composition may comprise dihydrodeoxymorphine. The composition may comprise ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib. The composition may comprise BIRB796, SB203580 or SB202190. The composition may comprise AKTi. The composition may comprise CX-4945, TPP 22 or ellagic acid.

[0175] The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; or any combination thereof. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW788388, dihydrodeoxymorphine or SB 525334; and a c-Jun kinase inhibitor. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; SGC-CBP30, I-CBP112, GNE272 or GNE409; DZNep, NepA, Adox or DZA; 5-ITU or ABT 702; or any combination thereof. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; a CBP / p300 bromodomain inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB505124, GW 788388, dihydrodeoxymorphine or SB 525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; SGC-CBP30, I-CBP112, GNE272 or GNE409; and a SAH hydrolase inhibitor. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; SGC-CBP30, I-CBP112, GNE272 or GNE409; and an adenosine kinase inhibitor.The composition may comprise CHIR99021 or CHIR98014; E-616452, A83-01, SB431542, SB505124, GW 788388, dihydrodeoxymorphine or SB 525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; and DZNep, NepA, Adox or DZA. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; and an adenosine kinase inhibitor. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; a c-Jun kinase inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; SGC-CBP30, I-CBP112, GNE272 or GNE409; DZNep, NepA, Adox or DZA; and an adenosine kinase inhibitor. The composition may further comprise TTNPB, Ch55 or AM580; EPZ004777 or EPZ5676; VTP50469, MI3454 or WDR5-IN-4; SETD2-IN-1, EPZ-719 or MMSET-IN-1; SAG, purinomorphamine, Hh-Ag1.5 or human SHH; Y-27632 or thiazovivin; dihydrodeoxymorphine; ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib; BIRB796, SB203580 or SB202190; AKTi; or CX-4945, TPP 22 or ellagic acid.

[0176] The composition may comprise CHIR99021; E-616452; TTNPB; JNKIN8; SGC-CBP30; DZNep; 5-ITU; EPZ004777; VTP50469; SETD2-IN-1; SAG; Y-27632; dihydrodeoxymorphine; ruxolitinib; BIRB796; AKTi; or CX-4945, or any combination thereof. The composition may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 of CHIR99021; E-616452; TTNPB; JNKIN8; SGC-CBP30; DZNep; 5-ITU; EPZ004777; VTP50469; SETD2-IN-1; SAG; Y-27632; dihydrodeoxymorphine; ruxolitinib; BIRB796; AKTi; or CX-4945. The composition may comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 of CHIR99021; E-616452; TTNPB; JNKIN8; SGC-CBP30; DZNep; 5-ITU; EPZ004777; VTP50469; SETD2-IN-1; SAG; Y-27632; dihydrodeoxymorphine; ruxolitinib; BIRB796; AKTi; or CX-4945. The composition may comprise CHIR99021; E-616452; TTNPB; JNKIN8; SGC-CBP30; DZNep; 5-ITU; EPZ004777; VTP50469; SETD2-IN-1; SAG; Y-27632; dihydrodeoxymorphine; ruxolitinib; BIRB796; AKTi; and CX-4945, TPP 22 or ellagic acid.

[0177] The composition may comprise CHIR99021. The composition may comprise E-616452. The composition may comprise TTNPB. The composition may comprise JNKIN8. The composition may comprise SGC-CBP30. The composition may comprise DZNep. The composition may comprise 5-ITU. The composition may comprise EPZ004777. The composition may comprise VTP50469. The composition may comprise SETD2-IN-1. The composition may comprise SAG. The composition may comprise Y-27632. The composition may comprise dihydrodeoxymorphine. The composition may comprise ruxolitinib. The composition may comprise BIRB796. The composition may comprise AKTi. The composition may comprise CX-4945, TPP 22 or ellagic acid.

[0178] The composition may comprise CHIR99021; E-616452; or JNKIN8; or any combination thereof. The composition may comprise CHIR99021; E-616452; and a c-Jun kinase inhibitor. The composition may comprise CHIR99021; E-616452; JNKIN8; SGC-CBP30; DZNep; or 5-ITU; or any combination thereof. The composition may comprise CHIR99021; E-616452; JNKIN8; a CBP / p300 bromodomain inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise CHIR99021; E-616452; JNKIN8; SGC-CBP30; and a SAH hydrolase inhibitor. The composition may comprise CHIR99021; E-616452; JNKIN8; SGC-CBP30; and an adenosine kinase inhibitor. The composition may comprise CHIR99021; E-616452; JNKIN8; and a SAH hydrolase inhibitor. The composition may comprise CHIR99021; E-616452; JNKIN8; and an adenosine kinase inhibitor. The composition may comprise CHIR99021; E-616452; a c-Jun kinase inhibitor; and a SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise CHIR99021; E-616452; JNKIN8; SGC-CBP30; DZNep; and an adenosine kinase inhibitor. The composition may further comprise TTNPB; EPZ004777; VTP50469; SETD2-IN-1; SAG; Y-27632; dihydrodeoxymorphine; ruxolitinib; BIRB796; AKTi; or CX-4945.

[0179] The composition may comprise at least about 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 10.5 μM, 11 μM, 11.5 μM, 12 μM, 12.5 μM, 13 μM, 13.5 μM, 14 μM, 14.5 μM, 15 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, 43 μM, 44 μM, 45 μM, 46 μM, 47 μM, 48 μM, 49 μM, 50 μM, 100 μM, 150 μM, 200 μM, 250 μM or more of CHIR99021 within the composition. The composition may comprise at most about 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 10.5 μM, 11 μM, 11.5 μM, 12 μM, 12.5 μM, 13 μM, 13.5 μM, 14 μM, 14.5 μM, 15 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 26 μM, 27 μM, 28 μM, 29 μM, 30 μM, 31 μM, 32 μM, 33 μM, 34 μM, 35 μM, 36 μM, 37 μM, 38 μM, 39 μM, 40 μM, 41 μM, 42 μM, 43 μM, 44 μM, 45 μM, 46 μM, 47 μM, 48 μM, 49 μM, 50 μM, 100 μM, 150 μM, 200 μM or 250 μM of CHIR99021 within the composition. The composition may comprise about 0.5 μM of CHIR99021 within the composition. The composition may comprise about 1 μM of CHIR99021 within the composition. The composition may comprise about 2 μM of CHIR99021 within the composition. The composition may comprise about 3 μM of CHIR99021 within the composition. The composition may comprise about 4 μM of CHIR99021 within the composition. The composition may comprise about 5 μM of CHIR99021 within the composition. The composition may comprise about 6 μM of CHIR99021 within the composition. The composition may comprise about 7 μM of CHIR99021 within the composition.The composition may contain about 8 μM CHIR99021 within the composition. The composition may contain about 9 μM CHIR99021 within the composition. The composition may contain about 10 μM CHIR99021 within the composition. The composition may contain about 15 μM CHIR99021 within the composition. The composition may contain about 20 μM CHIR99021 within the composition. The composition may contain about 30 μM CHIR99021 within the composition. The composition may contain about 40 μM CHIR99021 within the composition. The composition may contain about 50 μM CHIR99021 within the composition. The composition may contain from about 0.1 μM to about 100 μM CHIR99021 within the composition. The composition may contain from about 0.2 μM to about 75 μM CHIR99021 within the composition. The composition may contain from about 0.5 μM to about 50 μM CHIR99021 within the composition. The composition may contain from about 1 μM to about 25 μM CHIR99021 within the composition. The composition may contain from about 2 μM to about 12.5 μM CHIR99021 within the composition. The composition may contain from about 4 μM to about 6.25 μM CHIR99021 within the composition.

[0180] The composition may contain at least about 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, 500 μM or more of E-616452 within the composition. The composition may contain at most about 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM or 500 μM of E-616452 within the composition. The composition may contain about 1 μM of E-616452 within the composition. The composition may contain about 2 μM of E-616452 within the composition. The composition may contain about 3 μM of E-616452 within the composition. The composition may contain about 4 μM of E-616452 within the composition. The composition may contain about 5 μM of E-616452 within the composition. The composition may contain about 6 μM of E-616452 within the composition. The composition may contain about 7 μM of E-616452 within the composition. The composition may contain about 8 μM of E-616452 within the composition. The composition may contain about 9 μM of E-616452 within the composition. The composition may contain about 10 μM of E-616452 within the composition. The composition may contain about 15 μM of E-616452 within the composition. The composition may contain about 20 μM of E-616452 within the composition. The composition may contain about 30 μM of E-616452 within the composition. The composition may contain about 40 μM of E-616452 within the composition. The composition may contain about 50 μM of E-616452 within the composition. The composition may contain about 60 μM of E-616452 within the composition. The composition may contain about 70 μM of E-616452 within the composition. The composition may contain about 80 μM of E-616452 within the composition. The composition may contain about 90 μM of E-616452 within the composition. The composition may contain about 100 μM of E-616452 within the composition.The composition may comprise from about 1 μM to about 100 μM of E-616452 within the composition. The composition may comprise from about 2 μM to about 75 μM of E-616452 within the composition. The composition may comprise from about 3 μM to about 50 μM of E-616452 within the composition. The composition may comprise from about 4 μM to about 40 μM of E-616452 within the composition. The composition may comprise from about 5 μM to about 30 μM of E-616452 within the composition. The composition may comprise from about 7.5 μM to about 20 μM of E-616452 within the composition.

[0181] The composition may contain at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of JNKIN8 in the composition. The composition may contain at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of JNKIN8 in the composition. The composition may contain about 0.05 μM of JNKIN8 in the composition. The composition may contain about 0.1 μM of JNKIN8 in the composition. The composition may contain about 0.15 μM of JNKIN8 in the composition. The composition may contain about 0.2 μM of JNKIN8 in the composition. The composition may contain about 0.25 μM of JNKIN8 in the composition. The composition may contain about 0.3 μM of JNKIN8 in the composition. The composition may contain about 0.35 μM of JNKIN8 in the composition. The composition may contain about 0.4 μM of JNKIN8 in the composition. The composition may contain about 0.45 μM of JNKIN8 in the composition. The composition may contain about 0.5 μM of JNKIN8 in the composition. The composition may contain about 1 μM of JNKIN8 in the composition. The composition may contain about 1.5 μM of JNKIN8 in the composition. The composition may contain about 2 μM of JNKIN8 in the composition. The composition may contain about 2.5 μM of JNKIN8 in the composition. The composition may contain about 3 μM of JNKIN8 in the composition. The composition may contain about 3.5 μM of JNKIN8 in the composition. The composition may contain about 4 μM of JNKIN8 in the composition. The composition may contain about 4.5 μM of JNKIN8 in the composition.The composition may comprise about 5 μM JNKIN8 within the composition. The composition may comprise from about 0.05 μM to about 2.5 μM JNKIN8 within the composition. The composition may comprise from about 0.1 μM to about 1.875 μM JNKIN8 within the composition. The composition may comprise from about 0.15 μM to about 1.25 μM JNKIN8 within the composition. The composition may comprise from about 0.2 μM to about 1 μM JNKIN8 within the composition. The composition may comprise from about 0.25 μM to about 0.75 μM JNKIN8 within the composition. The composition may comprise from about 0.375 μM to about 0.5 μM JNKIN8 within the composition.

[0182] The composition may contain at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM or more of SGC-CBP30 within the composition. The composition may contain at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM or 100 μM of SGC-CBP30 within the composition. The composition may contain about 0.2 μM of SGC-CBP30 within the composition. The composition may contain about 0.4 μM of SGC-CBP30 within the composition. The composition may contain about 0.6 μM of SGC-CBP30 within the composition. The composition may contain about 0.8 μM of SGC-CBP30 within the composition. The composition may contain about 1 μM of SGC-CBP30 within the composition. The composition may contain about 1.2 μM of SGC-CBP30 within the composition. The composition may contain about 1.4 μM of SGC-CBP30 within the composition. The composition may contain about 1.6 μM of SGC-CBP30 within the composition. The composition may contain about 1.8 μM of SGC-CBP30 within the composition. The composition may contain about 2 μM of SGC-CBP30 within the composition. The composition may contain about 4 μM of SGC-CBP30 within the composition. The composition may contain about 6 μM of SGC-CBP30 within the composition. The composition may contain about 8 μM of SGC-CBP30 within the composition. The composition may contain about 10 μM of SGC-CBP30 within the composition. The composition may contain about 12 μM of SGC-CBP30 within the composition. The composition may contain about 14 μM of SGC-CBP30 within the composition. The composition may contain about 16 μM of SGC-CBP30 within the composition. The composition may contain about 18 μM of SGC-CBP30 within the composition. The composition may contain about 20 μM of SGC-CBP30 within the composition.The composition may comprise from about 0.2 μM to about 20 μM of SGC-CBP30 within the composition. The composition may comprise from about 0.4 μM to about 15 μM of SGC-CBP30 within the composition. The composition may comprise from about 0.6 μM to about 10 μM of SGC-CBP30 within the composition. The composition may comprise from about 0.8 μM to about 8 μM of SGC-CBP30 within the composition. The composition may comprise from about 1 μM to about 6 μM of SGC-CBP30 within the composition. The composition may comprise from about 1.5 μM to about 4 μM of SGC-CBP30 within the composition.

[0183] The composition may contain at least about 0.0004 μM, 0.0008 μM, 0.0012 μM, 0.0016 μM, 0.002 μM, 0.004 μM, 0.006 μM, 0.008 μM, 0.01 μM, 0.012 μM, 0.014 μM, 0.016 μM, 0.018 μM, 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.12 μM, 0.14 μM, 0.16 μM, 0.18 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.55 μM, 0.6 μM, 0.65 μM, 0.7 μM, 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM, 1 μM or more of DZNep in the composition. The composition may contain at most about 0.0004 μM, 0.0008 μM, 0.0012 μM, 0.0016 μM, 0.002 μM, 0.004 μM, 0.006 μM, 0.008 μM, 0.01 μM, 0.012 μM, 0.014 μM, 0.016 μM, 0.018 μM, 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.12 μM, 0.14 μM, 0.16 μM, 0.18 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.55 μM, 0.6 μM, 0.65 μM, 0.7 μM, 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM or 1 μM of DZNep in the composition. The composition may contain about 0.002 μM of DZNep in the composition. The composition may contain about 0.004 μM of DZNep in the composition. The composition may contain about 0.006 μM of DZNep in the composition. The composition may contain about 0.008 μM of DZNep in the composition. The composition may contain about 0.01 μM of DZNep in the composition. The composition may contain about 0.012 μM of DZNep in the composition. The composition may contain about 0.014 μM of DZNep in the composition. The composition may contain about 0.016 μM of DZNep in the composition. The composition may contain about 0.018 μM of DZNep in the composition. The composition may contain about 0.02 μM of DZNep in the composition. The composition may contain about 0.04 μM of DZNep in the composition. The composition may contain about 0.06 μM of DZNep in the composition. The composition may contain about 0.08 μM of DZNep in the composition. The composition may contain about 0.1 μM of DZNep in the composition. The composition may contain about 0.12 μM of DZNep in the composition. The composition may contain about 0.14 μM of DZNep in the composition.The composition may comprise about 0.16 μM DZNep within the composition. The composition may comprise about 0.18 μM DZNep within the composition. The composition may comprise about 0.2 μM DZNep within the composition. The composition may comprise from about 0.002 μM to about 0.2 μM of DZNep within the composition. The composition may comprise from about 0.0025 μM to about 0.15 μM of DZNep within the composition. The composition may comprise from about 0.005 μM to about 0.1 μM of DZNep within the composition. The composition may comprise from about 0.0075 μM to about 0.75 μM of DZNep within the composition. The composition may comprise from about 0.01 μM to about 0.5 μM of DZNep within the composition. The composition may comprise from about 0.015 μM to about 0.4 μM of DZNep within the composition.

[0184] The composition may contain at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of 5-ITU within the composition. The composition may contain at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of 5-ITU within the composition. The composition may contain about 0.05 μM of 5-ITU within the composition. The composition may contain about 0.1 μM of 5-ITU within the composition. The composition may contain about 0.15 μM of 5-ITU within the composition. The composition may contain about 0.2 μM of 5-ITU within the composition. The composition may contain about 0.25 μM of 5-ITU within the composition. The composition may contain about 0.3 μM of 5-ITU within the composition. The composition may contain about 0.35 μM of 5-ITU within the composition. The composition may contain about 0.4 μM of 5-ITU within the composition. The composition may contain about 0.45 μM of 5-ITU within the composition. The composition may contain about 0.5 μM of 5-ITU within the composition. The composition may contain about 1 μM of 5-ITU within the composition. The composition may contain about 1.5 μM of 5-ITU within the composition. The composition may contain about 2 μM of 5-ITU within the composition. The composition may contain about 2.5 μM of 5-ITU within the composition. The composition may contain about 3 μM of 5-ITU within the composition. The composition may contain about 3.5 μM of 5-ITU within the composition. The composition may contain about 4 μM of 5-ITU within the composition. The composition may contain about 4.5 μM of 5-ITU within the composition. The composition may contain about 5 μM of 5-ITU within the composition.The composition may comprise from about 0.05 μM to about 2.5 μM of 5-ITU within the composition. The composition may comprise from about 0.1 μM to about 1.875 μM of 5-ITU within the composition. The composition may comprise from about 0.15 μM to about 1.25 μM of 5-ITU within the composition. The composition may comprise from about 0.2 μM to about 1 μM of 5-ITU within the composition. The composition may comprise from about 0.25 μM to about 0.75 μM of 5-ITU within the composition. The composition may comprise from about 0.375 μM to about 0.5 μM of 5-ITU within the composition.

[0185] The composition may comprise at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM or more of TTNPB within the composition. The composition may comprise at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM or 100 μM of TTNPB within the composition. The composition may comprise about 0.2 μM of TTNPB within the composition. The composition may comprise about 0.4 μM of TTNPB within the composition. The composition may comprise about 0.6 μM of TTNPB. The composition may comprise about 0.8 μM of TTNPB within the composition. The composition may comprise about 1 μM of TTNPB within the composition. The composition may comprise about 1.2 μM of TTNPB within the composition. The composition may comprise about 1.4 μM of TTNPB within the composition. The composition may comprise about 1.6 μM of TTNPB within the composition. The composition may comprise about 1.8 μM of TTNPB within the composition. The composition may comprise about 2 μM of TTNPB within the composition. The composition may comprise about 4 μM of TTNPB within the composition. The composition may comprise about 6 μM of TTNPB within the composition. The composition may comprise about 8 μM of TTNPB within the composition. The composition may comprise about 10 μM of TTNPB within the composition. The composition may comprise about 12 μM of TTNPB within the composition. The composition may comprise about 14 μM of TTNPB within the composition. The composition may comprise about 16 μM of TTNPB within the composition. The composition may comprise about 18 μM of TTNPB within the composition. The composition may comprise about 20 μM of TTNPB within the composition. The composition may comprise from about 0.2 μM to about 20 μM of TTNPB within the composition. The composition may comprise from about 0.4 μM to about 15 μM of TTNPB within the composition. The composition may comprise from about 0.6 μM to about 10 μM of TTNPB within the composition.The composition may comprise from about 0.8 μM to about 8 μM of TTNPB within the composition. The composition may comprise from about 1 μM to about 6 μM of TTNPB within the composition. The composition may comprise from about 1.5 μM to about 4 μM of TTNPB within the composition.

[0186] The composition may comprise at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM or more of EPZ5676 within the composition. The composition may comprise at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM or 100 μM of EPZ5676 within the composition. The composition may comprise about 0.2 μM of EPZ5676 within the composition. The composition may comprise about 0.4 μM of EPZ5676 within the composition. The composition may comprise about 0.6 μM of EPZ5676 within the composition. The composition may comprise about 0.8 μM of EPZ5676 within the composition. The composition may comprise about 1 μM of EPZ5676 within the composition. The composition may comprise about 1.2 μM of EPZ5676 within the composition. The composition may comprise about 1.4 μM of EPZ5676 within the composition. The composition may comprise about 1.6 μM of EPZ5676. The composition may comprise about 1.8 μM of EPZ5676 within the composition. The composition may comprise about 2 μM of EPZ5676 within the composition. The composition may comprise about 4 μM of EPZ5676 within the composition. The composition may comprise about 6 μM of EPZ5676 within the composition. The composition may comprise about 8 μM of EPZ5676 within the composition. The composition may comprise about 10 μM of EPZ5676 within the composition. The composition may comprise about 12 μM of EPZ5676 within the composition. The composition may comprise about 14 μM of EPZ5676 within the composition. The composition may comprise about 16 μM of EPZ5676 within the composition. The composition may comprise about 18 μM of EPZ5676 within the composition. The composition may comprise about 20 μM of EPZ5676 within the composition. The composition may comprise from about 0.2 μM to about 20 μM of EPZ5676 within the composition. The composition may comprise from about 0.4 μM to about 15 μM of EPZ5676 within the composition.The composition may comprise from about 0.6 μM to about 10 μM of EPZ5676 within the composition. The composition may comprise from about 0.8 μM to about 8 μM of EPZ5676 within the composition. The composition may comprise from about 1 μM to about 6 μM of EPZ5676 within the composition. The composition may comprise from about 1.5 μM to about 4 μM of EPZ5676 within the composition.

[0187] The composition may comprise at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of VTP50469 within the composition. The composition may comprise at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of VTP50469 within the composition. The composition may comprise about 0.05 μM of VTP50469 within the composition. The composition may comprise about 0.1 μM of VTP50469 within the composition. The composition may comprise about 0.15 μM of VTP50469 within the composition. The composition may comprise about 0.2 μM of VTP50469 within the composition. The composition may comprise about 0.25 μM of VTP50469 within the composition. The composition may comprise about 0.3 μM of VTP50469 within the composition. The composition may comprise about 0.35 μM of VTP50469 within the composition. The composition may comprise about 0.4 μM of VTP50469 within the composition. The composition may comprise about 0.45 μM of VTP50469 within the composition. The composition may comprise about 0.5 μM of VTP50469 within the composition. The composition may comprise about 1 μM of VTP50469 within the composition. The composition may comprise about 1.5 μM of VTP50469 within the composition. The composition may comprise about 2 μM of VTP50469 within the composition. The composition may comprise about 2.5 μM of VTP50469 within the composition. The composition may comprise about 3 μM of VTP50469 within the composition. The composition may comprise about 3.5 μM of VTP50469 within the composition. The composition may comprise about 4 μM of VTP50469 within the composition.The composition may comprise about 4.5 μM of VTP50469 within the composition. The composition may comprise about 5 μM of VTP50469 within the composition. The composition may comprise from about 0.05 μM to about 2.5 μM of VTP50469 within the composition. The composition may comprise from about 0.1 μM to about 1.875 μM of VTP50469 within the composition. The composition may comprise from about 0.15 μM to about 1.25 μM of VTP50469 within the composition. The composition may comprise from about 0.2 μM to about 1 μM of VTP50469 within the composition. The composition may comprise from about 0.25 μM to about 0.75 μM of VTP50469 within the composition. The composition may comprise from about 0.375 μM to about 0.5 μM of VTP50469 within the composition.

[0188] The composition may comprise at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of SETD2-IN-1 within the composition. The composition may comprise at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.05 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.1 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.15 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.2 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.25 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.3 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.35 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.4 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.45 μM of SETD2-IN-1 within the composition. The composition may comprise about 0.5 μM of SETD2-IN-1 within the composition. The composition may comprise about 1 μM of SETD2-IN-1 within the composition. The composition may comprise about 1.5 μM of SETD2-IN-1 within the composition. The composition may comprise about 2 μM of SETD2-IN-1 within the composition. The composition may comprise about 2.5 μM of SETD2-IN-1 within the composition. The composition may comprise about 3 μM of SETD2-IN-1 within the composition.The composition may comprise about 3.5 μM of SETD2-IN-1 within the composition. The composition may comprise about 4 μM of SETD2-IN-1 within the composition. The composition may comprise about 4.5 μM of SETD2-IN-1 within the composition. The composition may comprise about 5 μM of SETD2-IN-1 within the composition. The composition may comprise from about 0.05 μM to about 2.5 μM of SETD2-IN-1 within the composition. The composition may comprise from about 0.1 μM to about 1.875 μM of SETD2-IN-1 within the composition. The composition may comprise from about 0.15 μM to about 1.25 μM of SETD2-IN-1 within the composition. The composition may comprise from about 0.2 μM to about 1 μM of SETD2-IN-1 within the composition. The composition may comprise from about 0.25 μM to about 0.75 μM of SETD2-IN-1 within the composition. The composition may comprise from about 0.375 μM to about 0.5 μM of SETD2-IN-1 within the composition.

[0189] The composition may contain at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of SAG in the composition. The composition may contain at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of SAG in the composition. The composition may contain about 0.05 μM of SAG in the composition. The composition may contain about 0.1 μM of SAG in the composition. The composition may contain about 0.15 μM of SAG in the composition. The composition may contain about 0.2 μM of SAG in the composition. The composition may contain about 0.25 μM of SAG in the composition. The composition may contain about 0.3 μM of SAG in the composition. The composition may contain about 0.35 μM of SAG in the composition. The composition may contain about 0.4 μM of SAG in the composition. The composition may contain about 0.45 μM of SAG in the composition. The composition may contain about 0.5 μM of SAG in the composition. The composition may contain about 1 μM of SAG in the composition. The composition may contain about 1.5 μM of SAG in the composition. The composition may contain about 2 μM of SAG in the composition. The composition may contain about 2.5 μM of SAG in the composition. The composition may contain about 3 μM of SAG in the composition. The composition may contain about 3.5 μM of SAG in the composition. The composition may contain about 4 μM of SAG in the composition. The composition may contain about 4.5 μM of SAG in the composition. The composition may contain about 5 μM of SAG in the composition. The composition may contain about 0.05 μM to about 2.5 μM of SAG in the composition.The composition may comprise from about 0.1 μM to about 1.875 μM SAG within the composition. The composition may comprise from about 0.15 μM to about 1.25 μM SAG within the composition. The composition may comprise from about 0.2 μM to about 1 μM SAG within the composition. The composition may comprise from about 0.25 μM to about 0.75 μM SAG within the composition. The composition may comprise from about 0.375 μM to about 0.5 μM SAG within the composition.

[0190] The composition may contain at least about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM, 25 μM or more of dihydrodeoxymorphine in the composition. The composition may contain at most about 0.01 μM, 0.02 μM, 0.03 μM, 0.04 μM, 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.75 μM, 1 μM, 1.25 μM, 1.5 μM, 1.75 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 3.25 μM, 3.5 μM, 3.75 μM, 4 μM, 4.25 μM, 4.5 μM, 4.75 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, 15 μM, 17.5 μM, 20 μM, 22.5 μM or 25 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.05 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.1 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.15 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.2 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.25 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.3 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.35 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.4 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.45 μM of dihydrodeoxymorphine in the composition. The composition may contain about 0.5 μM of dihydrodeoxymorphine in the composition. The composition may contain about 1 μM of dihydrodeoxymorphine in the composition. The composition may contain about 1.5 μM of dihydrodeoxymorphine in the composition. The composition may contain about 2 μM of dihydrodeoxymorphine in the composition. The composition may contain about 2.5 μM of dihydrodeoxymorphine in the composition. The composition may contain about 3 μM of dihydrodeoxymorphine in the composition. The composition may contain about 3.5 μM of dihydrodeoxymorphine in the composition. The composition may contain about 4 μM of dihydrodeoxymorphine in the composition. The composition may contain about 4.5 μM of dihydrodeoxymorphine in the composition. The composition may contain about 5 μM of dihydrodeoxymorphine in the composition.The composition may comprise from about 0.05 μM to about 2.5 μM of dihydrodeoxymorphine within the composition. The composition may comprise from about 0.1 μM to about 1.875 μM of dihydrodeoxymorphine within the composition. The composition may comprise from about 0.15 μM to about 1.25 μM of dihydrodeoxymorphine within the composition. The composition may comprise from about 0.2 μM to about 1 μM of dihydrodeoxymorphine within the composition. The composition may comprise from about 0.25 μM to about 0.75 μM of dihydrodeoxymorphine within the composition. The composition may comprise from about 0.375 μM to about 0.5 μM of dihydrodeoxymorphine within the composition.

[0191] The composition may contain at least about 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, 500 μM or more of Y-27632 in the composition. The composition may contain at most about 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 21 μM, 22 μM, 23 μM, 24 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM or 500 μM of Y-27632 in the composition. The composition may contain about 1 μM of Y-27632 in the composition. The composition may contain about 2 μM of Y-27632 in the composition. The composition may contain about 3 μM of Y-27632 in the composition. The composition may contain about 4 μM of Y-27632 in the composition. The composition may contain about 5 μM of Y-27632 in the composition. The composition may contain about 6 μM of Y-27632 in the composition. The composition may contain about 7 μM of Y-27632 in the composition. The composition may contain about 8 μM of Y-27632 in the composition. The composition may contain about 9 μM of Y-27632 in the composition. The composition may contain about 10 μM of Y-27632 in the composition. The composition may contain about 15 μM of Y-27632 in the composition. The composition may contain about 20 μM of Y-27632 in the composition. The composition may contain about 30 μM of Y-27632 in the composition. The composition may contain about 40 μM of Y-27632 in the composition. The composition may contain about 50 μM of Y-27632 in the composition. The composition may contain about 60 μM of Y-27632 in the composition. The composition may contain about 70 μM of Y-27632 in the composition. The composition may contain about 80 μM of Y-27632 in the composition. The composition may contain about 90 μM of Y-27632 in the composition. The composition may contain about 100 μM of Y-27632 in the composition. The composition may contain from about 1 μM to about 100 μM of Y-27632 in the composition.The composition may comprise from about 2 μM to about 75 μM of Y-27632 within the composition. The composition may comprise from about 3 μM to about 50 μM of Y-27632 within the composition. The composition may comprise from about 4 μM to about 40 μM of Y-27632 within the composition. The composition may comprise from about 5 μM to about 30 μM of Y-27632 within the composition. The composition may comprise from about 7.5 μM to about 20 μM of Y-27632 within the composition.

[0192] The composition may comprise at least about 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM, 50 μM or more of ruxolitinib within the composition. The composition may comprise at most about 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM or 50 μM of ruxolitinib within the composition. The composition may comprise about 0.1 μM of ruxolitinib within the composition. The composition may comprise about 0.2 μM of ruxolitinib within the composition. The composition may comprise about 0.3 μM of ruxolitinib within the composition. The composition may comprise about 0.4 μM of ruxolitinib within the composition. The composition may comprise about 0.5 μM of ruxolitinib within the composition. The composition may comprise about 0.6 μM of ruxolitinib within the composition. The composition may comprise about 0.7 μM of ruxolitinib within the composition. The composition may comprise about 0.8 μM of ruxolitinib within the composition. The composition may comprise about 0.9 μM of ruxolitinib within the composition. The composition may comprise about 1 μM of ruxolitinib within the composition.

[0193] The composition may contain at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM or more of BIRB796 within the composition. The composition may contain at least about 0.04 μM, 0.08 μM, 0.12 μM, 0.16 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, 1 μM, 1.2 μM, 1.4 μM, 1.6 μM, 1.8 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 11 μM, 12 μM, 13 μM, 14 μM, 15 μM, 16 μM, 17 μM, 18 μM, 19 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM or 100 μM of BIRB796 within the composition. The composition may contain about 0.2 μM of BIRB796 within the composition. The composition may contain about 0.4 μM of BIRB796 within the composition. The composition may contain about 0.6 μM of BIRB796 within the composition. The composition may contain about 0.8 μM of BIRB796 within the composition. The composition may contain about 1 μM of BIRB796 within the composition. The composition may contain about 1.2 μM of BIRB796 within the composition. The composition may contain about 1.4 μM of BIRB796 within the composition. The composition may contain about 1.6 μM of BIRB796 within the composition. The composition may contain about 1.8 μM of BIRB796 within the composition. The composition may contain about 2 μM of BIRB796 within the composition. The composition may contain about 4 μM of BIRB796 within the composition. The composition may contain about 6 μM of BIRB796 within the composition. The composition may contain about 8 μM of BIRB796 within the composition. The composition may contain about 10 μM of BIRB796 within the composition. The composition may contain about 12 μM of BIRB796 within the composition. The composition may contain about 14 μM of BIRB796 within the composition. The composition may contain about 16 μM of BIRB796 within the composition. The composition may contain about 18 μM of BIRB796 within the composition. The composition may contain about 20 μM of BIRB796 within the composition. The composition may contain from about 0.2 μM to about 20 μM of BIRB796 within the composition.The composition may comprise from about 0.4 μM to about 15 μM of BIRB796 within the composition. The composition may comprise from about 0.6 μM to about 10 μM of BIRB796 within the composition. The composition may comprise from about 0.8 μM to about 8 μM of BIRB796 within the composition. The composition may comprise from about 1 μM to about 6 μM of BIRB796 within the composition. The composition may comprise from about 1.5 μM to about 4 μM of BIRB796 within the composition.

[0194] The composition may contain at least about 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM, 50 μM or more of AKTi within the composition. The composition may contain at most about 0.02 μM, 0.04 μM, 0.06 μM, 0.08 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM, 8.5 μM, 9 μM, 9.5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, 45 μM or 50 μM of AKTi within the composition. The composition may contain about 0.1 μM of AKTi within the composition. The composition may contain about 0.2 μM of AKTi within the composition. The composition may contain about 0.3 μM of AKTi within the composition. The composition may contain about 0.4 μM of AKTi within the composition. The composition may contain about 0.5 μM of AKTi within the composition. The composition may contain about 0.6 μM of AKTi within the composition. The composition may contain about 0.7 μM of AKTi within the composition. The composition may contain about 0.8 μM of AKTi within the composition. The composition may contain about 0.9 μM of AKTi within the composition. The composition may contain about 1 μM of AKTi within the composition. The composition may contain about 2 μM of AKTi within the composition. The composition may contain about 3 μM of AKTi within the composition. The composition may contain about 4 μM of AKTi within the composition. The composition may contain about 5 μM of AKTi within the composition. The composition may contain about 6 μM of AKTi within the composition. The composition may contain about 7 μM of AKTi within the composition. The composition may contain about 8 μM of AKTi within the composition. The composition may contain about 9 μM of AKTi within the composition. The composition may contain about 10 μM of AKTi within the composition. The composition may contain from about 0.1 μM to about 10 μM of AKTi within the composition. The composition may contain from about 0.2 μM to about 7.5 μM of AKTi within the composition. The composition may contain from about 0.3 μM to about 5 μM of AKTi within the composition.The composition may comprise from about 0.4 μM to about 4 μM AKTi within the composition. The composition may comprise from about 0.5 μM to about 3 μM AKTi within the composition. The composition may comprise from about 0.75 μM to about 2 μM AKTi within the composition.

[0195] The composition may contain at least about 0.016 μM, 0.018 μM, 0.02 μM, 0.022 μM, 0.024 μM, 0.026 μM, 0.028 μM, 0.03 μM, 0.032 μM, 0.034 μM, 0.036 μM, 0.038 μM, 0.04 μM, 0.05 μM, 0.06 μM, 0.07 μM, 0.08 μM, 0.09 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.55 μM, 0.6 μM, 0.65 μM, 0.7 μM, 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM or more of CX-4945 within the composition. The composition may contain at most about 0.016 μM, 0.018 μM, 0.02 μM, 0.022 μM, 0.024 μM, 0.026 μM, 0.028 μM, 0.03 μM, 0.032 μM, 0.034 μM, 0.036 μM, 0.038 μM, 0.04 μM, 0.05 μM, 0.06 μM, 0.07 μM, 0.08 μM, 0.09 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.55 μM, 0.6 μM, 0.65 μM, 0.7 μM, 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM, 1 μM, 1.5 μM, 2 μM, 2.5 μM, 3 μM, 3.5 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8 μM of CX-4945 within the composition. The composition may contain about 0.08 μM of CX-4945 within the composition. The composition may contain about 0.1 μM of CX-4945 within the composition. The composition may contain about 0.2 μM of CX-4945 within the composition. The composition may contain about 0.3 μM of CX-4945 within the composition. The composition may contain about 0.4 μM of CX-4945 within the composition. The composition may contain about 0.5 μM of CX-4945 within the composition. The composition may contain about 0.6 μM of CX-4945 within the composition. The composition may contain about 0.7 μM of CX-4945 within the composition. The composition may contain about 0.8 μM of CX-4945 within the composition. The composition may contain about 0.9 μM of CX-4945 within the composition. The composition may contain about 1 μM of CX-4945 within the composition.The composition may comprise about 1.5 μM CX-4945 within the composition. The composition may comprise about 2 μM CX-4945 within the composition. The composition may comprise about 3 μM CX-4945 within the composition. The composition may comprise about 4 μM CX-4945 within the composition. The composition may comprise about 5 μM CX-4945 within the composition. The composition may comprise about 6 μM CX-4945 within the composition. The composition may comprise about 7 μM CX-4945 within the composition. The composition may comprise about 8 μM CX-4945 within the composition. The composition may comprise from about 0.08 μM to about 8 μM CX-4945 within the composition. The composition may comprise from about 0.1 μM to about 4 μM CX-4945 within the composition. The composition may comprise from about 0.15 μM to about 2 μM CX-4945 within the composition. The composition may comprise from about 0.25 μM to about 1.5 μM CX-4945 within the composition. The composition may comprise from about 0.5 μM to about 1 μM CX-4945 within the composition.

[0196] After contacting any population of stage 2 cells with any of the compositions described herein, the cells may be incubated under normoxic conditions. For example, the stage 2 cells may be incubated in up to 23%, 22%, 21%, 20% or 19% atmospheric oxygen. Normoxic conditions may include about 22% atmospheric oxygen. Normoxic conditions may include about 21% atmospheric oxygen. Normoxic conditions may include about 20% atmospheric oxygen.

[0197] After contacting any cell population of the stage 2 cells with any of the compositions described herein, the cell population of the stage 2 cells can be incubated with the composition for at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 25 days, or 30 days. The cell population of the stage 2 cells can be incubated with the composition for at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 25 days, or 30 days. The cell population of the stage 2 cells can be incubated with the composition for about 1 day. The cell population of the stage 2 cells can be incubated with the composition for about 2 days. The cell population of the stage 2 cells can be incubated with the composition for about 3 days. The cell population of the stage 2 cells can be incubated with the composition for about 4 days. The cell population of the stage 2 cells can be incubated with the composition for about 5 days. The cell population of the stage 2 cells can be incubated with the composition for about 6 days. The cell population of the stage 2 cells can be incubated with the composition for about 7 days. The cell population of the stage 2 cells can be incubated with the composition for about 8 days. The cell population of the stage 2 cells can be incubated with the composition for about 9 days. The cell population of the stage 2 cells can be incubated with the composition for about 10 days. The cell population of the stage 2 cells can be incubated with the composition for about 11 days. The cell population of the stage 2 cells can be incubated with the composition for about 12 days. The cell population of the stage 2 cells can be incubated with the composition for about 13 days. The cell population of the stage 2 cells can be incubated with the composition for about 14 days. The cell population of the stage 2 cells can be incubated with the composition for about 15 days. The cell population of the stage 2 cells can be incubated with the composition for about 16 days. The cell population of the stage 2 cells can be incubated with the composition for about 17 days. The cell population of the stage 2 cells can be incubated with the composition for about 18 days. The cell population of the stage 2 cells can be incubated with the composition for about 19 days. The cell population of the stage 2 cells can be incubated with the composition for about 20 days. The cell population of the stage 2 cells can be incubated with the composition for about 25 days.

[0198] Any composition may not contain feeder cells or serum. Any composition may not contain feeder cells and serum. Any composition may not contain feeder cells. Any composition may not contain serum. Any composition may contain feeder cells. Any composition may contain serum.

[0199] Stage 3

[0200] In some aspects, the present disclosure provides stage 3 methods and compositions for converting cells in an intermediate plastic state into cells with higher cellular potential (e.g., less-specialized cells), such as pluripotent stem cells - this conversion process is also referred to herein as "stage 3". The stage 3 method can be part of a conversion process for reprogramming cells in an intermediate plastic state into pluripotent stem cells. The stage 3 method can be the third stage of a conversion process for reprogramming somatic plastic state cells into pluripotent stem cells.

[0201] The stage 3 method can include contacting a first cell population with a first composition. The stage 3 method can include converting a subset of the first cell population into different cells after or during the contacting. The cell population containing the different cells can include a second cell population. The stage 3 method can include incubating the first cell population with the first composition for a period of time. The subset of the first cell population can be converted into different cells before, during, or after the incubation. In some cases, the stage 3 method can include removing the first composition from the second cell population. In other cases, the stage 3 method can include removing the first composition from the first cell population.

[0202] The first cell population of stage 3 cells can include any cell population of stage 1 or stage 2 cells. In some cases, the first cell population of stage 3 cells can include a second cell population of stage 1 or stage 2 cells. In some cases, the first cell population of stage 3 cells can include a composition, wherein the second cell population of stage 2 cells is separated from or removed from the chemical reprogramming factors of stage 2.

[0203] The second cell population of stage 3 cells can include pluripotent stem cells. Pluripotent stem cells obtained after contacting the cell population with the composition can be referred to as chemically induced pluripotent stem cells (CiPSCs). CiPSCs can include human CiPSCs (hCiPSCs). The first cell population of stage 3 cells can include pluripotent stem cells.

[0204] CiPSCs are not naturally occurring cells. CiPSCs can express a gene combination that is not expressed by naturally occurring cells. In some cases, a CiPSC can express at least one gene at a level that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 5-fold, 100-fold, or higher relative to a naturally occurring cell. In some cases, a CiPSC can express at least one gene at a level that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% lower relative to a naturally occurring cell. The second cell population of stage 3 cells can include somatic cells, epithelial-like cells, intermediate plastic state cells, or CiPSCs. The second cell population of stage 3 cells can include somatic cells, epithelial-like cells, intermediate plastic state cells, and CiPSCs. The second cell population of stage 3 cells may not include somatic cells, epithelial-like cells, or intermediate plastic state cells. In some cases, the second cell population of stage 3 cells can contain fewer somatic cells, epithelial-like cells, or intermediate plastic state cells than the first cell population of stage 3 cells. For example, the second cell population of stage 3 cells can have 0.001%, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 99% fewer somatic cells, epithelial-like cells, or intermediate plastic state cells than the first cell population of stage 3 cells. In some cases, the second cell population of stage 3 cells can contain more CiPSCs than the first cell population of stage 3 cells. For example, the second cell population of stage 3 cells can have 0.001%, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 100-fold, or more CiPSCs than the first cell population of stage 3 cells.

[0205] CiPSCs can express OCT4, SOX2, NANOG, FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1, or any combination thereof. CiPSCs can express OCT4. CiPSCs can express SOX2. CiPSCs can express NANOG. CiPSCs can express FGF4. CiPSCs can express ZFP57. CiPSCs can express DPPA5. CiPSCs can express REX1. CiPSCs can express DPPA4. CiPSCs can express TDGF1. CiPSCs can express TRA-1-60. CiPSCs can express TRA-1-81. CiPSCs can express SSEA4. CiPSCs can express KLF4. CiPSCs can express KLF17. CiPSCs can express DPPA3. CiPSCs can express DNMT3L. CiPSCs can express UTF1. CiPSCs can express one or more of OCT4, SOX2, NANOG, FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1.

[0206] CiPSCs can express OCT4, SOX2 or NANOG. CiPSCs can express OCT4, SOX2 and NANOG. CiPSCs can express OCT4 or SOX2. CiPSCs can express OCT4 or NANOG. CiPSCs can express SOX2 or NANOG. CiPSCs can express OCT4 and SOX2. CiPSCs can express OCT4 and NANOG. CiPSCs can express SOX2 and NANOG. CiPSCs can express OCT4, SOX2 and NANOG; and FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L or UTF1, or any combination thereof. CiPSCs can express OCT4, SOX2 and NANOG; and FGF4. CiPSCs can express OCT4, SOX2 and NANOG; and ZFP57. CiPSCs can express OCT4, SOX2 and NANOG; and DPPA5. CiPSCs can express OCT4, SOX2 and NANOG; and REX1. CiPSCs can express OCT4, SOX2 and NANOG; and DPPA4. CiPSCs can express OCT4, SOX2 and NANOG; and TDGF1. CiPSCs can express OCT4, SOX2 and NANOG; and TRA-1-60. CiPSCs can express OCT4, SOX2 and NANOG; and TRA-1-81. CiPSCs can express OCT4, SOX2 and NANOG; and SSEA4. CiPSCs can express OCT4, SOX2 and NANOG; and KLF4. CiPSCs can express OCT4, SOX2 and NANOG; and KLF17. CiPSCs can express OCT4, SOX2 and NANOG; and DPPA3. CiPSCs can express OCT4, SOX2 and NANOG; and DNMT3L. CiPSCs can express OCT4, SOX2 and NANOG; and UTF1. CiPSCs can express OCT4, SOX2 and NANOG; and one or more of FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DPPA5, DNMT3L, REX1 or UTF1.

[0207] CPISC can express OCT4, SOX2, and NANOG; a second gene; and a third gene. Epithelial-like cells can express OCT4, SOX2, and NANOG; one or more second genes; and one or more third genes. The second genes expressed by CPISC can include FGF4, ZFP57, DPPA5, or REX1, or any combination thereof. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express OCT4. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express SOX2. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express NANOG. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express OCT4, SOX2, or NANOG. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express OCT4, SOX2, and NANOG. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express OCT4, SOX2, or NANOG; a second gene; or a third gene. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express a second gene. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express a third gene. Somatic cells, epithelial-like cells, or intermediate plastic state cells may not express OCT4, SOX2, or NANOG; one or more second genes; and one or more third genes.

[0208] The second gene can include FGF4, ZFP57, DPPA5, or REX1, or any combination thereof. The second gene can include FGF4. The second gene can include ZFP57. The second gene can include DPPA5. The second gene can include REX1. The third gene can include DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1, or any combination thereof. The third gene can include DPPA4. The third gene can include TDGF1. The third gene can include TRA-1-60. The third gene can include TRA-1-81. The third gene can include SSEA4. The third gene can include KLF4. The third gene can include KLF17. The third gene can include DPPA3. The third gene can include DNMT3L. The third gene can include UTF1. Figure 24Exemplary CiPSCs expressing OCT4, SOX2, and NANOG as shown in the heatmap are shown. The x-axis and y-axis of the heatmap show the second and third genes, respectively. Each pixel of the heatmap represents a cell population. For example, cell 241 expresses OCT4, SOX2, NANOG, ZFP57, and SSEA4. Cell 242 expresses OCT4, SOX2, NANOG, REX1, or any combination of the third gene (e.g., TRA-1-60 and TRA-1-81). Cell 243 expresses OCT4, SOX2, NANOG, KLF17, or any combination of the second gene (e.g., DNMT3L and UTF1).

[0209] Cells of the second cell population of stage 3 cells may express higher levels of OCT4, SOX2, NANOG, FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1, or any combination thereof, relative to cells of the first cell population of stage 3 cells or any cell population of stage 1 or stage 2 cells. The higher expression level of any one or any combination of OC4, SOX2, NANOG, FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1 in cells of the second cell population of stage 3 cells can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 5-fold, 100-fold, or more higher than that of cells of the first cell population of stage 3 cells or any cell population of stage 1 or stage 2 cells. Cells of the first cell population of stage 3 cells or any cell population of stage 1 or stage 2 cells may express lower levels of any one of OCT4, SOX2, NANOG, FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1 relative to cells of the second cell population of stage 3 cells. The lower expression level of any one of OCT4, SOX2, NANOG, FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1 in cells of the first cell population of stage 3 cells or any cell population of stage 1 or stage 2 cells can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% lower than that of cells of the second cell population of stage 3 cells. The expression level can be measured by any method described herein. For example, gene expression can be measured by the method described in Example 2, and any one of SEQ ID NO: 1-83 (including controls) can be used to measure gene expression.

[0210] In some aspects, the present disclosure provides a composition that comprises reprogramming factors for stage 3 conversion, or comprises stage 3 cells (a first cell population or a second cell population), or comprises stage 3 cells (a first cell population or a second cell population) and reprogramming factors for stage 3 conversion. In some cases, the composition comprises a culture medium containing reprogramming factors for stage 3 conversion.

[0211] In some cases, the composition may comprise an isolated cell population of the second cell population of stage 3 cells. In some cases, the composition may comprise an isolated cell population of the first cell population of stage 3 cells. The isolated cell population of stage 3 cells may comprise at least about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more cells. The isolated cell population of stage 3 cells may comprise at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 cells. The isolated cell population of stage 3 cells may comprise at least one CiPSC. In some cases, the isolated cell population of stage 3 cells may comprise at least about 1, 1x10^1, 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more CiPSCs. The isolated cell population may comprise at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 CiPSCs. In some cases, the isolated cell population of stage 3 cells may comprise at least about 1x10^1, 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9, 1x10^10 or more CiPSCs, intermediate plastic state cells, epithelial-like cells or somatic cells, or any combination thereof. The isolated cell population of stage 3 cells may comprise at most about 1x10^2, 1x10^3, 1x10^4, 1x10^5, 1x10^6, 1x10^7, 1x10^8, 1x10^9 or 1x10^10 CiPSCs, intermediate plastic state cells, epithelial-like cells or somatic cells, or any combination thereof.

[0212] The composition may comprise chemical reprogramming factors. The composition may comprise a plurality of chemical reprogramming factors. The composition may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more chemical reprogramming factors. The composition may comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 chemical reprogramming factors. The composition may comprise 1 chemical reprogramming factor. The composition may comprise 2 chemical reprogramming factors. The composition may comprise 3 chemical reprogramming factors. The composition may comprise 4 chemical reprogramming factors. The composition may comprise 5 chemical reprogramming factors. The composition may comprise 6 chemical reprogramming factors. The composition may comprise 7 chemical reprogramming factors. The composition may comprise 8 chemical reprogramming factors. The composition may comprise 9 chemical reprogramming factors. The composition may comprise 10 chemical reprogramming factors. The composition may comprise 11 chemical reprogramming factors. The composition may comprise 12 chemical reprogramming factors. The composition may comprise 13 chemical reprogramming factors. The composition may comprise 14 chemical reprogramming factors. The composition may comprise 15 chemical reprogramming factors.

[0213] The composition may comprise a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylation inhibitor, a Dot1L inhibitor or a SAH hydrolase inhibitor, or any combination thereof. The composition may comprise at least 1, 2, 3, 4, 5, 6, 7 or 8 of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylation inhibitor, a Dot1L inhibitor or a SAH hydrolase inhibitor. The composition may comprise at most 1, 2, 3, 4, 5, 6, 7 or 8 of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylation inhibitor, a Dot1L inhibitor or a SAH hydrolase inhibitor. The composition...

Claims

1. A method for producing pluripotent stem cells, comprising: (a). obtaining epithelial-like cells expressing LIN28A; (b). transforming the epithelial-like cells or their progeny into intermediate plastic state cells expressing LIN28A and SALL4, and one or more of MSX2, NMYC, SDC1, WNT4, FGF19 or TOP2A; and (c). transforming the intermediate plastic state cells or their progeny into pluripotent stem cells.

2. The method according to claim 1, wherein transforming the epithelial-like cells or their progeny comprises contacting the epithelial-like cells with a composition comprising a glycogen kinase inhibitor, a TGFβ receptor inhibitor and a c-Jun kinase inhibitor.

3. The method according to claim 1 or claim 2, wherein the composition further comprises a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor.

4. The method according to any one of claims 1-3, wherein the composition further comprises a SAH hydrolase inhibitor or an adenosine kinase inhibitor.

5. A method for producing pluripotent stem cells, comprising: (a). obtaining epithelial-like cells expressing LIN28A; (b). contacting the epithelial-like cells or their progeny with the following substances: (i). a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor; (ii). a glycogen kinase inhibitor; (iii). a TGFβ receptor inhibitor; and (iv). a c-Jun kinase inhibitor, thereby transforming the epithelial-like cells or their progeny into intermediate plastic state cells expressing LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19 or TOP2A; and (c). transforming the intermediate plastic state cells or their progeny into pluripotent stem cells.

6. The method according to any one of claims 1-5, wherein the epithelial-like cells express one or more of KRT18, KRT19, WT1, NMYC, WNT2B, PAX8, SMAD3, GLI3 or TBX2.

7. The method according to any one of claims 1-6, wherein the epithelial-like cells express one or more of NMYC, WNT2B, PAX8, SMAD3 or GLI3.

8. The method according to claim 7, wherein the epithelial-like cells further express one or more of KRT18, KRT19, WT1 or TBX2.

9. The method according to any one of claims 1-8, wherein the intermediate plastic state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2.

10. The method according to claim 9, wherein the intermediate plastic state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2 or LEF1.

11. The method according to claim 10, wherein the mesoplastic state cells further express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2.

12. The method according to any one of claims 1-11, wherein the pluripotent stem cells express one or more of OCT4, SOX2 or NANOG.

13. The method according to any one of claims 1-12, wherein the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DPPA5, DNMT3L, REX1 or UTF1.

14. The method according to claim 13, wherein the pluripotent cells express one or more of FGF4, ZFP57, DPPA5 or REX1.

15. The method according to claim 14, wherein the pluripotent cells further express one or more of DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L or UTF1.

16. The method according to any one of claims 1-15, further comprising treating a population of somatic cells to convert at least one subset of the somatic cells in the population into epithelial-like cells.

17. The method according to claim 16, wherein the somatic cells comprise primary human adult adipose-derived mesenchymal stromal cells (hADSCs).

18. The method according to claim 16, wherein the somatic cells comprise fibroblasts.

19. The method according to any one of claims 16-18, wherein the method converts the somatic cells into pluripotent stem cells in less than about 50 days.

20. The method according to claim 19, wherein the method converts the somatic cells into pluripotent stem cells in at most about 32 days.

21. The method according to claim 20, wherein the method converts the somatic cells into pluripotent stem cells in at most about 24 days.

22. The method according to any one of claims 16-21, wherein the method results in the generation of one pluripotent stem cell per at most 1,000 somatic cells in the population of somatic cells.

23. The method according to claim 22, wherein the method results in the generation of one pluripotent stem cell per at most 200 somatic cells in the population of somatic cells.

24. The method according to claim 23, wherein the method results in the generation of one pluripotent stem cell per at most 50 somatic cells in the population of somatic cells.

25. The method according to any one of claims 16-24, further comprising inoculating the somatic cells at a density of at most about 1x10^6 cells per square centimeter (cm^2) of cell growth area.

26. The method according to claim 25, wherein the somatic cells are seeded at a density of at most about 5×10^5 cells per cm^2 of cell growth area.

27. The method according to claim 26, wherein the somatic cells are seeded at a density of at most about 2.5×10^5 cells per cm^2 of cell growth area.

28. A method for producing pluripotent stem cells, comprising: (a). obtaining a first cell population comprising epithelial-like cells expressing LIN28A; (b). contacting the first cell population with a second composition, the second composition comprising: (i). a glycogen kinase inhibitor; (ii). a TGFβ receptor inhibitor; and (iii). a c-Jun kinase inhibitor, thereby obtaining a second cell population; and (c). contacting the second cell population with a third composition, the third composition comprising: (i). a MEK inhibitor; (ii). a B-Raf inhibitor; and (iii). a histone deacetylase inhibitor, thereby obtaining a third cell population comprising pluripotent stem cells.

29. The method according to claim 28, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

30. The method according to claim 28 or claim 29, wherein the glycogen kinase inhibitor comprises CHIR99021.

31. The method according to claim 30, wherein CHIR99021 is present in the second composition at a concentration of about 0.5 micromolar (μM) to about 50 μM.

32. The method according to claim 31, wherein CHIR99021 is present in the second composition at a concentration of about 1 μM to about 25 μM.

33. The method according to claim 32, wherein CHIR99021 is present in the second composition at a concentration of about 2 μM to about 12.5 μM.

34. The method according to claim 33, wherein CHIR99021 is present in the second composition at a concentration of about 5 μM.

35. The method according to any one of claims 28-34, wherein the TGFβ receptor inhibitor is an ALK5 inhibitor.

36. The method according to claim 35, wherein the TGFβ receptor inhibitor comprises E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334, optionally, wherein the TGFβ receptor inhibitor comprises E-616452.

37. The method according to claim 36, wherein E-616452 is present in the second composition at a concentration of about 1 μM to about 100 μM.

38. The method according to claim 37, wherein E-616452 is present in the second composition at a concentration of about 2 μM to about 50 μM.

39. The method according to claim 38, wherein E-616452 is present in the second composition at a concentration of about 4 μM to about 25 μM.

40. The method according to claim 39, wherein E-616452 is present in the second composition at a concentration of about 10 μM.

41. The method according to any one of claims 28-40, wherein the c-Jun kinase inhibitor comprises JNKIN8, JNKIN7, JNKIN5 or JNKIN12.

42. The method according to claim 41, wherein the c-Jun kinase inhibitor comprises JNKIN8.

43. The method according to claim 42, wherein JNKIN8 is present in the second composition at a concentration of about 0.05 μM to about 5 μM.

44. The method according to claim 43, wherein JNKIN8 is present in the second composition at a concentration of about 0.1 μM to about 2.5 μM.

45. The method according to claim 44, wherein JNKIN8 is present in the second composition at a concentration of about 0.2 μM to about 1.25 μM.

46. The method according to claim 45, wherein JNKIN8 is present in the second composition at a concentration of about 0.5 μM.

47. The method according to any one of claims 28-46, wherein the MEK inhibitor comprises PD0325901, AZD8330 or TAK-733.

48. The method according to claim 47, wherein the MEK inhibitor comprises PD0325901.

49. The method according to claim 48, wherein PD0325901 is present in the third composition at a concentration of about 0.1 μM to about 10 μM.

50. The method according to claim 49, wherein PD0325901 is present in the third composition at a concentration of about 0.2 μM to about 5 μM.

51. The method according to claim 50, wherein PD0325901 is present in the third composition at a concentration of about 0.4 μM to about 2.5 μM.

52. The method according to claim 51, wherein PD0325901 is present in the third composition at a concentration of about 1 μM.

53. The method according to any one of claims 28-52, wherein the B-Raf inhibitor comprises SB590885, vemurafenib, RAF265 or PLX4720.

54. The method according to claim 53, wherein the B-Raf inhibitor comprises SB590885.

55. The method according to claim 54, wherein SB590885 is present in the third composition at a concentration of about 0.05 μM to about 5 μM.

56. The method according to claim 55, wherein SB590885 is present in the third composition at a concentration of about 0.1 μM to about 2.5 μM.

57. The method according to claim 56, wherein SB590885 is present in the third composition at a concentration of about 0.2 μM to about 1.25 μM.

58. The method according to claim 57, wherein SB590885 is present in the third composition at a concentration of about 0.5 μM.

59. The method according to any one of claims 28 - 58, wherein the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275, or HDACi I.

60. The method according to claim 59, wherein the histone deacetylase inhibitor comprises VPA.

61. The method according to claim 60, wherein VPA is present in the third composition at a concentration of about 0.1 millimolar (mM) to about 10 mM.

62. The method according to claim 61, wherein VPA is present in the third composition at a concentration of about 0.2 mM to about 5 mM.

63. The method according to claim 62, wherein VPA is present in the third composition at a concentration of about 0.4 mM to about 2.5 mM.

64. The method according to claim 63, wherein VPA is present in the third composition at a concentration of about 1 mM.

65. The method according to any one of claims 28 - 64, wherein the second composition further comprises a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor.

66. The method according to any one of claims 28 - 64, wherein the second composition further comprises: (a) a retinoic acid receptor (RAR) agonist; (b) a CBP / p300 bromodomain inhibitor; and (c) a SAH hydrolase inhibitor or an adenosine kinase inhibitor.

67. The method according to claim 66, wherein the RAR agonist comprises TTNPB, Ch55, or AM580.

68. The method according to claim 67, wherein the RAR agonist comprises TTNPB.

69. The method according to claim 68, wherein TTNPB is present in the composition at a concentration of about 0.2 μM to about 20 μM.

70. The method according to claim 69, wherein TTNPB is present in the composition at a concentration of about 0.4 μM to about 10 μM.

71. The method according to claim 70, wherein TTNPB is present in the composition at a concentration of about 0.8 μM to about 5 μM.

72. The method according to claim 71, wherein TTNPB is present in the composition at a concentration of about 2 μM.

73. The method according to any one of claims 66 - 72, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox, or DZA.

74. The method according to claim 73, wherein the SAH hydrolase inhibitor comprises DZNep.

75. The method according to claim 74, wherein DZNep is present in the second composition at a concentration of about 0.02 μM to about 2 μM.

76. The method according to claim 75, wherein DZNep is present in the second composition at a concentration of about 0.04 μM to about 1 μM.

77. The method according to claim 76, wherein DZNep is present in the second composition at a concentration of about 0.08 μM to about 0.5 μM.

78. The method according to claim 77, wherein DZNep is present in the second composition at a concentration of about 0.2 μM.

79. The method according to any one of claims 65-78, wherein the CBP / p300 bromodomain inhibitor comprises SGC-CBP30, I-CBP112 or GNE27.

80. The method according to claim 79, wherein the CBP / p300 bromodomain inhibitor comprises SGC-CBP30.

81. The method according to claim 80, wherein SGC-CBP30 is present in the second composition at a concentration of about 0.2 μM to about 20 μM.

82. The method according to claim 81, wherein SGC-CBP30 is present in the second composition at a concentration of about 0.4 μM to about 10 μM.

83. The method according to claim 82, wherein SGC-CBP30 is present in the second composition at a concentration of about 0.8 μM to about 5 μM.

84. The method according to claim 83, wherein SGC-CBP30 is present in the second composition at a concentration of about 2 μM.

85. The method according to any one of claims 65-84, wherein the adenosine kinase inhibitor comprises 5-iodotubercidin (5-ITU) or ABT 702.

86. The method according to claim 85, wherein the adenosine kinase inhibitor comprises 5-ITU.

87. The method according to claim 86, wherein 5-ITU is present in the composition at a concentration of about 0.05 μM to about 5 μM.

88. The method according to claim 87, wherein 5-ITU is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

89. The method according to claim 88, wherein 5-ITU is present in the composition at a concentration of about 0.2 μM to about 1 μM.

90. The method according to claim 89, wherein 5-ITU is present in the composition at a concentration of about 0.5 μM.

91. The method according to any one of claims 28-90, wherein the method comprises culturing the first cell population in the second composition for up to about 20 days.

92. The method according to claim 91, wherein the method comprises culturing the first cell population in the second composition for up to about 16 days.

93. The method according to claim 92, wherein the method comprises culturing the first cell population in the second composition for about 4 days to 16 days.

94. The method according to any one of claims 28-93, further comprising removing the second composition from the second cell population.

95. The method according to claim 94, wherein the method comprises culturing the second cell population in the third composition for up to about 20 days.

96. The method according to claim 95, wherein the method comprises culturing the second cell population in the third composition for up to about 12 days.

97. The method according to claim 96, wherein the method comprises culturing the second cell population in the third composition for about 4 days to 12 days.

98. The method according to any one of claims 28 - 97, wherein the epithelial-like cells or their progeny comprise a genetic modification.

99. The method according to claim 98, wherein the pluripotent stem cells or their progeny comprise a genetic modification.

100. The method according to claim 99, wherein the genetic modification comprises an exogenous nucleic acid sequence.

101. The method according to claim 100, wherein the exogenous nucleic acid sequence encodes a polypeptide.

102. The method according to claim 100 or claim 101, wherein the exogenous nucleic acid sequence comprises a sequence of a non-coding nucleic acid molecule.

103. The method according to any one of claims 98 - 102, wherein the genetic modification comprises an alteration of a genomic sequence.

104. The method according to any one of claims 98 - 103, wherein the genetic modification reduces the immunogenicity of the pluripotent stem cells or their progeny.

105. A method of reprogramming epithelial-like cells expressing LIN28A, comprising contacting a cell population comprising epithelial-like cells or their progeny with a composition comprising: (a). an SAH hydrolase inhibitor or an adenosine kinase inhibitor; (b). a glycogen kinase inhibitor; (c). a TGFβ receptor inhibitor; and (d). a c-Jun kinase inhibitor.

106. The method according to claim 105, wherein during the contacting, the cell population is incubated with about 21% atmospheric oxygen.

107. The method according to claim 105 or claim 106, wherein the composition comprises an adenosine kinase inhibitor.

108. The method according to claim 107, wherein the adenosine kinase inhibitor comprises 5-iodotubercidin (5-ITU) or ABT 702.

109. The method according to any one of claims 105 - 108, wherein the adenosine kinase inhibitor comprises 5-ITU.

110. The method according to claim 109, wherein 5-ITU is present in the composition at a concentration of about 0.05 micromolar (μM) to about 5 μM.

111. The method according to claim 110, wherein 5-ITU is present in the composition at a concentration of about 0.1 micromolar μM to about 2.5 μM.

112. The method according to claim 111, wherein 5-ITU is present in the composition at a concentration of about 0.2 micromolar μM to about 1 μM.

113. The method according to claim 112, wherein 5-ITU is present in the composition at a concentration of about 0.5 μM.

114. The method according to any one of claims 105 - 113, wherein the composition comprises an SAH hydrolase inhibitor.

115. The method according to claim 114, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

116. The method according to claim 115, wherein the SAH hydrolase inhibitor comprises DZNep.

117. The method according to claim 116, wherein DZNep is present in the second composition at a concentration of from about 0.02 μM to about 2 μM.

118. The method according to claim 117, wherein DZNep is present in the second composition at a concentration of from about 0.04 μM to about 1 μM.

119. The method according to claim 118, wherein DZNep is present in the second composition at a concentration of from about 0.08 μM to about 0.5 μM.

120. The method according to claim 119, wherein DZNep is present in the second composition at a concentration of about 0.2 micromolar (μM).

121. The method according to any one of claims 105 - 120, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

122. The method according to claim 121, wherein the glycogen kinase inhibitor comprises CHIR99021.

123. The method according to claim 122, wherein the glycogen kinase inhibitor comprises CHIR99021.

124. The method according to claim 123, wherein CHIR99021 is present in the composition at a concentration of from about 0.5 micromolar (μM) to about 50 μM.

125. The method according to claim 124, wherein CHIR99021 is present in the composition at a concentration of from about 1 μM to about 25 μM.

126. The method according to claim 125, wherein CHIR99021 is present in the composition at a concentration of from about 2 μM to about 12.5 μM.

127. The method according to claim 126, wherein CHIR99021 is present in the composition at a concentration of about 5 μM.

128. The method according to any one of claims 105 - 127, wherein the TGFβ receptor inhibitor is an ALK5 inhibitor.

129. The method according to claim 128, wherein the TGFβ receptor inhibitor comprises E - 616452, A83 - 01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334, optionally, wherein the TGFβ receptor inhibitor comprises E - 616452.

130. The method according to claim 129, wherein E - 616452 is present in the composition at a concentration of from about 1 micromolar (μM) to about 100 μM.

131. The method according to claim 130, wherein E - 616452 is present in the composition at a concentration of from about 2 μM to about 50 μM.

132. The method according to claim 131, wherein E - 616452 is present in the composition at a concentration of from about 4 μM to about 25 μM.

133. The method according to claim 132, wherein E - 616452 is present in the composition at a concentration of about 10 μM.

134. The method according to any one of claims 105-133, wherein the c-Jun kinase inhibitor comprises JNKIN8, JNKIN7, JNKIN5 or JNKIN12.

135. The method according to claim 134, wherein the c-Jun kinase inhibitor comprises JNKIN8.

136. The method according to claim 135, wherein JNKIN8 is present in the composition at a concentration of about 0.05 micromoles (μM) to about 50 μM.

137. The method according to claim 136, wherein JNKIN8 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

138. The method according to claim 137, wherein JNKIN8 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

139. The method according to claim 138, wherein JNKIN8 is present in the composition at a concentration of about 0.5 μM.

140. The method according to any one of claims 105-139, wherein the composition further comprises a CBP / p300 bromodomain inhibitor.

141. The method according to claim 140, wherein the CBP / p300 bromodomain inhibitor comprises SGC-CBP30, I-CBP112, GNE272 or GNE409.

142. The method according to claim 141, wherein the CBP / p300 bromodomain inhibitor comprises SGC-CBP30.

143. The method according to claim 142, wherein SGC-CBP30 is present in the composition at a concentration of about 0.2 micromoles (μM) to about 20 μM.

144. The method according to claim 143, wherein SGC-CBP30 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

145. The method according to claim 144, wherein SGC-CBP30 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

146. The method according to claim 145, wherein SGC-CBP30 is present in the composition at a concentration of about 2 μM.

147. The method according to any one of claims 105-146, wherein the composition further comprises one or more of a SETD2 inhibitor, an Akt inhibitor or a casein kinase 2 inhibitor.

148. The method according to claim 147, wherein the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719 or MMSET-IN-1.

149. The method according to claim 148, wherein the SETD2 inhibitor comprises SETD2-IN-1.

150. The method according to claim 149, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.05 μM to about 5 μM.

151. The method according to claim 150, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

152. The method according to claim 151, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

153. The method according to claim 152, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.4 μM.

154. The method according to any one of claims 147-153, wherein the Akt inhibitor comprises an AKT kinase inhibitor.

155. The method according to claim 154, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.1 μM to about 10 μM.

156. The method according to claim 155, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.2 μM to about 5 μM.

157. The method according to claim 156, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

158. The method according to claim 157, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 1 μM.

159. The method according to claim 158, wherein the casein kinase 2 inhibitor comprises CX-4945, TPP 22 or ellagic acid.

160. The method according to any one of claims 147-159, wherein the casein kinase 2 inhibitor comprises CX-4945.

161. The method according to claim 160, wherein CX-4945 is present in the composition at a concentration of about 0.08 μM to about 8 μM.

162. The method according to claim 161, wherein CX-4945 is present in the composition at a concentration of about 0.16 μM to about 4 μM.

163. The method according to claim 162, wherein CX-4945 is present in the composition at a concentration of about 0.32 μM to about 2 μM.

164. The method according to claim 163, wherein CX-4945 is present in the composition at a concentration of about 0.8 μM.

165. The method according to any one of claims 105-164, wherein the composition further comprises one or more of a Menin-MLL interaction inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor or a BMP receptor / AMPK inhibitor.

166. The method according to claim 165, wherein the Menin-MLL interaction inhibitor comprises VTP50469, MI3454 or WDR5-IN-4.

167. The method according to claim 166, wherein the Menin-MLL interaction inhibitor comprises VTP50469.

168. The method according to claim 167, wherein VTP50469 is present in the composition at a concentration of from about 0.05 micromoles (μM) to about 5 μM.

169. The method according to claim 168, wherein VTP50469 is present in the composition at a concentration of from about 0.1 μM to about 2.5 μM.

170. The method according to claim 169, wherein VTP50469 is present in the composition at a concentration of from about 0.2 μM to about 1.25 μM.

171. The method according to claim 170, wherein VTP50469 is present in the composition at a concentration of about 0.5 μM.

172. The method according to any one of claims 165 - 171, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5, or human SHH.

173. The method according to claim 172, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG.

174. The method according to claim 173, wherein SAG is present in the composition at a concentration of from about 0.05 micromoles (μM) to about 5 μM.

175. The method according to claim 174, wherein SAG is present in the composition at a concentration of from about 0.1 μM to about 2.5 μM.

176. The method according to claim 175, wherein SAG is present in the composition at a concentration of from about 0.2 μM to about 1.25 μM.

177. The method according to claim 176, wherein SAG is present in the composition at a concentration of about 0.5 μM.

178. The method according to any one of claims 165 - 177, wherein the ROCK inhibitor comprises Y-27632 or thiazovivin.

179. The method according to claim 178, wherein the ROCK inhibitor comprises Y-27632.

180. The method according to claim 179, wherein Y-27632 is present in the composition at a concentration of from about 1 μM to about 100 μM.

181. The method according to claim 180, wherein Y-27632 is present in the composition at a concentration of from about 2 μM to about 50 μM.

182. The method according to claim 181, wherein Y-27632 is present in the composition at a concentration of from about 4 μM to about 25 μM.

183. The method according to claim 182, wherein Y-27632 is present in the composition at a concentration of about 10 μM.

184. The method according to any one of claims 165 - 183, wherein the BMP receptor / AMPK inhibitor comprises dihydrodeoxymorphine.

185. The method according to claim 184, wherein dihydrodeoxymorphine is present in the composition at a concentration of from about 0.05 μM to about 5 μM.

186. The method according to claim 185, wherein dihydrodeoxymorphine is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

187. The method according to claim 186, wherein dihydrodeoxymorphine is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

188. The method according to claim 187, wherein dihydrodeoxymorphine is present in the composition at a concentration of about 0.5 μM.

189. The method according to any one of claims 105 - 188, wherein the composition further comprises a RAR agonist.

190. The method according to claim 189, wherein the RAR agonist comprises TTNPB, Ch55 or AM580.

191. The method according to claim 190, wherein the RAR agonist comprises TTNPB.

192. The method according to claim 191, wherein TTNPB is present in the composition at a concentration of about 0.2 μM to about 20 μM.

193. The method according to claim 192, wherein TTNPB is present in the composition at a concentration of about 0.4 μM to about 10 μM.

194. The method according to claim 193, wherein TTNPB is present in the composition at a concentration of about 0.8 μM to about 5 μM.

195. The method according to claim 194, wherein TTNPB is present in the composition at a concentration of about 2 μM.

196. The method according to any one of claims 105 - 195, wherein the composition further comprises one or more of a Dot1L inhibitor, a Jak1 / Jak2 inhibitor or a p38 MAPK inhibitor.

197. The method according to claim 196, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

198. The method according to claim 197, wherein the Dot1L inhibitor comprises EPZ5676.

199. The method according to claim 198, wherein EPZ5676 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

200. The method according to claim 199, wherein EPZ5676 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

201. The method according to claim 200, wherein EPZ5676 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

202. The method according to claim 201, wherein EPZ5676 is present in the composition at a concentration of about 2 μM.

203. The method according to any one of claims 197 - 202, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib.

204. The method according to claim 203, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib.

205. The method according to claim 204, wherein ruxolitinib is present in the composition at a concentration of from about 0.1 μM to about 10 μM.

206. The method according to claim 205, wherein ruxolitinib is present in the composition at a concentration of from about 0.2 μM to about 5 μM.

207. The method according to claim 206, wherein ruxolitinib is present in the composition at a concentration of from about 0.4 μM to about 2.5 μM.

208. The method according to claim 207, wherein ruxolitinib is present in the composition at a concentration of about 1 μM.

209. The method according to any one of claims 197 - 208, wherein the p38 MAPK inhibitor comprises BIRB796, SB203580 or SB202190.

210. The method according to claim 209, wherein the p38 MAPK inhibitor comprises BIRB796.

211. The method according to claim 210, wherein BIRB796 is present in the composition at a concentration of from about 0.2 μM to about 20 μM.

212. The method according to claim 211, wherein BIRB796 is present in the composition at a concentration of from about 0.4 μM to about 10 μM.

213. The method according to claim 212, wherein BIRB796 is present in the composition at a concentration of from about 0.8 μM to about 5 μM.

214. The method according to claim 213, wherein BIRB796 is present in the composition at a concentration of about 2 μM.

215. The method according to any one of claims 105 - 214, wherein the method comprises culturing a cell population in the composition for up to about 20 days.

216. The method according to claim 215, wherein the method comprises culturing a cell population in the composition for up to about 16 days.

217. The method according to claim 216, wherein the method comprises culturing a cell population in the composition for about 4 days to about 16 days.

218. The method according to any one of claims 105 - 217, wherein the method results in the transformation of epithelial cells into intermediate plastic state cells expressing LIN28A and SALL4, and one or more of MSX2, NMYC, SDC1, WNT4, FGF19 or TOP2A.

219. The method according to claim 218, wherein the intermediate plastic state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2.

220. The method according to claim 219, wherein the intermediate plastic state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2 or LEF1.

221. The method according to claim 220, wherein the intermediate plastic state cells further express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2.

222. The method according to any one of claims 105 - 221, wherein the intermediate plastic state cells or their progeny comprise a genetic modification.

223. The method according to claim 222, wherein the genetic modification comprises an exogenous nucleic acid sequence.

224. The method according to claim 223, wherein the exogenous nucleic acid sequence encodes a polypeptide.

225. The method according to claim 223 or claim 224, wherein the exogenous nucleic acid sequence comprises a sequence of a non - coding nucleic acid molecule.

226. The method according to any one of claims 222 - 225, wherein the genetic modification comprises an alteration of a genomic sequence.

227. The method according to any one of claims 222 - 226, wherein the genetic modification reduces the immunogenicity of the intermediate plastic state cells or their progeny.

228. A method of reprogramming somatic cells, comprising contacting a cell population comprising somatic cells with a composition comprising one or more of the following: (a). A glycogen kinase inhibitor; (b). A TGFβ receptor inhibitor; (c). A RAR agonist; and (d). An Akt inhibitor or a SETD2 inhibitor.

229. The method according to claim 228, wherein the somatic cells comprise primary human adult adipose - derived mesenchymal stromal cells (hADSC).

230. The method according to claim 228, wherein the somatic cells comprise fibroblasts.

231. The method according to any one of claims 228 - 230, wherein during the contacting, the cell population is incubated with up to about 10% atmospheric oxygen.

232. The method according to claim 231, wherein during the contacting, the cell population is incubated with up to about 5% atmospheric oxygen.

233. The method according to any one of claims 228 - 232, wherein the glycogen kinase inhibitor comprises CHIR99021.

234. The method according to claim 233, wherein CHIR99021 is present in the composition at a concentration of about 0.5 μM to about 50 μM.

235. The method according to claim 234, wherein CHIR99021 is present in the composition at a concentration of about 1 μM to about 25 μM.

236. The method according to claim 235, wherein CHIR99021 is present in the composition at a concentration of about 2 μM to about 12.5 μM.

237. The method according to claim 236, wherein CHIR99021 is present in the composition at a concentration of about 5 μM.

238. The method according to any one of claims 228 - 237, wherein the TGFβ receptor inhibitor is an ALK5 inhibitor.

239. The method according to claim 238, wherein the TGFβ receptor inhibitor comprises E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334, optionally, wherein the TGFβ receptor inhibitor comprises E-616452.

240. The method according to claim 239, wherein E-616452 is present in the composition at a concentration of about 1 μM to about 100 μM.

241. The method according to claim 240, wherein E-616452 is present in the composition at a concentration of about 2 μM to about 50 μM.

242. The method according to claim 241, wherein E-616452 is present in the composition at a concentration of about 4 μM to about 25 μM.

243. The method according to claim 242, wherein E-616452 is present in the composition at a concentration of about 10 μM.

244. The method according to any one of claims 228-243, wherein the RAR agonist comprises TTNPB, Ch55, or AM580.

245. The method according to claim 244, wherein the RAR agonist comprises TTNPB.

246. The method according to claim 245, wherein TTNPB is present in the composition at a concentration of about 0.2 μM to about 20 μM.

247. The method according to claim 246, wherein TTNPB is present in the composition at a concentration of about 0.4 μM to about 10 μM.

248. The method according to claim 247, wherein TTNPB is present in the composition at a concentration of about 0.8 μM to about 5 μM.

249. The method according to claim 248, wherein TTNPB is present in the composition at a concentration of about 2 μM.

250. The method according to any one of claims 228-249, wherein the composition comprises an Akt inhibitor.

251. The method according to claim 250, wherein the Akt inhibitor comprises an AKT kinase inhibitor.

252. The method according to claim 251, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.1 μM to about 10 μM.

253. The method according to claim 252, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.2 μM to about 5 μM.

254. The method according to claim 253, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

255. The method according to claim 254, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 1 μM.

256. The method according to any one of claims 228-255, wherein the composition comprises a SETD2 inhibitor.

257. The method according to claim 256, wherein the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719 or MMSET-IN-1.

258. The method according to claim 257, wherein the SETD2 inhibitor comprises SETD2-IN-1.

259. The method according to claim 258, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.05 μM to about 5 μM.

260. The method according to claim 259, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

261. The method according to claim 260, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

262. The method according to claim 261, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.4 μM.

263. The method according to any one of claims 228-262, wherein the composition is serum-free.

264. The method according to any one of claims 228-263, wherein the composition is feeder cell-free.

265. The method according to any one of claims 228-264, wherein the composition further comprises an agonist of the G protein-coupled receptor Smoothened or an inhibitor of the Menin-MLL interaction.

266. The method according to claim 265, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5 or human SHH.

267. The method according to claim 266, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG.

268. The method according to claim 267, wherein SAG is present in the composition at a concentration of about 0.05 μM to about 5 μM.

269. The method according to claim 268, wherein SAG is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

270. The method according to claim 269, wherein SAG is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

271. The method according to claim 270, wherein SAG is present in the composition at a concentration of about 0.5 μM.

272. The method according to any one of claims 266-271, wherein the inhibitor of the Menin-MLL interaction comprises VTP50469, MI3454 or WDR5-IN-4.

273. The method according to claim 272, wherein the inhibitor of the Menin-MLL interaction comprises VTP50469.

274. The method according to claim 273, wherein VTP50469 is present in the composition at a concentration of about 0.05 μM to about 5 μM.

275. The method according to claim 274, wherein VTP50469 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

276. The method according to claim 275, wherein VTP50469 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

277. The method according to claim 276, wherein VTP50469 is present in the composition at a concentration of about 0.5 μM.

278. The method according to any one of claims 228-277, wherein the composition further comprises a Jak1 / Jak2 inhibitor, an SAH hydrolase inhibitor, or a Dot1L inhibitor.

279. The method according to claim 278, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib.

280. The method according to claim 279, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib.

281. The method according to claim 280, wherein ruxolitinib is present in the composition at a concentration of about 0.1 μM to about 10 μM.

282. The method according to claim 281, wherein ruxolitinib is present in the composition at a concentration of about 0.2 μM to about 5 μM.

283. The method according to claim 282, wherein ruxolitinib is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

284. The method according to claim 283, wherein ruxolitinib is present in the composition at a concentration of about 1 μM.

285. The method according to any one of claims 279-284, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox, or DZA.

286. The method according to claim 285, wherein the SAH hydrolase inhibitor comprises DZNep.

287. The method according to claim 286, wherein DZNep is present in the second composition at a concentration of about 0.02 μM to about 2 μM.

288. The method according to claim 287, wherein DZNep is present in the second composition at a concentration of about 0.04 μM to about 1 μM.

289. The method according to claim 288, wherein DZNep is present in the second composition at a concentration of about 0.08 μM to about 0.5 μM.

290. The method according to claim 299, wherein DZNep is present in the second composition at a concentration of about 0.2 μM.

291. The method according to any one of claims 279-290, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

292. The method according to claim 291, wherein the Dot1L inhibitor comprises EPZ5676.

293. The method according to claim 292, wherein EPZ5676 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

294. The method according to claim 293, wherein EPZ5676 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

295. The method according to claim 294, wherein EPZ5676 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

296. The method according to claim 295, wherein EPZ5676 is present in the composition at a concentration of about 2 μM.

297. The method according to any one of claims 228 - 296, wherein the method comprises culturing a cell population in the composition for up to about 20 days.

298. The method according to claim 297, wherein the method comprises culturing a cell population in the composition for up to about 12 days.

299. The method according to claim 298, wherein the method comprises culturing a cell population in the composition for about 4 days to about 12 days.

300. The method according to any one of claims 228 - 299, wherein the method results in the conversion of somatic cells into epithelial - like cells expressing LIN28A.

301. The method according to claim 300, wherein the epithelial - like cells express one or more of KRT18, KRT19, WT1, NMYC, WNT2B, PAX8, SMAD3, GLI3, or TBX2.

302. The method according to claim 301, wherein the epithelial - like cells express one or more of NMYC, WNT2B, PAX8, SMAD3, or GLI3.

303. The method according to claim 302, wherein the epithelial - like cells further express one or more of KRT18, KRT19, WT1, or TBX2.

304. The method according to claim 303, wherein the epithelial - like cells or their progeny contain a genetic modification.

305. The method according to claim 304, wherein the genetic modification comprises an exogenous nucleic acid sequence.

306. The method according to claim 305, wherein the exogenous nucleic acid sequence encodes a polypeptide.

307. The method according to claim 305 or 306, wherein the exogenous nucleic acid sequence comprises a sequence of a non - coding nucleic acid molecule.

308. The method according to any one of claims 228 - 307, wherein the genetic modification comprises an alteration of a genomic sequence.

309. The method according to any one of claims 228 - 308, wherein the genetic modification reduces the immunogenicity of the epithelial - like cells or their progeny.

310. A method for producing pluripotent stem cells, comprising contacting a cell population comprising intermediate plastic state cells or their progeny with a composition comprising: (a). A MEK inhibitor; (b). A B - Raf inhibitor; and (c). Histone deacetylase inhibitors; thereby producing pluripotent stem cells, wherein the intermediate plastic state cells express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19 or TOP2A.

311. The method according to claim 310, wherein during the contact, the cell population is incubated with about 21% atmospheric oxygen.

312. The method according to claim 310 or claim 311, wherein the MEK inhibitor comprises PD0325901, AZD8330 or TAK-733.

313. The method according to claim 312, wherein the MEK inhibitor comprises PD0325901.

314. The method according to claim 313, wherein PD0325901 is present in the third composition at a concentration of about 0.1 μM to about 10 μM.

315. The method according to claim 314, wherein PD0325901 is present in the third composition at a concentration of about 0.2 μM to about 5 μM.

316. The method according to claim 315, wherein PD0325901 is present in the third composition at a concentration of about 0.4 μM to about 2.5 μM.

317. The method according to claim 316, wherein PD0325901 is present in the third composition at a concentration of about 1 μM.

318. The method according to any one of claims 310-317, wherein the B-Raf inhibitor comprises SB590885, vemurafenib, RAF265 or PLX4720.

319. The method according to claim 318, wherein the B-Raf inhibitor comprises SB590885.

320. The method according to claim 319, wherein SB590885 is present in the composition at a concentration of about 0.05 μM to about 5 μM.

321. The method according to claim 320, wherein SB590885 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

322. The method according to claim 321, wherein SB590885 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

323. The method according to claim 322, wherein SB590885 is present in the composition at a concentration of about 0.5 μM.

324. The method according to any one of claims 310-323, wherein the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275 or HDACi I.

325. The method according to claim 324, wherein the histone deacetylase inhibitor comprises VPA.

326. The method according to claim 325, wherein VPA is present in the composition at a concentration of about 0.1 millimolar (mM) to 10 mM.

327. The method according to claim 326, wherein VPA is present in the composition at a concentration of about 0.2 mM to 5 mM.

328. The method according to claim 327, wherein VPA is present in the composition at a concentration of about 0.4 mM to 2.5 mM.

329. The method according to claim 328, wherein VPA is present in the composition at a concentration of about 1 mM.

330. The method according to any one of claims 310 - 329, wherein the composition further comprises one or more of a Wnt inhibitor, a glycogen kinase inhibitor, or a ROCK inhibitor.

331. The method according to claim 330, wherein the composition further comprises a Wnt inhibitor.

332. The method according to claim 331, wherein the Wnt inhibitor comprises IWR-1 or IWP-2.

333. The method according to claim 332, wherein the Wnt inhibitor comprises IWR-1.

334. The method according to claim 333, wherein the Wnt inhibitor comprises IWP-2.

335. The method according to claim 334, wherein IWP-2 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

336. The method according to claim 335, wherein IWP-2 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

337. The method according to claim 336, wherein IWP-2 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

338. The method according to claim 337, wherein IWP-2 is present in the composition at a concentration of about 2 μM.

339. The method according to any one of claims 330 - 338, wherein the composition further comprises a glycogen kinase inhibitor.

340. The method according to claim 339, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

341. The method according to claim 340, wherein the glycogen kinase inhibitor comprises CHIR99021.

342. The method according to claim 341, wherein CHIR99021 is present in the composition at a concentration of about 0.1 micromolar (μM) to about 10 μM.

343. The method according to claim 342, wherein CHIR99021 is present in the composition at a concentration of about 0.2 μM to about 5 μM.

344. The method according to claim 343, wherein CHIR99021 is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

345. The method according to claim 344, wherein CHIR99021 is present in the composition at a concentration of about 1 μM.

346. The method according to any one of claims 330 - 345, wherein the composition further comprises a ROCK inhibitor.

347. The method according to claim 346, wherein the ROCK inhibitor comprises Y-27632 or thiazovivin.

348. The method according to claim 347, wherein the ROCK inhibitor comprises Y-27632.

349. The method according to claim 348, wherein Y-27632 is present in the composition at a concentration of about 1 μM to about 100 μM.

350. The method according to claim 349, wherein Y-27632 is present in the composition at a concentration of about 2 μM to about 50 μM.

351. The method according to claim 350, wherein Y-27632 is present in the composition at a concentration of about 4 μM to about 25 μM.

352. The method according to claim 351, wherein Y-27632 is present in the composition at a concentration of about 10 μM.

353. The method according to any one of claims 310-352, wherein the composition further comprises one or more of a histone demethylation inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

354. The method according to claim 353, wherein the composition further comprises a histone demethylation inhibitor.

355. The method according to claim 354, wherein the histone demethylation inhibitor comprises tranylcypromine.

356. The method according to claim 355, wherein tranylcypromine is present in the composition at a concentration of about 1 μM to about 100 μM.

357. The method according to claim 356, wherein tranylcypromine is present in the composition at a concentration of about 2 μM to about 50 μM.

358. The method according to claim 357, wherein tranylcypromine is present in the composition at a concentration of about 4 μM to about 25 μM.

359. The method according to claim 358, wherein tranylcypromine is present in the composition at a concentration of about 10 μM.

360. The method according to any one of claims 354-359, wherein the composition further comprises a Dot1L inhibitor.

361. The method according to claim 360, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

362. The method according to claim 361, wherein the Dot1L inhibitor comprises EPZ5676.

363. The method according to claim 362, wherein EPZ5676 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

364. The method according to claim 363, wherein EPZ5676 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

365. The method according to claim 364, wherein EPZ5676 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

366. The method according to claim 365, wherein EPZ5676 is present in the composition at a concentration of about 2 μM.

367. The method according to any one of claims 354 - 366, wherein the composition further comprises a SAH hydrolase inhibitor.

368. The method according to claim 367, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

369. The method according to claim 368, wherein the SAH hydrolase inhibitor comprises DZNep.

370. The method according to claim 369, wherein DZNep is present in the composition at a concentration of about 0.02 μM to about 20 μM.

371. The method according to claim 370, wherein DZNep is present in the composition at a concentration of about 0.04 μM to about 10 μM.

372. The method according to claim 371, wherein DZNep is present in the composition at a concentration of about 0.08 μM to about 5 μM.

373. The method according to claim 372, wherein DZNep is present in the composition at a concentration of about 0.2 μM.

374. The method according to any one of claims 310 - 373, wherein the contacting comprises culturing a cell population in the composition.

375. The method according to claim 374, further comprising, after culturing for about 5 days, replacing the composition with a second composition for culturing.

376. The method according to claim 375, wherein the second composition comprises a histone deacetylase inhibitor.

377. The method according to claim 376, wherein the concentration of the histone deacetylase inhibitor in the second composition is about 50% of the concentration of the histone deacetylase inhibitor in the composition.

378. The method according to claim 377, further comprising, after culturing in the second composition for about 5 days, replacing the second composition with a third composition for culturing.

379. The method according to claim 378, wherein the third composition does not comprise a histone deacetylase inhibitor, a histone demethylation inhibitor, a Dot1L inhibitor or a SAH hydrolase inhibitor.

380. The method according to any one of claims 310 - 379, wherein the method comprises culturing a cell population in the composition for up to about 20 days.

381. The method according to claim 380, wherein the method comprises culturing a cell population in the composition for up to about 12 days.

382. The method according to claim 381, wherein the method comprises culturing a cell population in the composition for about 4 days to about 12 days.

383. The method according to any one of claims 310 - 382, wherein the method causes intermediate plastic state cells or their progeny to transform into pluripotent stem cells.

384. The method according to claim 383, wherein the pluripotent stem cells express one or more of OCT4, SOX2 or NANOG.

385. The method according to claim 384, wherein the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DPPA5, DNMT3L, REX1 or UTF1.

386. The method according to claim 385, wherein the pluripotent cells express one or more of FGF4, ZFP57, DPPA5 or REX1.

387. The method according to claim 386, wherein the pluripotent cells further express one or more of DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DPPA5, DNMT3L, REX1 or UTF1.

388. The method according to any one of claims 310 - 387, wherein the pluripotent stem cells or their progeny comprise a genetic modification.

389. The method according to claim 388, wherein the genetic modification comprises an exogenous nucleic acid sequence.

390. The method according to claim 389, wherein the exogenous nucleic acid sequence encodes a polypeptide.

391. The method according to claim 389 or claim 390, wherein the exogenous nucleic acid sequence comprises a sequence of a non-coding nucleic acid molecule.

392. The method according to any one of claims 310 - 391, wherein the genetic modification comprises an alteration of a genomic sequence.

393. The method according to any one of claims 310 - 392, wherein the genetic modification reduces the immunogenicity of the pluripotent stem cells or their progeny.

394. An isolated cell population comprising cells in an intermediate plastic state, the cells in the intermediate plastic state expressing: (a). LIN28A and SALL4; (b). one or more of MSX2, NMYC, WNT4, FGF19 or TOP2A; and (c). one or more of MSX1, HOXB9, WT1, GATA2, HMGA2 or LEF1.

395. The isolated cell population according to claim 394, wherein the cells in the intermediate plastic state further express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2.

396. The isolated cell population according to claim 394 or claim 395, wherein the cells in the intermediate plastic state comprise a genetic modification.

397. The isolated cell population according to any one of claims 394 - 396, wherein the genetic modification comprises an exogenous nucleic acid sequence.

398. The isolated cell population according to claim 397, wherein the exogenous nucleic acid sequence encodes a polypeptide.

399. The isolated cell population according to claim 397 or claim 398, wherein the exogenous nucleic acid sequence comprises a sequence of a non-coding nucleic acid molecule.

400. An isolated cell population according to any one of claims 396 - 399, wherein said genetic modification comprises an alteration of a genomic sequence.

401. An isolated cell population according to any one of claims 396 - 400, wherein said genetic modification reduces the immunogenicity of said intermediate plastic state cells.

402. A composition comprising intermediate plastic state cells expressing LIN28A, SALL4, and one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A; and one or more of a glycogen kinase inhibitor, a TGFβ receptor inhibitor, a RAR agonist, a c-Jun kinase inhibitor, a CBP / p300 bromodomain inhibitor, a SAH hydrolase inhibitor, or an adenosine kinase inhibitor, a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, a BMP receptor / AMPK inhibitor, a Jak1 / Jak2 inhibitor, a p38 MAPK inhibitor, an Akt inhibitor, a casein kinase 2 inhibitor.

403. The composition according to claim 402, wherein said glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

404. The composition according to claim 403, wherein said glycogen kinase inhibitor comprises CHIR99021.

405. The composition according to any one of claims 402 - 404, wherein said TGFβ receptor inhibitor comprises E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334.

406. The composition according to claim 405, wherein said TGFβ receptor inhibitor comprises E-616452.

407. The composition according to claim 406, wherein said RAR agonist comprises TTNPB, Ch55, or AM580.

408. The composition according to claim 407, wherein said RAR agonist comprises TTNPB.

409. The composition according to any one of claims 402 - 408, wherein said c-Jun kinase inhibitor comprises JNKIN7, JNKIN5, or JNKIN12.

410. The composition according to claim 409, wherein said c-Jun kinase inhibitor comprises JNKIN8.

411. The composition according to any one of claims 402 - 410, wherein said CBP / p300 bromodomain inhibitor comprises SGC-CBP30, I-CBP112, GNE272, or GNE409.

412. The composition according to claim 411, wherein said CBP / p300 bromodomain inhibitor comprises SGC-CBP30.

413. The composition according to any one of claims 402-412, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

414. The composition according to claim 413, wherein the SAH hydrolase inhibitor comprises DZNep.

415. The composition according to any one of claims 402-414, wherein the adenosine kinase inhibitor comprises 5-iodotubercidin or ABT 702.

416. The composition according to claim 415, wherein the adenosine kinase inhibitor comprises 5-iodotubercidin (5-ITU).

417. The composition according to any one of claims 402-416, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

418. The composition according to claim 417, wherein the Dot1L inhibitor comprises EPZ5676.

419. The composition according to any one of claims 402-418, wherein the Menin-MLL interaction inhibitor comprises VTP50469, MI3454 or WDR5-IN-4.

420. The composition according to claim 419, wherein the Menin-MLL interaction inhibitor comprises VTP50469.

421. The composition according to any one of claims 402-420, wherein the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719 or MMSET-IN-1.

422. The composition according to claim 421, wherein the SETD2 inhibitor comprises SETD2-IN-1.

423. The composition according to any one of claims 402-422, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG, purinomorphamine, Hh-Ag1.5 or human SHH.

424. The composition according to claim 423, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG.

425. The composition according to claim 424, wherein the ROCK inhibitor comprises Y-27632 or thiazovivin.

426. The composition according to claim 425, wherein the ROCK inhibitor comprises Y-27632.

427. The composition according to claim 426, wherein the BMP receptor / AMPK inhibitor comprises dihydrodeoxymorphine.

428. The composition according to any one of claims 402-427, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib.

429. The composition according to claim 428, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib.

430. The composition according to any one of claims 402 - 429, wherein the p38 MAPK inhibitor comprises BIRB796, SB203580 or SB202190.

431. The composition according to claim 430, wherein the p38 MAPK inhibitor comprises BIRB796.

432. The composition according to any one of claims 402 - 431, wherein the Akt inhibitor comprises an AKT kinase inhibitor.

433. The composition according to any one of claims 402 - 432, wherein the casein kinase 2 inhibitor comprises CX - 4945, TPP 22 or ellagic acid.

434. The composition according to claim 433, wherein the casein kinase 2 inhibitor comprises CX - 4945.

435. A composition comprising: epithelial - like cells expressing LIN28A; and (a). an SAH hydrolase inhibitor or an adenosine kinase inhibitor; (b). a glycogen kinase inhibitor; (c). a TGFβ receptor inhibitor; and (d). a c - Jun kinase inhibitor.

436. The composition according to claim 435, further comprising a CBP / p300 bromodomain inhibitor.

437. A composition comprising: (a). an SAH hydrolase inhibitor or an adenosine kinase inhibitor; (b). a glycogen kinase inhibitor; (c). a TGFβ receptor inhibitor; (d). a c - Jun kinase inhibitor; and (e). a CBP / p300 bromodomain inhibitor.

438. The composition according to any one of claims 435 - 437, wherein the composition comprises an adenosine kinase inhibitor.

439. The composition according to claim 438, wherein the adenosine kinase inhibitor comprises 5 - iodotubercidin or ABT 702.

440. The composition according to claim 439, wherein the adenosine kinase inhibitor comprises 5 - iodotubercidin (5 - ITU).

441. The composition according to claim 440, wherein 5 - ITU is present in the composition at a concentration of about 0.05 micromolar (μM) to about 5 μM.

442. The composition according to claim 441, wherein 5 - ITU is present in the composition at a concentration of about 0.1 micromolar μM to about 2.5 μM.

443. The composition according to claim 442, wherein 5 - ITU is present in the composition at a concentration of about 0.2 micromolar μM to about 1 μM.

444. The composition according to claim 443, wherein 5 - ITU is present in the composition at a concentration of about 0.5 μM.

445. The composition according to any one of claims 435 - 444, wherein the composition comprises an SAH hydrolase inhibitor.

446. The composition according to claim 445, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

447. The composition according to claim 446, wherein the SAH hydrolase inhibitor comprises DZNep.

448. The composition according to claim 447, wherein DZNep is present in the composition at a concentration of about 0.02 μM to about 20 μM.

449. The composition according to claim 448, wherein DZNep is present in the composition at a concentration of about 0.04 μM to about 10 μM.

450. The composition according to claim 449, wherein DZNep is present in the composition at a concentration of about 0.08 μM to about 5 μM.

451. The composition according to claim 450, wherein DZNep is present in the composition at a concentration of about 0.2 μM.

452. The composition according to any one of claims 435 - 451, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

453. The composition according to claim 452, wherein the glycogen kinase inhibitor comprises CHIR99021.

454. The composition according to claim 453, wherein CHIR99021 is present in the composition at a concentration of about 0.5 micromolar (μM) to about 50 μM.

455. The composition according to claim 454, wherein CHIR99021 is present in the composition at a concentration of about 1 μM to about 25 μM.

456. The composition according to claim 455, wherein CHIR99021 is present in the composition at a concentration of about 2 μM to about 12.5 μM.

457. The composition according to claim 456, wherein CHIR99021 is present in the composition at a concentration of about 5 μM.

458. The composition according to any one of claims 435 - 457, wherein the TGFβ receptor inhibitor comprises E - 616452, A83 - 01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334.

459. The composition according to claim 458, wherein the TGFβ receptor inhibitor comprises E - 616452.

460. The composition according to claim 459, wherein E - 616452 is present in the composition at a concentration of about 1 micromolar (μM) to about 100 μM.

461. The composition according to claim 460, wherein E - 616452 is present in the composition at a concentration of about 2 μM to about 50 μM.

462. The composition according to claim 461, wherein E - 616452 is present in the composition at a concentration of about 4 μM to about 25 μM.

463. The composition according to claim 462, wherein E - 616452 is present in the composition at a concentration of about 10 μM.

464. The composition according to any one of claims 435 - 463, wherein the c-Jun kinase inhibitor comprises JNKIN8, JNKIN7, JNKIN5 or JNKIN12.

465. The composition according to claim 464, wherein the c-Jun kinase inhibitor comprises JNKIN8.

466. The composition according to claim 465, wherein JNKIN is present in the composition at a concentration of from about 0.05 micromoles (μM) to about 50 μM.

467. The composition according to claim 466, wherein JNKIN is present in the composition at a concentration of from about 0.1 μM to about 2.5 μM.

468. The composition according to claim 467, wherein JNKIN is present in the composition at a concentration of from about 0.2 μM to about 1.25 μM.

469. The composition according to claim 468, wherein JNKIN is present in the composition at a concentration of about 0.5 μM.

470. The composition according to any one of claims 436 - 469, wherein the CBP / p300 bromodomain inhibitor comprises SGC-CBP30, I-CBP112, GNE272 or GNE409.

471. The composition according to claim 470, wherein the CBP / p300 bromodomain inhibitor comprises SGC-CBP30.

472. The composition according to claim 471, wherein SGC-CBP30 is present in the composition at a concentration of from about 0.2 μM to about 20 μM.

473. The composition according to claim 472, wherein SGC-CBP30 is present in the composition at a concentration of from about 0.4 μM to about 10 μM.

474. The composition according to claim 473, wherein SGC-CBP30 is present in the composition at a concentration of from about 0.8 μM to about 5 μM.

475. The composition according to claim 474, wherein SGC-CBP30 is present in the composition at a concentration of about 2 μM.

476. The composition according to any one of claims 435 - 475, further comprising one or more of a SETD2 inhibitor, an Akt inhibitor or a casein kinase 2 inhibitor.

477. The composition according to claim 476, wherein the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719 or MMSET-IN-1.

478. The composition according to claim 477, wherein the SETD2 inhibitor comprises SETD2-IN-1.

479. The composition according to claim 478, wherein SETD2-IN-1 is present in the composition at a concentration of from about 0.05 μM to about 5 μM.

480. The composition according to claim 479, wherein SETD2-IN-1 is present in the composition at a concentration of from about 0.1 μM to about 2.5 μM.

481. The composition according to claim 480, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

482. The composition according to claim 481, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.4 μM.

483. The composition according to any one of claims 435-482, wherein the Akt inhibitor comprises an AKT kinase inhibitor.

484. The composition according to claim 483, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.1 μM to about 10 μM.

485. The composition according to claim 484, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.2 μM to about 5 μM.

486. The composition according to claim 485, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

487. The composition according to claim 486, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 1 μM.

488. The composition according to any one of claims 435-487, wherein the casein kinase 2 inhibitor comprises CX-4945, TPP 22 or ellagic acid.

489. The composition according to claim 488, wherein the casein kinase 2 inhibitor comprises CX-4945.

490. The composition according to claim 489, wherein CX-4945 is present in the composition at a concentration of about 0.08 μM to about 8 μM.

491. The composition according to claim 490, wherein CX-4945 is present in the composition at a concentration of about 0.16 μM to about 4 μM.

492. The composition according to claim 491, wherein CX-4945 is present in the composition at a concentration of about 0.32 μM to about 2 μM.

493. The composition according to claim 492, wherein CX-4945 is present in the composition at a concentration of about 0.8 μM.

494. The composition according to any one of claims 435-493, further comprising one or more of a Menin-MLL interaction inhibitor, an agonist of the G protein-coupled receptor Smoothened, a ROCK inhibitor, or a BMP receptor / AMPK inhibitor.

495. The composition according to claim 494, wherein the Menin-MLL interaction inhibitor comprises VTP50469, MI3454 or WDR5-IN-4.

496. The composition according to claim 495, wherein the Menin-MLL interaction inhibitor comprises VTP50469.

497. The composition according to claim 496, wherein VTP50469 is present in the composition at a concentration of about 0.05 micromoles (μM) to about 5 μM.

498. The composition according to claim 497, wherein VTP50469 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

499. The composition according to claim 498, wherein VTP50469 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

500. The composition according to claim 499, wherein VTP50469 is present in the composition at a concentration of about 0.5 μM.

501. The composition according to any one of claims 494 - 500, wherein the agonist of the G protein - coupled receptor Smoothened comprises SAG, purmorphamine, Hh - Ag1.5 or human SHH.

502. The composition according to claim 501, wherein the agonist of the G protein - coupled receptor Smoothened comprises SAG.

503. The composition according to claim 502, wherein SAG is present in the composition at a concentration of about 0.05 micromoles (μM) to about 5 μM.

504. The composition according to claim 503, wherein SAG is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

505. The composition according to claim 504, wherein SAG is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

506. The composition according to claim 505, wherein SAG is present in the composition at a concentration of about 0.5 μM.

507. The composition according to any one of claims 494 - 506, wherein the ROCK inhibitor comprises Y - 27632 or thiazovivin.

508. The composition according to claim 507, wherein the ROCK inhibitor comprises Y - 27632.

509. The composition according to claim 508, wherein Y27632 is present in the composition at a concentration of about 1 μM to about 100 μM.

510. The composition according to claim 509, wherein Y27632 is present in the composition at a concentration of about 2 μM to about 50 μM.

511. The composition according to claim 510, wherein Y27632 is present in the composition at a concentration of about 4 μM to about 25 μM.

512. The composition according to claim 511, wherein Y27632 is present in the composition at a concentration of about 10 μM.

513. The composition according to any one of claims 494 - 512, wherein the BMP receptor / AMPK inhibitor comprises dihydrodeoxymorphine.

514. The composition according to claim 513, wherein dihydrodeoxymorphine is present in the composition at a concentration of about 0.05 μM to about 5 μM.

515. The composition according to claim 514, wherein dihydrodeoxymorphine is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

516. The composition according to claim 515, wherein dihydrodeoxymorphine is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

517. The composition according to claim 516, wherein dihydrodeoxymorphine is present in the composition at a concentration of about 0.5 μM.

518. The composition according to any one of claims 435 - 517, further comprising one or more of a Dot1L inhibitor, a Jak1 / Jak2 inhibitor, or a p38 MAPK inhibitor.

519. The composition according to claim 518, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

520. The composition according to claim 519, wherein the Dot1L inhibitor comprises EPZ5676.

521. The composition according to claim 520, wherein EPZ5676 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

522. The composition according to claim 521, wherein EPZ5676 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

523. The composition according to claim 522, wherein EPZ5676 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

524. The composition according to claim 523, wherein EPZ5676 is present in the composition at a concentration of about 2 μM.

525. The composition according to any one of claims 518 - 524, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib.

526. The composition according to claim 525, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib.

527. The composition according to claim 526, wherein ruxolitinib is present in the composition at a concentration of about 0.1 μM to about 10 μM.

528. The composition according to claim 527, wherein ruxolitinib is present in the composition at a concentration of about 0.2 μM to about 5 μM.

529. The composition according to claim 528, wherein ruxolitinib is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

530. The composition according to claim 529, wherein ruxolitinib is present in the composition at a concentration of about 1 μM.

531. The composition according to any one of claims 518 - 530, wherein the p38 MAPK inhibitor comprises BIRB796, SB203580, or SB202190.

532. The composition according to claim 531, wherein the p38 MAPK inhibitor comprises BIRB796.

533. The composition according to claim 532, wherein BIRB796 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

534. The composition according to claim 533, wherein BIRB796 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

535. The composition according to claim 534, wherein BIRB796 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

536. The composition according to claim 535, wherein BIRB796 is present in the composition at a concentration of about 2 μM.

537. The composition according to any one of claims 435 - 536, further comprising a RAR agonist.

538. The composition according to claim 537, wherein the RAR agonist comprises TTNPB, Ch55 or AM580.

539. The composition according to claim 538, wherein the RAR agonist comprises TTNPB.

540. The composition according to claim 539, wherein TTNPB is present in the composition at a concentration of about 0.2 μM to about 20 μM.

541. The composition according to claim 540, wherein TTNPB is present in the composition at a concentration of about 0.4 μM to about 10 μM.

542. The composition according to claim 541, wherein TTNPB is present in the composition at a concentration of about 0.8 μM to about 5 μM.

543. The composition according to claim 542, wherein TTNPB is present in the composition at a concentration of about 2 μM.

544. An isolated cell population comprising epithelial - like cells that express LIN28A and one or more of NMYC, WNT2B, PAX8, SMAD3 or GLI3.

545. The isolated cell population according to claim 544, wherein the isolated cell population comprising epithelial - like cells expresses one or more of KRT18, KRT19, WT1 or TBX2.

546. The isolated cell population according to claim 544 or claim 545, wherein the isolated cell population comprising epithelial - like cells does not express any one of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1 or TWIST2.

547. A composition comprising: epithelial - like cells that express LIN28A; and (a). a glycogen kinase inhibitor, (b). a TGFβ receptor inhibitor, (c). a RAR agonist, and (d). an Akt inhibitor or a SETD2 inhibitor.

548. The composition according to claim 547, wherein the composition comprises an Akt inhibitor.

549. The composition according to claim 548, wherein the Akt inhibitor comprises an AKT kinase inhibitor.

550. The composition according to any one of claims 547 - 549, wherein the composition comprises a SETD2 inhibitor.

551. The composition according to claim 550, wherein the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719 or MMSET-IN-1.

552. The composition according to claim 551, wherein the SETD2 inhibitor comprises SETD2-IN-1.

553. A composition comprising: epithelial-like cells expressing LIN28A and one or more of NMYC, WNT2B, PAX8, SMAD3 or GLI3; and (a). a glycogen kinase inhibitor, (b). a TGFβ receptor inhibitor, and (c). a RAR agonist.

554. The composition according to claim 553, wherein the composition comprises an Akt inhibitor or a SETD2 inhibitor.

555. The composition according to claim 554, wherein the composition comprises an Akt inhibitor.

556. The composition according to claim 555, wherein the Akt inhibitor comprises an AKT kinase inhibitor.

557. The composition according to any one of claims 553-556, wherein the composition comprises a SETD2 inhibitor.

558. The composition according to claim 557, wherein the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719 or MMSET-IN-1.

559. The composition according to claim 558, wherein the SETD2 inhibitor comprises SETD2-IN-1.

560. The composition according to any one of claims 547-559, wherein the composition is serum-free.

561. The composition according to any one of claims 547-560, wherein the composition is feeder cell-free.

562. The composition according to any one of claims 547-561, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

563. The composition according to claim 562, wherein the glycogen kinase inhibitor comprises CHIR99021.

564. The composition according to any one of claims 547-563, wherein the TGFβ receptor inhibitor comprises E-616452, A83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334.

565. The composition according to claim 564, wherein the TGFβ receptor inhibitor comprises E-616452.

566. The composition according to any one of claims 547-565, wherein the RAR agonist comprises TTNPB, Ch55 or AM580.

567. The composition according to claim 566, wherein the RAR agonist comprises TTNPB.

568. The composition according to any one of claims 547-567, which further comprises an agonist of G protein-coupled receptor Smoothened or an inhibitor of Menin-MLL interaction.

569. The composition according to claim 568, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5, or human SHH.

570. The composition according to claim 569, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG.

571. The composition according to any one of claims 568-570, wherein the Menin-MLL interaction inhibitor comprises VTP50469, MI3454, or WDR5-IN-4.

572. The composition according to claim 571, wherein the Menin-MLL interaction inhibitor comprises VTP50469.

573. The composition according to any one of claims 547-572, further comprising a Jak1 / Jak2 inhibitor, an SAH hydrolase inhibitor, and a Dot1L inhibitor.

574. The composition according to claim 573, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib.

575. The composition according to claim 574, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib.

576. The composition according to any one of claims 573-575, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox, or DZA.

577. The composition according to claim 576, wherein the SAH hydrolase inhibitor comprises DZNep.

578. The composition according to any one of claims 573-577, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

579. The composition according to claim 578, wherein the Dot1L inhibitor comprises EPZ5676.

580. A composition comprising: (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, (c) a RAR agonist, and (d) an Akt inhibitor or a SETD2 inhibitor.

581. The composition according to claim 580, wherein the composition further comprises somatic cells.

582. The composition according to claim 581, wherein the somatic cells comprise primary human adult adipose-derived mesenchymal stromal cells (hADSCs).

583. The composition according to claim 582, wherein the somatic cells comprise fibroblasts.

584. The composition according to any one of claims 580-583, wherein the composition is serum-free.

585. The composition according to any one of claims 580-584, wherein the composition is feeder cell-free.

586. The composition according to any one of claims 580-585, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

587. The composition according to claim 586, wherein the glycogen kinase inhibitor comprises CHIR99021.

588. The composition according to claim 587, wherein CHIR99021 is present in the composition at a concentration of about 0.5 micromolar (μM) to about 50 μM.

589. The composition according to claim 588, wherein CHIR99021 is present in the composition at a concentration of about 1 μM to about 25 μM.

590. The composition according to claim 589, wherein CHIR99021 is present in the composition at a concentration of about 2 μM to about 12.5 μM.

591. The composition according to claim 590, wherein CHIR99021 is present in the composition at a concentration of about 5 μM.

592. The composition according to any one of claims 580 - 591, wherein the TGFβ receptor inhibitor is an ALK5 inhibitor.

593. The composition according to claim 592, wherein the TGFβ receptor inhibitor comprises E - 616452, A83 - 01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334, optionally, wherein the TGFβ receptor inhibitor comprises E - 616452.

594. The composition according to claim 593, wherein E - 616452 is present in the composition at a concentration of about 1 μM to about 100 μM.

595. The composition according to claim 594, wherein E - 616452 is present in the composition at a concentration of about 2 μM to about 50 μM.

596. The composition according to claim 595, wherein E - 616452 is present in the composition at a concentration of about 4 μM to about 25 μM.

597. The composition according to claim 596, wherein E - 616452 is present in the composition at a concentration of about 10 μM.

598. The composition according to any one of claims 580 - 597, wherein the RAR agonist comprises TTNPB, Ch55 or AM580.

599. The composition according to claim 598, wherein the RAR agonist comprises TTNPB.

600. The composition according to claim 599, wherein TTNPB is present in the composition at a concentration of about 0.2 μM to about 20 μM.

601. The composition according to claim 600, wherein TTNPB is present in the composition at a concentration of about 0.4 μM to about 10 μM.

602. The composition according to claim 601, wherein TTNPB is present in the composition at a concentration of about 0.8 μM to about 5 μM.

603. The composition according to claim 602, wherein TTNPB is present in the composition at a concentration of about 2 μM.

604. The composition according to any one of claims 580 - 603, wherein the composition comprises an Akt inhibitor.

605. The composition according to claim 604, wherein the Akt inhibitor comprises an AKT kinase inhibitor.

606. The composition according to claim 605, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.1 μM to about 10 μM.

607. The composition according to claim 606, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.2 μM to about 5 μM.

608. The composition according to claim 607, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

609. The composition according to claim 608, wherein the AKT kinase inhibitor is present in the composition at a concentration of about 1 μM.

610. The composition according to any one of claims 580 - 609, wherein the composition comprises a SETD2 inhibitor.

611. The composition according to claim 610, wherein the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719 or MMSET-IN-1.

612. The composition according to claim 611, wherein the SETD2 inhibitor comprises SETD2-IN-1.

613. The composition according to claim 612, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.05 μM to about 5 μM.

614. The composition according to claim 613, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

615. The composition according to claim 614, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

616. The composition according to claim 615, wherein SETD2-IN-1 is present in the composition at a concentration of about 0.4 μM.

617. The composition according to any one of claims 580 - 616, which further comprises an agonist of the G protein-coupled receptor Smoothened or an inhibitor of the Menin-MLL interaction.

618. The composition according to claim 617, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5 or human SHH.

619. The composition according to claim 618, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG.

620. The composition according to claim 619, wherein SAG is present in the composition at a concentration of about 0.05 micromoles (μM) to about 5 μM.

621. The composition according to claim 620, wherein SAG is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

622. The composition according to claim 621, wherein SAG is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

623. The composition according to claim 622, wherein SAG is present in the composition at a concentration of about 0.5 μM.

624. The composition according to any one of claims 617-623, wherein the Menin-MLL interaction inhibitor comprises VTP50469, MI3454 or WDR5-IN-4.

625. The composition according to claim 624, wherein the Menin-MLL interaction inhibitor comprises VTP50469.

626. The composition according to claim 625, wherein VTP50469 is present in the composition at a concentration of about 0.05 micromoles (μM) to about 5 μM.

627. The composition according to claim 626, wherein VTP50469 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

628. The composition according to claim 627, wherein VTP50469 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

629. The composition according to claim 628, wherein VTP50469 is present in the composition at a concentration of about 0.5 μM.

630. The composition according to any one of claims 580-629, further comprising a Jak1 / Jak2 inhibitor, an SAH hydrolase inhibitor, a Dot1L inhibitor.

631. The composition according to claim 630, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib.

632. The composition according to claim 631, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib.

633. The composition according to claim 632, wherein ruxolitinib is present in the composition at a concentration of about 0.1 μM to about 10 μM.

634. The composition according to claim 633, wherein ruxolitinib is present in the composition at a concentration of about 0.2 μM to about 5 μM.

635. The composition according to claim 634, wherein ruxolitinib is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

636. The composition according to claim 635, wherein ruxolitinib is present in the composition at a concentration of about 1 μM.

637. The composition according to any one of claims 630-636, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

638. The composition according to claim 637, wherein the SAH hydrolase inhibitor comprises DZNep.

639. The composition according to claim 638, wherein DZNep is present in the composition at a concentration of about 0.002 μM to about 0.2 μM.

640. The composition according to claim 639, wherein DZNep is present in the composition at a concentration of about 0.004 μM to about 0.1 μM.

641. The composition according to claim 640, wherein DZNep is present in the composition at a concentration of from about 0.008 μM to about 0.05 μM.

642. The composition according to claim 641, wherein DZNep is present in the composition at a concentration of about 0.02 μM.

643. The composition according to any one of claims 630 - 642, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

644. The composition according to claim 643, wherein the Dot1L inhibitor comprises EPZ5676.

645. The composition according to claim 644, wherein EPZ5676 is present in the composition at a concentration of from about 0.2 μM to about 20 μM.

646. The composition according to claim 645, wherein EPZ5676 is present in the composition at a concentration of from about 0.4 μM to about 10 μM.

647. The composition according to claim 646, wherein EPZ5676 is present in the composition at a concentration of from about 0.8 μM to about 5 μM.

648. The composition according to claim 647, wherein EPZ5676 is present in the composition at a concentration of about 2 μM.

649. A composition comprising: intermediate plastic state cells that express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19 or TOP2A; and one or more of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a glycogen kinase inhibitor, a ROCK inhibitor, a histone demethylation inhibitor, a Dot1L inhibitor or a SAH hydrolase inhibitor.

650. The composition according to claim 649, wherein the intermediate plastic state cells express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2.

651. The composition according to claim 649 or claim 650, wherein the MEK inhibitor comprises PD0325901, AZD8330 or TAK-733.

652. The composition according to claim 651, wherein the MEK inhibitor comprises PD0325901.

653. The composition according to claim 652, wherein PD0325901 is present in the third composition at a concentration of from about 0.1 μM to about 10 μM.

654. The composition according to claim 653, wherein PD0325901 is present in the third composition at a concentration of from about 0.2 μM to about 5 μM.

655. The composition according to claim 654, wherein PD0325901 is present in the third composition at a concentration of from about 0.4 μM to about 2.5 μM.

656. The composition according to claim 655, wherein PD0325901 is present in the third composition at a concentration of about 1 μM.

657. The composition according to any one of claims 649 - 656, wherein the B-Raf inhibitor comprises SB590885, vemurafenib, RAF265 or PLX4720.

658. The composition according to claim 657, wherein the B-Raf inhibitor comprises SB590885.

659. The composition according to claim 658, wherein SB590885 is present in the composition at a concentration of about 0.05 μM to about 5 μM.

660. The composition according to claim 659, wherein SB590885 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

661. The composition according to claim 660, wherein SB590885 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

662. The composition according to claim 661, wherein SB590885 is present in the composition at a concentration of about 0.5 μM.

663. The composition according to any one of claims 649 - 662, wherein the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275 or HDACi IV.

664. The composition according to claim 663, wherein the histone deacetylase inhibitor comprises valproic acid (VPA).

665. The composition according to claim 664, wherein VPA is present in the composition at a concentration of about 0.1 millimolar (mM) to 10 mM.

666. The composition according to claim 665, wherein VPA is present in the composition at a concentration of about 0.2 mM to 5 mM.

667. The composition according to claim 666, wherein VPA is present in the composition at a concentration of about 0.4 mM to 2.5 mM.

668. The composition according to claim 667, wherein VPA is present in the composition at a concentration of about 1 mM.

669. The composition according to any one of claims 649 - 668, wherein the histone demethylation inhibitor comprises tranylcypromine.

670. The composition according to claim 669, wherein tranylcypromine is present in the composition at a concentration of about 1 μM to about 100 μM.

671. The composition according to claim 670, wherein tranylcypromine is present in the composition at a concentration of about 2 μM to about 50 μM.

672. The composition according to claim 671, wherein tranylcypromine is present in the composition at a concentration of about 4 μM to about 25 μM.

673. The composition according to claim 672, wherein tranylcypromine is present in the composition at a concentration of about 10 μM.

674. The composition according to any one of claims 649 - 673, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

675. The composition according to claim 674, wherein the Dot1L inhibitor comprises EPZ5676.

676. The composition according to claim 675, wherein EPZ5676 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

677. The composition according to claim 676, wherein EPZ5676 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

678. The composition according to claim 677, wherein EPZ5676 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

679. The composition according to claim 678, wherein EPZ5676 is present in the composition at a concentration of about 2 μM.

680. The composition according to any one of claims 649 - 679, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

681. The composition according to claim 680, wherein the SAH hydrolase inhibitor comprises DZNep.

682. The composition according to claim 681, wherein DZNep is present in the composition at a concentration of about 0.02 μM to about 20 μM.

683. The composition according to claim 682, wherein DZNep is present in the composition at a concentration of about 0.04 μM to about 10 μM.

684. The composition according to claim 683, wherein DZNep is present in the composition at a concentration of about 0.08 μM to about 5 μM.

685. The composition according to claim 684, wherein DZNep is present in the composition at a concentration of about 0.2 μM.

686. The composition according to any one of claims 649 - 685, wherein the Wnt inhibitor comprises IWR-1 or IWP-2.

687. The composition according to claim 686, wherein the Wnt inhibitor comprises IWR-1.

688. The composition according to claim 686 or claim 687, wherein the Wnt inhibitor comprises IWP-2.

689. The composition according to claim 688, wherein IWP-2 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

690. The composition according to claim 689, wherein IWP-2 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

691. The composition according to claim 690, wherein IWP-2 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

692. The composition according to claim 691, wherein IWP-2 is present in the composition at a concentration of about 2 μM.

693. The composition according to any one of claims 649 - 692, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

694. The composition according to claim 693, wherein the glycogen kinase inhibitor comprises CHIR99021.

695. The composition according to claim 694, wherein CHIR99021 is present in the composition at a concentration of about 0.1 micromolar (μM) to about 10 μM.

696. The composition according to claim 695, wherein CHIR99021 is present in the composition at a concentration of about 0.2 μM to about 5 μM.

697. The composition according to claim 696, wherein CHIR99021 is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

698. The composition according to claim 697, wherein CHIR99021 is present in the composition at a concentration of about 1 μM.

699. The composition according to any one of claims 649 - 698, wherein the ROCK inhibitor comprises Y - 27632 or thiazovivin.

700. The composition according to claim 699, wherein the ROCK inhibitor comprises Y - 27632.

701. The composition according to claim 700, wherein Y - 27632 is present in the composition at a concentration of about 1 μM to about 100 μM.

702. The composition according to claim 701, wherein Y - 27632 is present in the composition at a concentration of about 2 μM to about 50 μM.

703. The composition according to claim 702, wherein Y - 27632 is present in the composition at a concentration of about 4 μM to about 25 μM.

704. The composition according to claim 703, wherein Y - 27632 is present in the composition at a concentration of about 10 μM.

705. A composition comprising: (a). a MEK inhibitor, a B - Raf inhibitor, and a histone deacetylase inhibitor; and (b). a histone demethylation inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

706. The composition according to claim 705, wherein the composition further comprises pluripotent stem cells expressing OCT4, SOX2, and NANOG.

707. The composition according to claim 705 or claim 706, wherein the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, or REX1.

708. The composition according to any one of claims 705 - 707, wherein the pluripotent cells express one or more of DPPA4, TDGF1, TRA - 1 - 60, TRA - 1 - 81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1.

709. The composition according to any one of claims 705 - 708, wherein the MEK inhibitor comprises PD0325901, AZD8330 or TAK - 733.

710. The composition according to claim 709, wherein the MEK inhibitor comprises PD0325901.

711. The composition according to any one of claims 705 - 710, wherein the B - Raf inhibitor comprises SB590885, vemurafenib, RAF265 or PLX4720.

712. The composition according to claim 711, wherein the B - Raf inhibitor comprises SB590885.

713. The composition according to any one of claims 705 - 712, wherein the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275 or HDACi IV.

714. The composition according to claim 713, wherein the histone deacetylase inhibitor comprises VPA.

715. The composition according to any one of claims 705 - 714, wherein the composition comprises a histone demethylation inhibitor.

716. The composition according to claim 715, wherein the histone demethylation inhibitor comprises tranylcypromine.

717. The composition according to any one of claims 705 - 716, wherein the composition comprises a Dot1L inhibitor.

718. The composition according to claim 717, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

719. The composition according to claim 718, wherein the Dot1L inhibitor comprises EPZ5676.

720. The composition according to any one of claims 705 - 719, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

721. The composition according to claim 720, wherein the SAH hydrolase inhibitor comprises DZNep.

722. The composition according to any one of claims 705 - 721, further comprising a Wnt inhibitor, a glycogen kinase inhibitor or a ROCK inhibitor.

723. The composition according to claim 722, wherein the composition comprises a Wnt inhibitor.

724. The composition according to claim 723, wherein the Wnt inhibitor comprises IWR - 1 or IWP - 2.

725. The composition according to claim 724, wherein the Wnt inhibitor comprises IWR - 1.

726. The composition according to claim 724 or claim 725, wherein the Wnt inhibitor comprises IWP - 2.

727. The composition according to any one of claims 722 - 726, wherein the composition comprises a glycogen kinase inhibitor.

728. The composition according to claim 727, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

729. The composition according to claim 728, wherein the glycogen kinase inhibitor comprises CHIR99021.

730. The composition according to claim 729, wherein the glycogen kinase inhibitor comprises CHIR98014.

731. The composition according to any one of claims 722-730, wherein the composition comprises a ROCK inhibitor.

732. The composition according to claim 731, wherein the ROCK inhibitor comprises Y-27632 or thiazovivin.

733. The composition according to claim 732, wherein the ROCK inhibitor comprises Y-27632.

734. The composition according to any one of claims 706-733, wherein the pluripotent stem cells comprise a genetic modification.

735. The composition according to claim 734, wherein the genetic modification comprises an exogenous nucleic acid sequence.

736. The composition according to claim 735, wherein the exogenous nucleic acid sequence encodes a polypeptide.

737. The composition according to claim 735 or 736, wherein the exogenous nucleic acid sequence comprises a sequence of a non-coding nucleic acid molecule.

738. The composition according to any one of claims 734-737, wherein the genetic modification comprises an alteration of a genomic sequence.

739. The composition according to any one of claims 734-738, wherein the genetic modification reduces the immunogenicity of the pluripotent stem cells.

740. The composition according to claim 705, wherein the MEK inhibitor comprises PD0325901, AZD8330 or TAK-733.

741. The composition according to claim 740, wherein the MEK inhibitor comprises PD0325901.

742. The composition according to claim 741, wherein PD0325901 is present in the third composition at a concentration of about 0.1 μM to about 10 μM.

743. The composition according to claim 742, wherein PD0325901 is present in the third composition at a concentration of about 0.2 μM to about 5 μM.

744. The composition according to claim 743, wherein PD0325901 is present in the third composition at a concentration of about 0.4 μM to about 2.5 μM.

745. The composition according to claim 744, wherein PD0325901 is present in the third composition at a concentration of about 1 μM.

746. The composition according to claim 705 and any one of claims 740-745, wherein the B-Raf inhibitor comprises SB590885, vemurafenib, RAF265 or PLX4720.

747. The composition according to claim 746, wherein the B-Raf inhibitor comprises SB590885.

748. The composition according to claim 747, wherein SB590885 is present in the composition at a concentration of about 0.05 μM to about 5 μM.

749. The composition according to claim 748, wherein SB590885 is present in the composition at a concentration of about 0.1 μM to about 2.5 μM.

750. The composition according to claim 749, wherein SB590885 is present in the composition at a concentration of about 0.2 μM to about 1.25 μM.

751. The composition according to claim 750, wherein SB590885 is present in the composition at a concentration of about 0.5 μM.

752. The composition according to any one of claims 705 and 740 - 751, wherein the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275, or HDACi IV.

753. The composition according to claim 752, wherein the histone deacetylase inhibitor comprises valproic acid (VPA).

754. The composition according to claim 753, wherein VPA is present in the composition at a concentration of about 0.1 millimolar (mM) to 10 mM.

755. The composition according to claim 754, wherein VPA is present in the composition at a concentration of about 0.2 mM to 5 mM.

756. The composition according to claim 755, wherein VPA is present in the composition at a concentration of about 0.4 mM to 2.5 mM.

757. The composition according to claim 756, wherein VPA is present in the composition at a concentration of about 1 mM.

758. The composition according to any one of claims 705 and 740 - 757, wherein the histone demethylation inhibitor comprises tranylcypromine.

759. The composition according to claim 758, wherein tranylcypromine is present in the composition at a concentration of about 1 μM to about 100 μM.

760. The composition according to claim 759, wherein tranylcypromine is present in the composition at a concentration of about 2 μM to about 50 μM.

761. The composition according to claim 760, wherein tranylcypromine is present in the composition at a concentration of about 4 μM to about 25 μM.

762. The composition according to claim 761, wherein tranylcypromine is present in the composition at a concentration of about 10 μM.

763. The composition according to any one of claims 705 and 740 - 762, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

764. The composition according to claim 763, wherein the Dot1L inhibitor comprises EPZ5676.

765. The composition according to claim 764, wherein EPZ5676 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

766. The composition according to claim 765, wherein EPZ5676 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

767. The composition according to claim 766, wherein EPZ5676 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

768. The composition according to claim 767, wherein EPZ5676 is present in the composition at a concentration of about 2 μM.

769. The composition according to any one of claims 705 and 740 - 768, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

770. The composition according to claim 769, wherein the SAH hydrolase inhibitor comprises DZNep.

771. The composition according to claim 770, wherein DZNep is present in the composition at a concentration of about 0.02 μM to about 20 μM.

772. The composition according to claim 771, wherein DZNep is present in the composition at a concentration of about 0.04 μM to about 10 μM.

773. The composition according to claim 772, wherein DZNep is present in the composition at a concentration of about 0.08 μM to about 5 μM.

774. The composition according to claim 773, wherein DZNep is present in the composition at a concentration of about 0.2 μM.

775. The composition according to any one of claims 705 and 740 - 774, wherein the Wnt inhibitor comprises IWR-1 or IWP-2.

776. The composition according to claim 775, wherein the Wnt inhibitor comprises IWR-1.

777. The composition according to claim 775 or claim 776, wherein the Wnt inhibitor comprises IWP-2.

778. The composition according to claim 777, wherein IWP-2 is present in the composition at a concentration of about 0.2 μM to about 20 μM.

779. The composition according to claim 778, wherein IWP-2 is present in the composition at a concentration of about 0.4 μM to about 10 μM.

780. The composition according to claim 779, wherein IWP-2 is present in the composition at a concentration of about 0.8 μM to about 5 μM.

781. The composition according to claim 780, wherein IWP-2 is present in the composition at a concentration of about 2 μM.

782. The composition according to any one of claims 705 and 740 - 781, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

783. The composition according to claim 782, wherein the glycogen kinase inhibitor comprises CHIR99021.

784. The composition according to claim 783, wherein CHIR99021 is present in the composition at a concentration of about 0.1 micromole (μM) to about 10 μM.

785. The composition according to claim 784, wherein CHIR99021 is present in the composition at a concentration of about 0.2 μM to about 5 μM.

786. The composition according to claim 785, wherein CHIR99021 is present in the composition at a concentration of about 0.4 μM to about 2.5 μM.

787. The composition according to claim 786, wherein CHIR99021 is present in the composition at a concentration of about 1 μM.

788. The composition according to any one of claims 705 and 740 - 787, wherein the ROCK inhibitor comprises Y-27632 or thiazovivin.

789. The composition according to claim 788, wherein the ROCK inhibitor comprises Y-27632.

790. The composition according to claim 789, wherein Y-27632 is present in the composition at a concentration of about 1 μM to about 100 μM.

791. The composition according to claim 790, wherein Y-27632 is present in the composition at a concentration of about 2 μM to about 50 μM.

792. The composition according to claim 791, wherein Y-27632 is present in the composition at a concentration of about 4 μM to about 25 μM.

793. The composition according to claim 792, wherein Y-27632 is present in the composition at a concentration of about 10 μM.

794. The composition according to any one of claims 473 - 543, 580, 584 - 705, 709 - 733 or 740 - 793, wherein the composition is a culture medium for culturing cells.

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