Chemical reprogramming method and pluripotent stem cells

Abstract

In some embodiments, the present invention provides methods and compositions for cell conversion. These methods can convert a cell population containing one cell type into another cell population containing another cell type. The converted cell type can have enhanced cell differentiation potential. The converted cell type can include pluripotent stem cells. The compositions provided herein can include chemical reprogramming factors for converting cells. The compositions provided herein can include chemical reprogramming factors and cells. Furthermore, reagents for carrying out the cell conversion methods are provided. In addition, methods and compositions are provided for using various cell types obtained by the methods and / or compositions provided herein.

Description

[Background technology]

[0001] The demand for cellular resources for applications in basic research, therapeutics, agriculture, and the food industry remains enormous. Improved methods for the industrial-scale production of stem cells and cells of various differentiation states and cell types remain elusive.

[0002] Cell identity is established during development to acquire and maintain exclusive cellular functions in somatic cells. Manipulating cell identity through cell reprogramming can generate desired cell types, which has broad applications in disease modeling, drug discovery, and regenerative medicine. Mouse and human somatic cells can be reprogrammed into pluripotent stem cells using cytokines (including oocyte-constitutive factors and transcription factors). Alternatively, somatic cells can be induced into pluripotent stem cells by chemical reprogramming using only small molecule compounds. However, the efficiency and kinetics of chemical reprogramming systems in human cells require further improvement to achieve robust pluripotent stem cell induction from human somatic cells. Summary of the Invention

[0003] In some aspects, the present invention 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 containing at least one cell type into a cell population containing another cell type, the latter exhibiting increased differentiation potential. The various cells produced by the methods and / or compositions can include pluripotent stem cells or other intermediate differentiation stage cells, which have enhanced potential for transformation into pluripotent stem cells compared to undifferentiated cells. These intermediate differentiation stage cells can include epithelial-like cells, intermediate plastic state cells, their progeny, or their derivatives.

[0004] The methods and compositions described herein can produce cells with enhanced differentiation potential without genetic modification. In some cases, producing stem cells or cells in various differentiation states without genetic modification can reduce the adverse effects of genetic modification. These adverse effects may include unintended induced mutations in stem cells. In some cases, these adverse effects are caused by the exogenous nucleic acid molecules or sequences used to genetically modify the cells. Cells with unintended mutations may have various adverse characteristics, including, but not limited to, enhanced or uncontrollable cell proliferation (which may lead to neoplastic diseases, such as cancer), unpredictable differentiation characteristics, and / or poor cellular senescence. By utilizing chemical reprogramming factors, the methods and compositions provided herein can eliminate these adverse effects of genetic modification. Furthermore, even when genetic modification is required for downstream purposes after generating transformed cells, the methods and compositions provided herein can reduce the adverse effects described herein.

[0005] By using the chemical programming factors described herein, the methods and compositions can improve the scalability of producing stem cells and cells with various differentiation states. Compared to existing methods, these methods and compositions can produce stem cells or cells with various differentiation states in a shorter time. Therefore, the methods and compositions can meet the demand for cell resources applied to basic research, therapeutics, agriculture, and the food industry.

[0006] In some embodiments, the present invention provides methods for producing pluripotent stem cells. In one embodiment, the 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 plasticity state cells that express LIN28A and SALL4, and one or more of MSX2, NMYC, SDC1, WNT4, FGF19, or TOP2A, and (c) converting the intermediate plasticity state cells or their progeny into pluripotent stem cells.

[0007] In some embodiments, converting 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. 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.

[0008] In some embodiments, the present invention provides a method for producing pluripotent stem cells. In one embodiment, the method for producing pluripotent stem cells includes: (a) obtaining epithelial-like cells that express LIN28A; (b) converting the epithelial-like cells or their progeny cells into intermediate plasticity state cells that express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A, by contacting the epithelial-like cells or their progeny cells 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; and (c) converting the intermediate plasticity state cells or their progeny cells into pluripotent stem cells.

[0009] 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 intermediate plasticity state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, intermediate plasticity state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1. In some embodiments, intermediate plasticity state cells further express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, pluripotent stem cells express one or more of OCT4, SOX2, or NANOG. In some embodiments, 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 REX 1. 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.

[0010] In some embodiments, the method further comprises treating the somatic cell population to convert at least a subset of somatic cells of the cell population into epithelial-like 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 method converts the somatic cells into pluripotent stem cells in less than about 50 days. In some embodiments, the method converts the somatic cells into pluripotent stem cells in up to about 32 days. In some embodiments, the method converts the somatic cells into pluripotent stem cells in up to about 24 days. In some embodiments, the method produces 1 pluripotent stem cell for every 1,000 somatic cells in the somatic cell population. In some embodiments, the method produces 1 pluripotent stem cell for every 200 somatic cells in the somatic cell population. In some embodiments, the method produces 1 pluripotent stem cell for every 50 somatic cells in the somatic cell population. In some embodiments, the method further comprises: 2 ) up to approximately 1 x 10 6 In some embodiments, the cell culture area is 1 cm. 2 Maximum of about 5 x 10 5 In some embodiments, the somatic cells are seeded at a cell density of 1 cm. 2 Maximum of approx. 2.5 x 10 5 Seed somatic cells at a cell density of 1000 cells / well.

[0011] In some embodiments, the present invention provides a method for producing pluripotent stem cells. In one embodiment, the method for producing pluripotent stem cells includes: (a) obtaining a first cell population comprising epithelial-like cells expressing LIN28A; (b) contacting the first cell population with a second composition comprising (i) a glycogen kinase inhibitor, (ii) a TGFβ receptor inhibitor, and (iii) a c-Jun kinase inhibitor to obtain a second cell population; and (c) contacting the second cell population with a third composition comprising (i) a MEK inhibitor, (ii) a B-Raf inhibitor, and (iii) a histone deacetylase inhibitor to obtain a third cell population comprising pluripotent stem cells.

[0012] 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 second composition is about 0.5 micromolar (μM) to about 50 μM. In some embodiments, the amount of CHIR99021 present in the second composition is about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the second composition is 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 is E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine (Dorsomorphine), or SB 525334, optionally wherein the TGFβ receptor inhibitor comprises E-616452. In some embodiments, the amount of E-616452 present in the second composition is about 1 μM to about 100 μM. In some embodiments, the amount of E-616452 present in the second composition is about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the second composition is 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 comprises JNKIN8, JNKIN7, JNKIN5, or JNKIN12. In some embodiments, the c-Jun kinase inhibitor comprises JNKIN8. In some embodiments, the amount of JNKIN8 present in the second composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of JNKIN8 present in the second composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of JNKIN8 present in the second composition is 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 comprises PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor comprises PD0325901. In some embodiments, the amount of PD0325901 present in the third composition is about 0.1 μM to about 10 μM. In some embodiments, the amount of PD0325901 present in the third composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of PD0325901 present in the third composition is 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 comprises SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor comprises SB590885. In some embodiments, the amount of SB590885 present in the third composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of SB590885 present in the third composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SB590885 present in the third composition is 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 comprises valproic acid (VPA), LMK235, MS275, or HDACi I. In some embodiments, the histone deacetylase inhibitor comprises VPA. In some embodiments, the amount of VPA present in the third composition is about 0.1 millimolar (mM) to about 10 mM. In some embodiments, the amount of VPA present in the third composition is about 0.2 mM to about 5 mM. In some embodiments, the amount of VPA present in the third composition is 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 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 about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is 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 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 about 0.02 μM to about 2 μM. In some embodiments, the amount of DZNep present in the second composition is about 0.04 μM to about 1 μM. In some embodiments, the amount of DZNep present in the second composition is 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 comprises SGC-CBP30, I-CBP112, or GNE27. In some embodiments, the CBP / p300 bromodomain inhibitor comprises SGC-CBP30. In some embodiments, the amount of SGC-CBP30 present in the second composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of SGC-CBP30 present in the second composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of SGC-CBP30 present in the second composition is 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 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 about 0.05 μM to about 5 μM. In some embodiments, the amount of 5-ITU present in the composition is about 0.1 micromolar μM to about 2.5 μM. In some embodiments, the amount of 5-ITU present in the composition is 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.

[0013] In some embodiments, the method comprises culturing the first population of cells in the second composition for up to about 20 days. In some embodiments, the method comprises culturing the first population of cells in the second composition for up to about 16 days. In some embodiments, the method comprises culturing the first population of cells in the second composition for about 4 to 16 days. In some embodiments, the method further comprises removing the second composition from the second population of cells. In some embodiments, the method comprises culturing the second population of cells in a third composition for up to about 20 days. In some embodiments, the method comprises culturing the second population of cells in the third composition for up to about 12 days. In some embodiments, the method comprises culturing the second population of cells in the third composition for about 4 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 comprises an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence comprises a sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification comprises altering a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the pluripotent stem cells or their progeny.

[0014] In some embodiments, the present invention provides methods for reprogramming epithelial-like cells that express LIN28A. In one embodiment, the method for reprogramming epithelial-like cells that express LIN28A comprises contacting a population of cells 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.

[0015] In some embodiments, the cell population is incubated with about 21% atmospheric oxygen gas during the contact period. 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 about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of 5-ITU present in the composition is about 0.1 micromolar μM to about 2.5 μM. In some embodiments, the amount of 5-ITU present in the composition is 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 about 0.02 μM to about 2 μM. In some embodiments, the amount of DZNep present in the second composition is about 0.04 μM to about 1 μM. In some embodiments, the amount of DZNep present in the second composition is 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 about 0.5 micromolar (μM) to about 50 μM. In some embodiments, CHIR99021 is present in the composition at an amount of about 1 μM to about 25 μM, In some embodiments, CHIR99021 is present in the composition at an amount of 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, A 83-01, 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 about 1 micromolar (μM) to about 100 μM. In some embodiments, the amount of E-616452 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the composition is 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 comprises JNKIN8, JNKIN7, JNKIN5, or JNKIN12. In some embodiments, the c-Jun kinase inhibitor comprises JNKIN8. In some embodiments, the amount of JNKIN8 present in the composition is about 0.05 micromolar (μM) to about 50 μM. In some embodiments, the amount of JNKIN8 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of JNKIN8 present in the composition is 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 comprises SGC-CBP30, I-CBP112, GNE272, or GNE409. In some embodiments, the CBP / p300 bromodomain inhibitor comprises SGC-CBP30. In some embodiments, the amount of SGC-CBP30 present in the composition is about 0.2 micromolar (μM) to about 20 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is about 0.4 μM to about 10 μM.In some embodiments, the amount of SGC-CBP30 present in the composition is 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 comprises SETD2-in-1, EPZ-719, or MMSET-in-1. In some embodiments, the SETD2 inhibitor comprises SETD2-in-1. In some embodiments, the amount of SETD2-in-1 present in the composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of SETD2-in-1 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SETD2-in-1 present in the composition is 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 comprises an AKT kinase inhibitor. In some embodiments, the amount of AKT kinase inhibitor present in the composition is about 0.1 μM to about 10 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is 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 inhibitor comprises CX-4945, TPP 22, or ellagic acid. In some embodiments, the casein kinase 2 inhibitor comprises CX-4945. In some embodiments, the amount of CX-4945 present in the composition is about 0.08 μM to about 8 μM. In some embodiments, the amount of CX-4945 present in the composition is about 0.16 μM to about 4 μM. In some embodiments, CX-4945 is present in the composition at an amount of about 0.32 μM to about 2 μM, hi some embodiments, CX-4945 is present in the composition at 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 comprises VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the menin-MLL interaction inhibitor comprises VTP50469. In some embodiments, the amount of VTP50469 present in the composition is about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of VTP50469 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of VTP50469 present in the composition is 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 comprises SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG. In some embodiments, the amount of SAG present in the composition is about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of SAG present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SAG present in the composition is 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 comprises Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor comprises Y-27632. In some embodiments, the amount of Y-27632 present in the composition is about 1 μM to about 100 μM. In some embodiments, the amount of Y-27632 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of Y-27632 present in the composition is 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 comprises dihydrodeoxymorphine (Dorsomorphin). In some embodiments, the amount of dihydrodeoxymorphine present in the composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of dihydrodeoxymorphine present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of dihydrodeoxymorphine present in the composition is 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 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 about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is 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 comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676. In some embodiments, the amount of EPZ5676 present in the composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is 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 about 0.1 μM to about 10 μM. In some embodiments, the amount of ruxolitinib present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of ruxolitinib present in the composition is 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 is BIRB796, SB203580 or. In some embodiments, the p38 MAPK inhibitor comprises BIRB796. In some embodiments, the amount of BIRB796 present in the composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of BIRB796 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of BIRB796 present in the composition is about 0.8 μM to about 5 μM. In some embodiments, the amount of BIRB796 present in the composition is about 2 μM.

[0016] In some embodiments, the method comprises culturing the cell population in the composition for up to about 20 days. In some embodiments, the method comprises culturing the cell population in the composition for up to about 16 days. In some embodiments, the method comprises culturing the cell population in the composition for from about 4 days to about 16 days.

[0017] In some embodiments, the method converts epithelial-like cells into intermediate plasticity state cells that express LIN28A and SALL4 and one or more of MSX2, NMYC, SDC1, WNT4, FGF19, or TOP2A. In some embodiments, the intermediate plasticity state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, the intermediate plasticity state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1. In some embodiments, the intermediate plasticity state cells further express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2.

[0018] In some embodiments, the intermediate plasticity state cell or its progeny comprises a genetic modification. In some embodiments, the genetic modification comprises an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence comprises the sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification comprises an alteration of a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the intermediate plasticity state cell or its progeny.

[0019] In some embodiments, the present invention provides methods for reprogramming somatic cells. In one embodiment, the method for reprogramming somatic cells comprises contacting a population of cells comprising somatic cells with a composition comprising one or more of: (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, (c) a RAR agonist, and (d) an Akt inhibitor or a SETD2 inhibitor.

[0020] 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 cells are incubated with up to about 10% atmospheric oxygen gas during the contacting period. In some embodiments, the cells are incubated with up to about 5% atmospheric oxygen gas during the contacting period. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021. In some embodiments, the amount of CHIR99021 present in the composition is about 0.5 μM to about 50 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the composition is 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, A 83-01, 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 about 1 μM to about 100 μM. In some embodiments, the amount of E-616452 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the composition is 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 about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is 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 includes an Akt inhibitor. In some embodiments, the Akt inhibitor includes an AKT kinase inhibitor. In some embodiments, the amount of AKT kinase inhibitor present in the composition is about 0.1 μM to about 10 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is 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 composition includes 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 about 0.05 μM to about 5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SETD2-IN-1 present in the composition is 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 a Menin-MLL interaction inhibitor. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG. In some embodiments, the amount of SAG present in the composition is about 0.05 μM to about 5 μM. In some embodiments, SAG is present in the composition in an amount from about 0.1 μM to about 2.5 μM.In some embodiments, the amount of SAG present in the composition is 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 Menin-MLL interaction inhibitor comprises VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the Menin-MLL interaction inhibitor comprises VTP50469. In some embodiments, the amount of VTP50469 present in the composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of VTP50469 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of VTP50469 present in the composition is 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, an SAH hydrolase inhibitor, or a Dot1L inhibitor. 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 about 0.1 μM to about 10 μM. In some embodiments, the amount of ruxolitinib present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of ruxolitinib present in the composition is 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 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 about 0.02 μM to about 2 μM.In some embodiments, the amount of DZNep present in the second composition is about 0.04 μM to about 1 μM. In some embodiments, the amount of DZNep present in the second composition is 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 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 about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.8 μM to about 5 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 2 μM.

[0021] In some embodiments, the method comprises culturing the cell population in the composition for up to about 20 days. In some embodiments, the method comprises culturing the cell population in the composition for up to about 12 days. In some embodiments, the method comprises culturing the cell population in the composition for about 4 to about 12 days. In some embodiments, the method converts the somatic cells into epithelial-like cells that express 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 further express one or more of KRT18, KRT19, WT1, or TBX2. In some embodiments, the epithelial-like cells or their progeny comprise a genetic modification. In some embodiments, the genetic modification comprises an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence comprises the sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification comprises an alteration of a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the epithelial-like cells or their progeny.

[0022] In some embodiments, the present invention provides methods for generating pluripotent stem cells. In one embodiment, the method for generating pluripotent stem cells comprises contacting a population of cells comprising intermediate plasticity state cells or their progeny with a composition comprising (a) a MEK inhibitor, (b) a B-Raf inhibitor, and (c) a histone deacetylase inhibitor to generate pluripotent stem cells. The intermediate plasticity state cells express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A.

[0023] In some embodiments, the cell population is incubated with about 21% atmospheric oxygen gas during the contact period. In some embodiments, the MEK inhibitor comprises PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor comprises PD0325901. In some embodiments, the amount of PD0325901 present in the third composition is about 0.1 μM to about 10 μM. In some embodiments, the amount of PD0325901 present in the third composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of PD0325901 present in the third composition is 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 comprises SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor comprises SB590885. In some embodiments, the amount of SB590885 present in the composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of SB590885 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SB590885 present in the composition is 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 comprises valproic acid (VPA), LMK235, MS275, or HDACi I. In some embodiments, the histone deacetylase inhibitor comprises VPA. In some embodiments, the amount of VPA present in the composition is about 0.1 millimolar (mM) to 10 mM. In some embodiments, the amount of VPA present in the composition is about 0.2 mM to 5 mM. In some embodiments, the amount of VPA present in the composition is 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 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 comprises IWR-1 or IWP-2. In some embodiments, the Wnt inhibitor comprises IWR-1. In some embodiments, the Wnt inhibitor comprises IWP-2. In some embodiments, the amount of IWP-2 present in the composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of IWP-2 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of IWP-2 present in the composition is 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, the amount of CHIR99021 present in the composition is about 0.1 micromolar (μM) to about 10 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of CHIR99021 present in the composition is 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 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, the amount of Y-27632 present in the composition is about 1 μM to about 100 μM. In some embodiments, the amount of Y-27632 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of Y-27632 present in the composition is 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 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, the tranylcypromine is present in the composition at an amount of about 1 μM to about 100 μM. In some embodiments, the tranylcypromine is present in the composition at an amount of about 2 μM to about 50 μM. In some embodiments, the tranylcypromine is present in the composition at an amount of about 4 μM to about 25 μM. In some embodiments, the tranylcypromine is present in the composition at 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, the EPZ5676 is present in the composition at an amount of about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is 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 composition further 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 about 0.02 μM to about 20 μM. In some embodiments, the amount of DZNep present in the composition is about 0.04 μM to about 10 μM. In some embodiments, the amount of DZNep present in the composition is 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 comprises culturing the population of cells in the composition, and in some embodiments, the method further comprises, after about 5 days of culturing, replacing the composition with a second composition and culturing.In some embodiments, the second composition comprises 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 comprises, after culturing in the second composition for about 5 days, replacing the second composition with a third composition and culturing. In some embodiments, the third composition does not comprise a histone deacetylase inhibitor, a histone demethylation inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

[0024] In some embodiments, the method comprises culturing the cell population in the composition for up to about 20 days. In some embodiments, the method comprises culturing the cell population in the composition for up to about 12 days. In some embodiments, the method comprises culturing the cell population in the composition for about 4 to about 12 days. In some embodiments, the method converts the intermediate plasticity 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 REX 1. 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, REX 1, or UTF1.

[0025] In some embodiments, the pluripotent stem cells or their progeny cells have a genetic modification. In some embodiments, the genetic modification comprises an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence comprises the sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification comprises an alteration of a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the pluripotent stem cells or their progeny cells.

[0026] In some embodiments, the present invention provides an isolated population of cells. In one embodiment, the isolated population of cells includes intermediate plasticity 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.

[0027] In some embodiments, the intermediate plasticity state cells further express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, the intermediate plasticity state cells have a genetic modification. In some embodiments, the genetic modification comprises an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence comprises the sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification comprises an alteration of a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the intermediate plasticity state cells.

[0028] In some embodiments, the present invention provides a composition. In some embodiments, the composition provided by the present invention is a medium for culturing cells. In one embodiment, the composition provided by the present invention comprises intermediate plasticity state cells expressing LIN28A and 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, or a casein kinase 2 inhibitor.

[0029] In some embodiments, the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014. In some embodiments, the glycogen kinase inhibitor comprises CHIR99021. In some embodiments, the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334. In some embodiments, the TGFβ receptor inhibitor comprises E-616452. In some embodiments, the RAR agonist comprises TTNPB, Ch55, or AM580. In some embodiments, the RAR agonist comprises TTNPB. In some embodiments, the c-Jun kinase inhibitor comprises JNKIN7, JNKIN5, or JNKIN12. In some embodiments, the c-Jun kinase inhibitor comprises JNKIN8. In some embodiments, the CBP / p300 bromodomain inhibitor comprises SGC-CBP30, I-CBP112, GNE272, or GNE409. In some embodiments, the CBP / p300 bromodomain inhibitor comprises SGC-CBP30. 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 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 Dot1L inhibitor comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676. In some embodiments, the Menin-MLL interaction inhibitor comprises VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the Menin-MLL interaction inhibitor comprises VTP50469. 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.In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG. In some embodiments, the ROCK inhibitor comprises Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor comprises Y-27632. In some embodiments, the BMP receptor / AMPK inhibitor comprises dihydrodeoxymorphine. 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 p38 MAPK inhibitor comprises BIRB796, SB203580, or SB202190. In some embodiments, the p38 MAPK inhibitor comprises BIRB796. In some embodiments, the Akt inhibitor comprises an AKT kinase inhibitor. In some embodiments, the casein kinase 2 inhibitor comprises CX-4945, TPP 22, or ellagic acid. In some embodiments, the casein kinase 2 inhibitor comprises CX-4945.

[0030] In one aspect, the present invention provides 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.

[0031] In some embodiments, the composition further comprises a CBP / p300 bromodomain inhibitor.

[0032] In one aspect, the composition provided herein comprises (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.

[0033] 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 about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of 5-ITU present in the composition is about 0.1 micromolar μM to about 2.5 μM. In some embodiments, the amount of 5-ITU present in the composition is 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 about 0.02 μM to about 20 μM. In some embodiments, the amount of DZNep present in the composition is about 0.04 μM to about 10 μM. In some embodiments, the amount of DZNep present in the composition is 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 about 0.5 micromolar (μM) to about 50 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 2 μM to about 12.5 μM. In some embodiments, CHIR99021 is present in the composition at about 5 μM.In some embodiments, the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, 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 about 1 micromolar (μM) to about 100 μM. In some embodiments, the amount of E-616452 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the composition is 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 comprises JNKIN8, JNKIN7, JNKIN5, or JNKIN12. In some embodiments, the c-Jun kinase inhibitor comprises JNKIN8. In some embodiments, the amount of JNKIN present in the composition is about 0.05 micromolar (μM) to about 50 μM. In some embodiments, the amount of JNKIN present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of JNKIN present in the composition is 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 inhibitor comprises SGC-CBP30, I-CBP112, GNE272, or GNE409. In some embodiments, the CBP / p300 bromodomain inhibitor comprises SGC-CBP30. In some embodiments, the amount of SGC-CBP30 present in the composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of SGC-CBP30 present in the composition is 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 comprises SETD2-in-1, EPZ-719, or MMSET-in-1. In some embodiments, the SETD2 inhibitor comprises SETD2-in-1. In some embodiments, the SETD2-in-1 is present in the composition at an amount of about 0.05 μM to about 5 μM. In some embodiments, the SETD2-in-1 is present in the composition at an amount of about 0.1 μM to about 2.5 μM. In some embodiments, the SETD2-in-1 is present in the composition at an amount of about 0.2 μM to about 1.25 μM. In some embodiments, the SETD2-in-1 is present in the composition at an amount of about 0.4 μM. In some embodiments, the Akt inhibitor comprises an AKT kinase inhibitor. In some embodiments, the AKT kinase inhibitor is present in the composition at an amount of about 0.1 μM to about 10 μM. In some embodiments, the AKT kinase inhibitor is present in the composition at an amount of about 0.2 μM to about 5 μM. In some embodiments, the amount of the AKT kinase inhibitor present in the composition is 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 casein kinase 2 inhibitor comprises CX-4945, TPP 22, or ellagic acid. In some embodiments, the casein kinase 2 inhibitor comprises CX-4945. In some embodiments, the amount of CX-4945 present in the composition is about 0.08 μM to about 8 μM. In some embodiments, the amount of CX-4945 present in the composition is about 0.16 μM to about 4 μM. In some embodiments, the amount of CX-4945 present in the composition is 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 comprises VTP50469, MI3454, or WDR5-IN-4.In some embodiments, the Menin-MLL interaction inhibitor comprises VTP50469. In some embodiments, the amount of VTP50469 present in the composition is about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of VTP50469 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of VTP50469 present in the composition is 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 comprises SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG. In some embodiments, the amount of SAG present in the composition is about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of SAG present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SAG present in the composition is 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 comprises Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor comprises Y-27632. In some embodiments, the amount of Y27632 present in the composition is about 1 μM to about 100 μM. In some embodiments, the amount of Y27632 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of Y27632 present in the composition is 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 comprises dihydrodeoxymorphine. In some embodiments, the amount of dihydrodeoxymorphine present in the composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of dihydrodeoxymorphine present in the composition is about 0.1 μM to about 2.5 μM.In some embodiments, the amount of dihydrodeoxymorphine present in the composition is 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 includes 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 about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is 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 about 0.1 μM to about 10 μM. In some embodiments, the amount of ruxolitinib present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of ruxolitinib present in the composition is 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, BIRB796 is present in the composition in an amount of about 0.2 μM to about 20 μM.In some embodiments, the amount of BIRB796 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of BIRB796 present in the composition is 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 about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of TTNPB present in the composition is about 0.8 μM to about 5 μM. In some embodiments, the amount of TTNPB present in the composition is about. 2 μM.

[0034] In some embodiments, the present invention provides an isolated population of cells. In one embodiment, the isolated population of cells comprises epithelial-like cells that express LIN28A and one or more of NMYC, WNT2B, PAX8, SMAD3, or GLI3.

[0035] In some embodiments, the isolated population of cells comprising epithelial-like cells express one or more of KRT18, KRT19, WT1, or TBX2. In some embodiments, the isolated population of cells comprising epithelial-like cells does not express any one of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2.

[0036] In one aspect, the composition provided by the present invention comprises an epithelial-like cell expressing LIN28A, and (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, (c) an RAR agonist, and (d) an Akt inhibitor or a SETD2 inhibitor.

[0037] 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.

[0038] In one aspect, the present invention provides 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.

[0039] 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 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. 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 TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334. In some embodiments, the TGFβ receptor inhibitor comprises E-616452. In some embodiments, the RAR agonist comprises TTNPB, Ch55, or AM580. In some embodiments, the RAR agonist comprises TTNPB. In some embodiments, the composition further comprises an agonist of the G protein-coupled receptor Smoothened or a Menin-MLL interaction inhibitor. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG. In some embodiments, the Menin-MLL interaction inhibitor comprises VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the Menin-MLL interaction inhibitor comprises VTP50469. 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 comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib. In some embodiments, the Jak1 / Jak2 inhibitor comprises ruxolitinib. 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 Dot1L inhibitor comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676.

[0040] In one aspect, the composition provided herein comprises (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, (c) an RAR agonist, and (d) an Akt inhibitor or a SETD2 inhibitor.

[0041] 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-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 about 0.5 micromolar (μM) to about 50 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 1 μM to about 25 μM. In some embodiments, the amount of CHIR99021 present in the composition is 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, A 83-01, 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 about 1 μM to about 100 μM. In some embodiments, the amount of E-616452 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of E-616452 present in the composition is 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 about 0.2 μM to about 20 μM. In some embodiments, the amount of TTNPB present in the composition is about 0.4 μM to about 10 μM.In some embodiments, the amount of TTNPB present in the composition is 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 AKT kinase inhibitor present in the composition is about 0.1 μM to about 10 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of AKT kinase inhibitor present in the composition is 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 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. In some embodiments, the amount of SETD2-in-1 present in the composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of SETD2-in-1 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SETD2-in-1 present in the composition is 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 a Menin-MLL interaction inhibitor. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5, or human SHH. In some embodiments, the agonist of the G protein-coupled receptor Smoothened comprises SAG. In some embodiments, the amount of SAG present in the composition is about 0.05 micromolar (μM) to about 5 μM. In some embodiments, SAG is present in the composition in an amount from about 0.1 μM to about 2.5 μM.In some embodiments, the amount of SAG present in the composition is 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 menin-MLL interaction inhibitor comprises VTP50469, MI3454, or WDR5-IN-4. In some embodiments, the menin-MLL interaction inhibitor comprises VTP50469. In some embodiments, the amount of VTP50469 present in the composition is about 0.05 micromolar (μM) to about 5 μM. In some embodiments, the amount of VTP50469 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of VTP50469 present in the composition is 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, an SAH hydrolase inhibitor, or a Dot1L inhibitor. 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 about 0.1 μM to about 10 μM. In some embodiments, the amount of ruxolitinib present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of ruxolitinib present in the composition is 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 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 about 0.002 μM to about 0.2 μM.In some embodiments, the amount of DZNep present in the composition is about 0.004 μM to about 0.1 μM. In some embodiments, the amount of DZNep present in the composition is 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 comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676. In some embodiments, the amount of EPZ5676 present in the composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.8 μM to about 5 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 2 μM.

[0042] In one aspect, the present invention provides a composition comprising an intermediate plasticity state cell expressing 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 demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

[0043] In some embodiments, the intermediate plasticity state cells express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2. In some embodiments, the MEK inhibitor comprises PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor comprises PD0325901. In some embodiments, the amount of PD0325901 present in the third composition is about 0.1 μM to about 10 μM. In some embodiments, the amount of PD0325901 present in the third composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of PD0325901 present in the third composition is 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 comprises SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor comprises SB590885. In some embodiments, the amount of SB590885 present in the composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of SB590885 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SB590885 present in the composition is 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 comprises valproic acid (VPA), LMK235, MS275, or HDACi IV. In some embodiments, the histone deacetylase inhibitor comprises valproic acid (VPA). In some embodiments, the amount of VPA present in the composition is about 0.1 millimolar (mM) to 10 mM. In some embodiments, the amount of VPA present in the composition is about 0.2 mM to 5 mM. In some embodiments, the amount of VPA present in the composition is 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 comprises tranylcypromine.In some embodiments, the amount of tranylcypromine present in the composition is about 1 μM to about 100 μM. In some embodiments, the amount of tranylcypromine present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of tranylcypromine present in the composition is 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 comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676. In some embodiments, the amount of EPZ5676 present in the composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is 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 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 about 0.02 μM to about 20 μM. In some embodiments, the amount of DZNep present in the composition is about 0.04 μM to about 10 μM. In some embodiments, the amount of DZNep present in the composition is 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 comprises IWR-1 or IWP-2. In some embodiments, the Wnt inhibitor comprises IWR-1. In some embodiments, the Wnt inhibitor comprises IWP-2. In some embodiments, the amount of IWP-2 present in the composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of IWP-2 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of IWP-2 present in the composition is 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 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 about 0.1 micromolar (μM) to about 10 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of CHIR99021 present in the composition is 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 comprises Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor comprises Y-27632. In some embodiments, the amount of Y-27632 present in the composition is about 1 μM to about 100 μM. In some embodiments, the amount of Y-27632 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of Y-27632 present in the composition is about 4 μM to about 25 μM. In some embodiments, the amount of Y-27632 present in the composition is about 10 μM.

[0044] In one aspect, the composition provided herein comprises (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.

[0045] 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.

[0046] In some embodiments, the MEK inhibitor comprises PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor comprises PD0325901. In some embodiments, the B-Raf inhibitor comprises SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor comprises SB590885. In some embodiments, the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275, or HDACi IV. In some embodiments, the histone deacetylase inhibitor comprises VPA. In some embodiments, the composition comprises a histone demethylation inhibitor. In some embodiments, the histone demethylation inhibitor comprises tranylcypromine. In some embodiments, the composition 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, the SAH hydrolase inhibitor comprises DZNep, NepA, Adox, or DZA. In some embodiments, the SAH hydrolase inhibitor comprises 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 inhibitor comprises IWR-1 or IWP-2. In some embodiments, the Wnt inhibitor comprises IWR-1. In some embodiments, the Wnt inhibitor comprises IWP-2. In some embodiments, the composition 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, the glycogen kinase inhibitor comprises CHIR98014. In some embodiments, the composition 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, the pluripotent stem cells retain the genetic modification. In some embodiments, the genetic modification comprises an exogenous nucleic acid sequence. In some embodiments, the exogenous nucleic acid sequence encodes a polypeptide. In some embodiments, the exogenous nucleic acid sequence comprises a sequence of a non-coding nucleic acid molecule. In some embodiments, the genetic modification comprises an alteration of a genomic sequence. In some embodiments, the genetic modification reduces the immunogenicity of the pluripotent stem cells. In some embodiments, the MEK inhibitor comprises PD0325901, AZD8330, or TAK-733. In some embodiments, the MEK inhibitor comprises PD0325901. In some embodiments, the amount of PD0325901 present in the third composition is about 0.1 μM to about 10 μM. In some embodiments, the amount of PD0325901 present in the third composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of PD0325901 present in the third composition is 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 comprises SB590885, vemurafenib, RAF265, or PLX4720. In some embodiments, the B-Raf inhibitor comprises SB590885. In some embodiments, the amount of SB590885 present in the composition is about 0.05 μM to about 5 μM. In some embodiments, the amount of SB590885 present in the composition is about 0.1 μM to about 2.5 μM. In some embodiments, the amount of SB590885 present in the composition is 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 comprises valproic acid (VPA), LMK235, MS275, or HDACi IV. In some embodiments, the histone deacetylase inhibitor comprises valproic acid (VPA). In some embodiments, the VPA is present in the composition at an amount of about 0.1 millimolar (mM) to 10 mM. In some embodiments, the VPA is present in the composition at an amount of about 0.2 mM to 5 mM.In some embodiments, the amount of VPA present in the composition is 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 comprises tranylcypromine. In some embodiments, the amount of tranylcypromine present in the composition is about 1 μM to about 100 μM. In some embodiments, the amount of tranylcypromine present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of tranylcypromine present in the composition is 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 comprises EPZ004777 or EPZ5676. In some embodiments, the Dot1L inhibitor comprises EPZ5676. In some embodiments, the amount of EPZ5676 present in the composition is about 0.2 μM to about 20 μM. In some embodiments, the amount of EPZ5676 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of EPZ5676 present in the composition is 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 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 about 0.02 μM to about 20 μM. In some embodiments, the amount of DZNep present in the composition is about 0.04 μM to about 10 μM. In some embodiments, the amount of DZNep present in the composition is 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 composition comprises a Wnt inhibitor IWR-1 or IWP-2. In some embodiments, the Wnt inhibitor comprises IWR-1. In some embodiments, the Wnt inhibitor comprises IWP-2. In some embodiments, the amount of IWP-2 present in the composition is about 0.2 μM to about 20 μM.In some embodiments, the amount of IWP-2 present in the composition is about 0.4 μM to about 10 μM. In some embodiments, the amount of IWP-2 present in the composition is 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 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 about 0.1 micromolar (μM) to about 10 μM. In some embodiments, the amount of CHIR99021 present in the composition is about 0.2 μM to about 5 μM. In some embodiments, the amount of CHIR99021 present in the composition is 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 comprises Y-27632 or thiazovivin. In some embodiments, the ROCK inhibitor comprises Y-27632. In some embodiments, the amount of Y-27632 present in the composition is about 1 μM to about 100 μM. In some embodiments, the amount of Y-27632 present in the composition is about 2 μM to about 50 μM. In some embodiments, the amount of Y-27632 present in the composition is about 4 μM to about 25 μM. In some embodiments, the amount of Y-27632 present in the composition is about 10 μM.

[0047] Those skilled in the art will readily appreciate other aspects and advantages of the present disclosure from the following detailed description of the invention, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details can be modified in various obvious respects without departing from the present disclosure. Accordingly, the drawings and description should be regarded as illustrative, and not restrictive.

[0048] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event that a publication, patent, or patent application incorporated by reference conflicts with a disclosure in the specification, the specification is intended to supersede and / or supersede such conflicting material. [Brief explanation of the drawings]

[0049] The novel features of the present disclosure are set forth with particularity in the appended claims. For a better understanding of the features and advantages of the present disclosure, reference may be had to the following description and drawings (also referred to herein as "figures"), which set forth illustrative embodiments, in which the principles of the present disclosure are utilized. [Figure 1] FIG. 1 shows a schematic diagram of converting somatic cells into chemically induced human pluripotent stem cells (hCiPSCs). [Figure 2] FIG. 1 shows another schematic diagram of converting somatic cells into hCiPSCs. [Figure 3] FIG. 1 shows representative images of cells at the end of the first stage of the transformation process using various media. [Figure 4] FIG. 1 shows the number of hCiPSC colonies generated in the first stage of the transformation process using various media. [Figure 5] FIG. 1 shows the number of hCiPSC colonies generated during the first stage of transformation using a series of different media. [Figure 6] FIG. 1 shows the number of hCiPSC colonies generated in first-stage transformation medium with or without a SETD2 inhibitor. [Figure 7A] FIG. 1 shows the number of hCiPSC colonies generated in second-stage transformation medium with or without an adenosine kinase inhibitor. [Figure 7B] FIG. 1 shows the number of hCiPSC colonies generated in second-stage transformation medium with or without a Menin-MLL interaction inhibitor. [Figure 8] FIG. 1 shows representative images of immunofluorescence analysis of pluripotency markers in hCiPSCs derived from human adipose-derived mesenchymal stromal cells (hADSCs). [Figure 9] FIG. 1 shows representative images of morphological analysis of hCiPSCs derived from hADSCs. [Figure 10] FIG. 1 shows reprogramming efficiency in generating hCiPS cells from different donors. [Figure 11] FIG. 1 shows a comparison of the number of hCiPSC colonies generated by the method of the present invention and other methods. [Figure 12] FIG. 1 shows representative images of immunofluorescence analysis of different pluripotency markers in hCiPSCs derived from hADSCs. [Figure 13] FIG. 1 shows reverse transcription (RT)-quantitative PCR (qPCR) analysis of pluripotency markers in the indicated hCiPSCs and controls. [Figure 14] Representative images of hematoxylin-eosin staining of endoderm (airway epithelium), mesoderm (cartilage), and ectoderm (retinal pigment epithelium and neural tissue) in single teratomas derived from the indicated hCiPSC clones. [Figure 15A] FIG. 1 shows immunofluorescence analysis of regeneration-related genes at the end of the first and second stages. [Figure 15B] FIG. 1 shows the expression analysis of somatic cell-related genes and regeneration-related genes in hADSCs and cells at the end of the second stage. [Figure 16] FIG. 1 shows GO term enrichment analysis of up-regulated genes in hADSCs and cells at the end of stage 2. [Figure 17] FIG. 1 shows the number of hCiPSC colonies using various second-stage transformation media. [Figure 18] FIG. 1 shows the number of hCiPSC colonies generated in second-stage transformation medium with or without a serine-threonine kinase Akt inhibitor and a casein kinase 2 inhibitor. [Figure 19]FIG. 1 shows the number of hCiPSC colonies using various stage 3 transformation media. [Figure 20] FIG. 1 shows exemplary epithelial-like cells expressing LIN28A at stage 1 or stage 2 depicted in a heat map. [Figure 21] FIG. 1 shows an exemplary composition comprising chemical reprogramming factors and optional cells in a first stage. [Figure 22] FIG. 1 shows the gene expression profile of exemplary intermediate plasticity state cells at stage 2. [Figure 23] FIG. 1 shows an exemplary composition comprising chemical reprogramming factors and optional cells in a second stage. [Figure 24] FIG. 1 shows exemplary CiPSCs expressing OCT4, SOX2, and NANOG shown in a heatmap. [Figure 25] FIG. 1 shows an exemplary composition comprising chemical reprogramming factors and optional cells in a third stage. DETAILED DESCRIPTION OF THE INVENTION

[0050] definition As used herein, the terms "conversion" or "reprogramming," and their grammatical equivalents, refer to a process of changing or reversing the differentiation state of a cell (e.g., a somatic cell), in the case of a cell. A conversion process, as used herein, refers to the conversion of a cell of a first cell type to a cell of a second cell type, or the conversion of one or more progeny cells of a cell of a first cell type to a cell of a second cell type.

[0051] As used herein, the term "differentiation" and its grammatical equivalents refer to the process by which a less differentiated cell (e.g., a relatively immature cell with a relatively high cell potency) changes into a more differentiated cell type (e.g., a relatively mature cell with a relatively low cell potency). The term "dedifferentiation" refers to the process by which a more differentiated cell changes into a less differentiated cell type (e.g., a relatively immature cell with a relatively high cell potency).

[0052] As used herein, the term "cell potency" refers to the ability of a cell to differentiate into cells of different cell lineages. For example, without being bound by theory, pluripotent cells (e.g., stem cells) have the ability to differentiate into cells belonging to or derived from any one of the three germ layers and therefore have high cell differentiation potential. The three germ layers are endoderm (e.g., stomach lining, digestive tract, lungs), mesoderm (e.g., muscle, bone, blood, urogenital system), and ectoderm (e.g., epidermal tissue and nervous system). Multipotent cells (e.g., certain types of stem cells such as hematopoietic stem cells, cardiac stem cells, or neural stem cells) have the ability to generate cells derived from multiple (but limited) lineages (e.g., blood lineage, cardiac cell lineage, neural cell lineage) and have lower cell differentiation potential than pluripotent cells. Lineage-committed or terminally differentiated cells have lower cell differentiation potential.

[0053] As used herein, the term "isolated cell population" refers to a group of cells that do not occur in nature.

[0054] As used herein, the term "cell population" or grammatical equivalents refers to a group of cells, their progeny, and / or cells derived therefrom. For example, a first cell population may include a first cell or the progeny of the first cell.

[0055] As used herein, the term "progeny cell," when used in reference to a cell, refers to any daughter cell resulting from mitosis of that cell or from mitosis of any progeny cell of that cell.

[0056] When the terms "at least," "greater than," or "greater than or equal to" are placed before the first number in a series of two or more numbers, the term "at least" or "greater than" applies to each and every number in the series.

[0057] When the terms "maximum," "not exceed," "less than," or "equal to or less than" precede the first number in a series of two or more numbers, the term "not exceed" or "less than" applies to each and every number in the series.

[0058] As used herein, the singular forms "a," "an," and "said" include plural references unless the context clearly dictates otherwise.

[0059] The term "and / or" as used herein in sentences such as "A and / or B" is intended to include both A and B, A or B, A alone, and B alone. Similarly, the term "and / or" as used in sentences such as "A, B and / or C" includes 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.

[0060] As used herein, the term "about" or "approximately" is intended to encompass, in the case of measurable values ​​(e.g., amounts or concentrations), variations of 20%, 10%, 5%, 1%, 0.5%, and even 0.1% of the given value. For example, based on common practice in the art, "about" may mean ±10%. Alternatively, "about" may mean a range of ±20%, ±10%, ±5%, or ±1% of the given value. Alternatively, particularly in biological systems or processes, the term may mean within an order of magnitude of the numerical value, up to 5-fold or 2-fold. When specific values ​​are described in the application and claims, unless otherwise specified, "about" should be interpreted to mean a range of tolerance for the particular value. Furthermore, when numerical ranges, subranges, or both are provided, the numerical ranges or subranges may include their endpoints. The terms "essentially," "essentially free," "essentially absent," and "about," when used to describe an order, position, or both, are used to indicate that the value is within a reasonably expected range. For example, a numerical value may be a value of a given value (or numerical range) ±0.1%, a given value (or numerical range) ±1%, a given value (or numerical range) ±2%, a given value (or numerical range) ±5%, a given value (or numerical range) ±10%, etc. Any numerical ranges recited herein are intended to include all subranges therein.

[0061] method In some embodiments, the present invention provides methods and compositions for cell conversion. In some cases, the method may include contacting a first cell population with a composition comprising one or more reprogramming factors. In some cases, the contacting may include incubating the first cell population with the composition comprising one or more reprogramming factors for a predetermined period of time. After contacting, at least a subset of the first cell population may be converted into a different cell. The converted cell population may comprise a second cell population. During or after conversion, the first cell population and the second cell population may have different biological characteristics. The different biological characteristics may include different gene expression, different protein expression, different cell proliferation characteristics (e.g., cell division or cell growth / cell mass increase), different cell size, different cell number, different cellular genome modifications (e.g., epigenetic modifications), different cell cycle stages, different senescence stages, or different differentiation stages or types, and any combination thereof. The first cell population and the second cell population may differ in the presence of cells with at least two different cellular activities. The first and second cell populations may differ in that they comprise different cell types, which may have different cellular activities as described herein.

[0062] In some embodiments, the present invention provides methods and compositions for converting cells in multiple steps. The methods and compositions for converting cells may include at least two, three, four, five, or more steps. The methods and compositions for converting cells may include up to two, three, four, or more steps. The methods and compositions for converting cells may include up to two steps. The methods and compositions for converting cells may include up to three steps. The methods and compositions for converting cells may include at least three steps. The three steps may include a first step (or step I), a second step (or step II), and / or a third step (or step III). The methods and compositions described herein may include a first step of converting somatic cells into cells with higher cellular potential (e.g., less differentiated cells), such as epithelial-like cells. The methods and compositions described herein may include a second step of converting epithelial-like cells into cells with higher cellular potential (e.g., less differentiated cells), such as intermediate plasticity state cells. The methods and compositions described herein may include a third step of converting intermediate plasticity state cells into cells with greater cellular differentiation potential (e.g., less differentiated cells), such as pluripotent stem cells. The methods and compositions described herein may include a first step, a second step, and a third step. One step of the steps may include contacting a first cell population with a first composition and converting at least a subset of the first cell population into a different cell. The converted cell population may include a second cell population.

[0063] In some cases, the method may include: (1) contacting a first population of cells with a first composition; (2) converting at least a subset of the first population of cells into a different cell type to generate a second population of cells comprising the converted cells; (3) contacting the second population of cells with a second composition; (4) converting at least a subset of the second population of cells into a different cell type to generate a third population of cells comprising the converted cells; (5) contacting the third population of cells with a third composition; and (6) converting at least a subset of the third population of cells into a different cell type to generate a fourth population of cells comprising the converted cells. The first composition, the second composition, and the third composition may each include one or more reprogramming factors. Any one of the first composition, the second composition, or the third composition may include one or more reprogramming factors. The first composition, the second composition, and the third composition may be different. The first cell population, the second cell population, the third cell population, and the fourth cell population may be different. In some cases, at least one cell of the cell populations contacted with the composition may be cultured before, during, or after contact, in each case. In some cases, the cell population contacted with the composition may be cultured before, during, or after conversion, in each case. In culturing the cells, the cells may undergo cell proliferation.

[0064] The ordinal number of a cell group or composition should not be construed as limiting the cell group or composition to a particular cell group or composition relative to other cell groups or compositions, and in some cases should be understood to be for the purpose of distinguishing the cell group or composition from other cell groups or compositions.

[0065] In some cases, the method may include: (1) contacting a first cell population comprising somatic cells with a first composition; (2) converting at least a subset of the somatic cells or their progeny cells into a different cell type to generate a second cell population comprising transformed cells comprising epithelial-like cells; (3) contacting the second cell population comprising epithelial-like cells with a second composition; (4) converting at least a subset of the second cell population into a different cell type to generate a third cell population comprising transformed cells comprising intermediate plasticity state cells; (5) contacting the third cell population comprising intermediate plasticity state cells with a third composition; and (6) converting at least a subset of the third cell population comprising intermediate plasticity state cells into a different cell type to generate a fourth cell population comprising transformed cells comprising pluripotent stem cells.

[0066] In some cases, the method may convert a population of cells comprising somatic cells into another population of cells comprising pluripotent stem cells within a pluripotent stem cell conversion period. The pluripotent stem cell conversion period may include the period from contacting the population of cells comprising somatic cells to generating at least one pluripotent stem cell. The pluripotent stem cell conversion period may be less than about 100 days, less than 90 days, less than 80 days, less than 70 days, less than 60 days, less than 59 days, less than 58 days, less than 57 days, less than 56 days, less than 55 days, less than 54 days, less than 53 days, less than 52 days, less than 51 days, less than 50 days, less than 49 days, less than 48 days, less than 47 days, less than 46 days, less than 45 days, less than 44 days, less than 43 days, less than 42 days, less than 41 days, less than 40 days, less than 39 days, less than 38 days, or less than 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 transformation period may be less than about 55 days. The pluripotent stem cell transformation period may be less than about 54 days. The pluripotent stem cell transformation period may be less than about 53 days. The pluripotent stem cell transformation period may be less than about 52 days. The pluripotent stem cell transformation period may be less than about 51 days. The pluripotent stem cell transformation period may be less than about 50 days. The pluripotent stem cell conversion period may be less than about 49 days. The pluripotent stem cell conversion period may be less than about 48 days. The pluripotent stem cell conversion period may be less than about 47 days. The pluripotent stem cell conversion period may be less than about 46 days. The pluripotent stem cell conversion period may be less than about 45 days. The pluripotent stem cell conversion period may be less than about 44 days. The pluripotent stem cell conversion period may be less than about 43 days. The pluripotent stem cell conversion period may be less than about 42 days. The pluripotent stem cell conversion period may be less than about 41 days. The pluripotent stem cell conversion period may be less than about 40 days. The pluripotent stem cell conversion period may be less than about 39 days. The pluripotent stem cell conversion period may be less than about 38 days. The pluripotent stem cell conversion period may be less than about 37 days.The pluripotent stem cell conversion period may be less than about 36 days. The pluripotent stem cell conversion period may be less than about 35 days. The pluripotent stem cell conversion period may be less than about 34 days. The pluripotent stem cell conversion period may be less than about 33 days. The pluripotent stem cell conversion period may be less than about 32 days. The pluripotent stem cell conversion period may be less than about 31 days. The pluripotent stem cell conversion period may be less than about 30 days. The pluripotent stem cell conversion period may be less than about 29 days. The pluripotent stem cell conversion period may be less than about 28 days. The pluripotent stem cell conversion period may be less than about 27 days. The pluripotent stem cell conversion period may be less than about 26 days. The pluripotent stem cell conversion period may be less than about 25 days. The pluripotent stem cell conversion period may be less than about 24 days. The pluripotent stem cell conversion period may be less than about 23 days. The pluripotent stem cell conversion period may be less than about 22 days. The pluripotent stem cell conversion period may be less than about 21 days. The pluripotent stem cell conversion period may be less than about 20 days. The pluripotent stem cell conversion period may be less than about 19 days. The pluripotent stem cell conversion period may be less than about 18 days. The pluripotent stem cell conversion period may be less than about 17 days. The pluripotent stem cell conversion period may be less than about 16 days. The pluripotent stem cell conversion period may be less than about 15 days.

[0067] In some cases, the method may convert a cell population containing somatic cells into another cell population containing pluripotent stem cells at a pluripotent stem cell conversion efficiency. The pluripotent stem cell conversion efficiency may be measured as the ratio (e.g., percentage) of the number of pluripotent stem cells generated to the number of somatic cells, where the method disclosed herein is applied to the number of pluripotent stem cells generated. For example, if the method generates one pluripotent stem cell from 1,000 somatic cells, the pluripotent stem cell conversion efficiency of the method is 0.1%. In some cases, the efficiency of pluripotent stem cell conversion by the method may 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 conversion efficiency of pluripotent stem cells by the method may 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 conversion efficiency of pluripotent stem cells by the method may be about 0.0005%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.0006%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.0007%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.0008%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.0009%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.001%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.002%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.003%.The conversion efficiency of pluripotent stem cells produced by the method may be about 0.004%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.005%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.006%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.007%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.008%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.009%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.01%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.02%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.03%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.04%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.05%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.06%. The conversion efficiency of pluripotent stem cells produced by the method may be about 0.07%. The conversion efficiency of pluripotent stem cells by the method may be about 0.08%, about 0.09%, or about 0.1%.

[0068] In some cases, the present invention provides a method for producing pluripotent stem cells. In some cases, the method includes obtaining and converting epithelial-like cells that express LIN28A. In some cases, the method includes converting the epithelial-like cells or their progeny into intermediate plasticity state cells for further conversion. In some cases, the intermediate plasticity 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 plasticity state cells into pluripotent stem cells. In some cases, converting the 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 contacted with the epithelial-like cells further comprises a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor. In some cases, the composition contacted with the epithelial-like cells further comprises a SAH hydrolase inhibitor or an adenosine kinase inhibitor.

[0069] 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 include (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 include (1) a MEK inhibitor, (2) a B-Raf inhibitor, and (3) a histone deacetylase inhibitor.

[0070] 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 population of cells including 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.

[0071] In some cases, epithelial-like cells expressing LIN28A are obtained by reprogramming a cell population containing epithelial cells. Epithelial cells can be converted into epithelial-like cells expressing LIN28A by contacting the epithelial cells with a composition comprising one or more reprogramming factors. 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.

[0072] The cells of any of the cell groups 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.

[0073] Phase 1 In some embodiments, the present disclosure provides methods and compositions for converting somatic cells into cells with greater cellular differentiation potential (e.g., less differentiated cells), such as epithelial-like cells. Such conversion processes are also referred to herein as "first stage." First stage methods may be part of a conversion process for reprogramming somatic cells into pluripotent stem cells. First stage methods may be the first stage in a conversion process for reprogramming somatic cells into pluripotent stem cells.

[0074] The first-stage method may include contacting a first cell population with a first composition. The first-stage method may include converting a subset of the first cell population into different cells after or during the contact period. The cell population comprising different cells may include a second cell population. The first-stage method may include incubating the first cell population with the first composition for a predetermined period of time. A subset of the first cell population may be converted into different cells before, during, or after the incubation. In some cases, the first-stage method may include removing the first composition from the second cell population. In other cases, the first-stage method may include removing the first composition from the first cell population.

[0075] The first population of 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 eggs). The somatic cells may not include gametophytes. In some cases, the somatic cells may further include muscle cells, adipocytes, connective tissue cells, vascular cells, neurons, bone cells, or skin cells. The first population of stage 1 cells may include fibroblasts, primary human adult adipose-derived mesenchymal stromal cells (hADSCs), smooth muscle cells, cardiac myocytes, 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 population of stage 1 cells may include fibroblasts or hADSCs. The first population of stage 1 cells may include fibroblasts. The first population of stage 1 cells may comprise primary human adult adipose-derived mesenchymal stromal cells (hADSCs). The first population of stage 1 cells may comprise smooth muscle cells. The first population of stage 1 cells may comprise cardiomyocytes. The first population of stage 1 cells may comprise skeletal muscle cells. The first population of stage 1 cells may comprise neurons. The first population of stage 1 cells may comprise red blood cells. The first population of stage 1 cells may comprise white blood cells. The first population of stage 1 cells may comprise platelets. The first population of stage 1 cells may comprise osteoblasts. The first population of stage 1 cells may comprise osteoclasts. The first population of stage 1 cells may comprise squamous cells. The first population of stage 1 cells may comprise basal cells. The first population of stage 1 cells may comprise melanocytes. The first population of staged cells may include cells of intestinal epithelial origin. The first population of staged cells may include neonatal (e.g., foreskin) or adult fibroblasts. The first population of staged cells may include epithelial cells, endothelial cells, mesenchymal-derived cells, parenchymal cells (e.g., hepatocytes), neural cells, or connective tissue cells, or any combination thereof. The first population of staged cells may be free of non-somatic cells.In some cases, the first population of cells in the first stage may include germ cells.

[0076] A first population of stage 1 cells can be isolated by disaggregating an appropriate organ or tissue. For example, tissues or organs can be mechanically disaggregated and / or treated with digestive enzymes and / or chelating agents that weaken the bonds between adjacent cells, thereby dispersing the tissue and preparing a single-cell suspension without significant cell disruption. Enzymatic treatment can be performed by mincing the tissue followed by treatment with one or more enzymes (e.g., trypsin, chymotrypsin, collagenase, elastase and / or hyaluronidase, DNase, pronase, dispase, etc.). Mechanical disaggregation can be accomplished by a variety of methods, including, but not limited to, grinders, blenders, sieves, homogenizers, pressure chambers, or ultrasonic generators.

[0077] The second population of cells in the first stage can include epithelial-like cells. The epithelial-like cells can be non-naturally occurring cells. The epithelial-like cells can express a combination of genes not expressed in naturally occurring cells. The epithelial-like cells can express at least one gene at a level of expression 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 more, greater than that of naturally occurring cells. The epithelial-like cells may express at least one gene at a level of expression 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 population of staged cells may comprise somatic cells or epithelial-like cells. The second population of staged cells may comprise somatic cells and epithelial-like cells. The second population of staged cells may be free of somatic cells. In some cases, the second population of staged cells may comprise fewer somatic cells than the first population of staged cells. For example, the second population of staged 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 population of staged cells. In some cases, the second population of staged cells may include more epithelial-like cells than the first population of staged cells. For example, the second population of cells in the first stage may contain 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 more epithelial-like cells than the first population of cells in the first stage.

[0078] Epithelial-like cells may express LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. Epithelial-like cells may express LIN28A. Epithelial-like cells may express NMYC. Epithelial-like cells may express WNT2B. Epithelial-like cells may express PAX8. Epithelial-like cells may express SMAD3. Epithelial-like cells may express GLI3. Epithelial-like cells may express KRT18. Epithelial-like cells may express KRT19. Epithelial-like cells may express WT1. Epithelial-like cells may express TBX2. Epithelial-like cells may express LIN28A and one or more of NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2. 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 express LIN28A and KRT18. The epithelial-like cells may express LIN28A and KRT19. The epithelial-like cells may express LIN28A and WT1. The epithelial-like cells may express LIN28A and TBX2. The epithelial-like cells may not express MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1 or TWIST2, or any combination thereof. The epithelial-like cells may not express MMP1. The epithelial-like cells may not express ZEB1. The epithelial-like cells may not express VIM. The epithelial-like cells may not express COL1A1. The epithelial-like cells may not express COL5A1. The epithelial-like cells may not express COL6A2. The epithelial-like cells may not express PRRX1. The epithelial-like cells may not express SNAI2. The epithelial-like cells may not express TWIST1. The epithelial-like cells may not express TWIST2.Epithelial-like cells may express LIN28A but may not express MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof. Epithelial-like cells may express LIN28A but may not express VIM. Epithelial-like cells may express LIN28A but may not express COL1A1. Epithelial-like cells may express LIN28A but may not express COL5A1. Epithelial-like cells may express LIN28A but may not express COL6A2. Epithelial-like cells may express LIN28A but may not express PRRX1. Epithelial-like cells may express LIN28A but may not express SNAI2. Epithelial-like cells may express LIN28A but may not express TWIST1. Epithelial-like cells may express LIN28A but may not express TWIST2. The epithelial-like cells may express LIN28A and one or more of NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, but may not express MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof.

[0079] The first population of stage 1 cells may not include epithelial-like cells of the present invention. The somatic cells of the first population of 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 cell may not express LIN28A, and may not express one or more of NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2. The somatic cell may not express LIN28A or NMYC. The somatic cell may not express LIN28A or WNT2B. The somatic cell may not express LIN28A or PAX8. The somatic cell may not express LIN28A or SMAD3. The somatic cell may not express LIN28A or GLI3. The somatic cell may not express LIN28A or KRT18. The somatic cell may not express LIN28A or KRT19. The somatic cell may not express LIN28A or WT1. The somatic cell may not express LIN28A or TBX2. The somatic cell may express MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof. The somatic cell may express MMP1. The somatic cell may express ZEB1. The somatic cell may express VIM. The somatic cell may express COL1A1. The somatic cell may express COL5A1. The somatic cell may express COL6A2. The somatic cell may express PRRX1. The somatic cell may express SNAI2. The somatic cell may express TWIST1. The somatic cell may express TWIST2.

[0080] Epithelial-like cells may express LIN28A and a second gene, but may not express a third gene. Epithelial-like cells may express LIN28A and one or more second genes, but may not express one or more third genes. The second genes expressed in epithelial-like cells may 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 may express a third gene. Somatic cells may not express LIN28A or one or more second genes, but may express one or more third genes. The second gene expressed in epithelial-like cells but not in somatic cells may include NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. The second gene may include NMYC. The second gene may include WNT2B. The second gene may include PAX8. The second gene may include SMAD3. The second gene may include GLI3. The second gene may include KRT18. The second gene may include KRT19. The second gene may include WT1. The second gene may include TBX2. The third gene not expressed in epithelial-like cells may include MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2, or any combination thereof. The third gene may include MMP1. The third gene may include ZEB1. The third gene may include VIM. The third gene may include COL1A1. The third gene may include COL5A1. The third gene may include COL6A2. The third gene may include PRRX1. The third gene may include SNAI2. The third gene may include TWIST1. The third gene may include TWIST2. Figure 20 shows exemplary epithelial-like cells expressing LIN28A in stage 1 or stage 2 depicted in a heat map.The y-axis and x-axis in the heatmap indicate the second and third genes, respectively. Each pixel in the heatmap 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 the second gene (e.g., NYMC and WNT2B) but does not express TWIST1. Cell 203 expresses LIN28A and KRT19 but does not express any combination of the third gene (e.g., MMP1 and VIM).

[0081] Compared to the cells of the first population of cells in the first stage, the cells of the second population of cells in the first stage may express higher levels of LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1, or TBX2, or any combination thereof. The higher expression level of any one of LIN28A, NMYC, WNT2B, PAX8, SMAD3, GLI3, KRT18, KRT19, WT1 or TBX2 in cells of the second population of staged cells may 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 in cells of the first population of staged cells compared to cells of the first population of staged cells. Compared to the cells of the first cell population of cells in the first stage, the cells of the second cell population of cells in the first stage may express lower levels of any one of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1 or TWIST2. The lower expression level of any one of MMP1, ZEB1, VIM, COL1A1, COL5A1, COL6A2, PRRX1, SNAI2, TWIST1, or TWIST2 in cells of the second population of staged 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 than in cells of the first population of staged cells. Expression levels may be measured by any method described herein. For example, gene expression may be measured by the method described in Example 2. Gene expression may be measured using any one of SEQ ID NOs: 1-83 (including a control).

[0082] In some embodiments, the present invention provides a composition comprising reprogramming factors used in the first stage of conversion, or a composition comprising cells in the first stage (first cell population or second cell population), or a composition comprising cells in the first stage (first cell population or second cell population) and reprogramming factors used in the first stage of conversion. In some cases, the composition comprises a medium containing the reprogramming factors used in the first stage of conversion.

[0083] In some cases, the composition may comprise a separated population of a second population of stage 1 cells. In some cases, the composition may comprise a separated population of a first population of stage 1 cells. The separated population of stage 1 cells may comprise at least about 1 x 10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The isolated population of cells in the first stage may contain up to about 1 x 10 cells or more. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 or 1×10 10 The dissociated population of stage 1 cells may comprise at least one epithelial-like cell. In some cases, the dissociated population of stage 1 cells may comprise at least about 1 x 10 cells. 1 , 1×10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10The isolated cell population may comprise up to about 1 x 10 or more epithelial-like cells. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 or 1×10 10 In some cases, the isolated population of cells in the first stage may comprise at least about 1 x 10 epithelial-like cells. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The isolated cell population may contain up to about 1 x 10 somatic cells or more. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 or 1×10 10 In some cases, the isolated population of cells in the first stage may comprise at least about 1 x 10 somatic cells. 1 , 1×10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The isolated population of cells in the first stage may comprise up to about 1 x 10 somatic cells, epithelial-like cells, or a combination thereof. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×108 , 1×10 9 or 1×10 10 The cells may comprise epithelial-like cells, somatic cells, or a combination thereof.

[0084] The composition may comprise a chemical reprogramming factor. The composition may comprise multiple 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 up to 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 one chemical reprogramming factor. The composition may comprise two chemical reprogramming factors. The composition may comprise three chemical reprogramming factors. The composition may comprise four chemical reprogramming factors. The composition may comprise five chemical reprogramming factors. The composition may comprise six chemical reprogramming factors. The composition may comprise seven chemical reprogramming factors. The composition may comprise eight chemical reprogramming factors. The composition may include 9 chemical reprogramming factors. The composition may include 10 chemical reprogramming factors. The composition may include 11 chemical reprogramming factors. The composition may include 12 chemical reprogramming factors. The composition may include 13 chemical reprogramming factors. The composition may include 14 chemical reprogramming factors. The composition may include 15 chemical reprogramming factors. The composition may include 16 chemical reprogramming factors. The composition may include 17 chemical reprogramming factors. The composition may include 18 chemical reprogramming factors. The composition may include 19 chemical reprogramming factors. The composition may include 20 chemical reprogramming factors. The chemical reprogramming factors in the composition may include any of the chemical reprogramming factors described herein.

[0085] 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 up to 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.

[0086] 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.

[0087] 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, or 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.

[0088] The composition may comprise somatic cells and at least one, two, three, four, five, six, seven, eight, nine, or ten 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, or any combination thereof. The composition may comprise somatic cells and at least one, two, three, four, five, six, seven, eight, nine, or ten 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 up to 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.

[0089] 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.

[0090] 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, 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 comprise any somatic cell described herein. For example, the somatic cells may comprise fibroblasts or hADSCs.

[0091] The composition may comprise epithelial-like cells; and at least one, two, three, four, five, six, seven, eight, nine, or ten 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, or any combination thereof. The composition may comprise epithelial-like cells; and at least one, two, three, four, five, six, seven, eight, nine, or ten 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 epithelial-like cells; and up to 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 epithelial-like 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.

[0092] The composition may comprise epithelial-like cells, a GSK inhibitor, and a TGFβ receptor inhibitor. The composition may comprise epithelial-like cells, a TGFβ receptor inhibitor, and an RAR agonist. The composition may comprise epithelial-like cells, a GSK inhibitor, and an RAR agonist. The composition may comprise epithelial-like cells and a GSK inhibitor. The composition may comprise epithelial-like cells and a TGFβ receptor inhibitor. The composition may comprise epithelial-like cells and an RAR agonist. The composition may comprise epithelial-like cells and an Akt inhibitor. The composition may comprise epithelial-like cells and a SETD2 inhibitor. The composition may comprise epithelial-like cells and a Dot1L inhibitor. The composition may comprise epithelial-like cells and an agonist of the G protein-coupled receptor Smoothened. The composition may comprise epithelial-like cells and a Jak1 / Jak2 inhibitor. The composition may comprise epithelial-like cells and an SAH hydrolase inhibitor. The composition may comprise epithelial-like cells and a Menin-MLL interaction inhibitor.

[0093] 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, or 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 ... or 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. 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.

[0094] Figure 21 shows an exemplary composition comprising chemical reprogramming factors and optional cells in the first stage. In Figure 21, "A" indicates a combination of a GSK inhibitor, a TGFβ receptor inhibitor, and an RAR agonist. "B" indicates an Akt inhibitor in the composition, where the composition may or may not contain an Akt inhibitor. "C" indicates 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, where the composition may or may not contain any compound in group C. "D" indicates somatic cells, epithelial-like cells, or a combination of somatic cells and epithelial-like cells, where the composition may or may not contain any one of these cells. For example, ABC1C2 refers to a composition comprising 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.

[0095] The composition may include CHIR99021 or CHIR98014. The composition may include E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334. The composition may include TTNPB, Ch55, or AM580. The composition may include SETD2-IN-1, EPZ-719, or MMSET-IN-1. The composition may include EPZ004777 or EPZ5676. The composition may include SAG, purmorphamine, Hh-Ag1.5, or human SHH. The composition may include ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib. The composition may include DZNep, NepA, Adox, or DZA. The composition may include VTP50469, MI3454, or WDR5-IN-4.

[0096] The composition is CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; Akt inhibitors; 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 is CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; Akt inhibitors; 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.

[0097] 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, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; or TTNPB, Ch55 or AM580. The composition may include CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; and TTNPB, Ch55 or AM580. The composition may include 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; or any combination thereof. The composition may include CHIR99021 or CHIR98014; E-616452, A 83-01, 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 include 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 include CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; and an Akt inhibitor. The composition may include 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, A 83-01, 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, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; TTNPB, Ch55 or AM580; and a SETD2 inhibitor.

[0098] The composition may include CHIR99021. The composition may include E-616452. The composition may include TTNPB. The composition may include AKTi. The composition may include SETD2-IN-1. The composition may include EPZ5676. The composition may include SAG. The composition may include ruxolitinib. The composition may include DZNep. The composition may include VTP50469.

[0099] 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.

[0100] The composition may include CHIR99021, E-616452, or TTNPB, or any combination thereof. The composition may include CHIR99021, E-616452, or TTNPB. The composition may include CHIR99021, E-616452, and TTNPB. The composition may include CHIR99021, E-616452, TTNPB, AKTi, or SETD2-IN-1, or any combination thereof. The composition may include CHIR99021, E-616452, TTNPB, AKTi, or SETD2-IN-1. The composition may include CHIR99021, E-616452, TTNPB, AKTi, and SETD2-IN-1. The composition may include CHIR99021, E-616452, TTNPB, or AKTi, or any combination thereof. The composition may include CHIR99021, E-616452, TTNPB, or AKTi. The composition may include CHIR99021, E-616452, TTNPB, and AKTi. The composition may include CHIR99021, E-616452, TTNPB, or SETD2-IN-1, or any combination thereof. The composition may include CHIR99021, E-616452, TTNPB, or SETD2-IN-1. The composition may include CHIR99021, E-616452, TTNPB, and SETD2-IN-1.

[0101] The composition is at least about 0.1 micromolar (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 The composition may contain up to 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 μM, 3 μM, 3.5 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 μM, 4 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 may be included in the composition.The composition may comprise about 1 μM CHIR99021 in the composition. The composition may comprise about 2 μM CHIR99021 in the composition. The composition may comprise about 3 μM CHIR99021 in the composition. The composition may comprise about 4 μM CHIR99021 in the composition. The composition may comprise about 5 μM CHIR99021 in the composition. The composition may comprise about 6 μM CHIR99021 in the composition. The composition may comprise about 7 μM CHIR99021 in the composition. The composition may comprise about 8 μM CHIR99021 in the composition. The composition may comprise about 9 μM CHIR99021 in the composition. The composition may comprise about 10 μM CHIR99021 in the composition. The composition may contain about 15 μM CHIR99021 in the composition. The composition may contain about 20 μM CHIR99021 in the composition. The composition may contain about 30 μM CHIR99021 in the composition. The composition may contain about 40 μM CHIR99021 in the composition. The composition may contain about 50 μM CHIR99021 in the composition. The composition may contain about 0.1 μM to about 100 μM CHIR99021 in the composition. The composition may contain about 0.2 μM to about 75 μM CHIR99021 in the composition. The composition may contain about 0.5 μM to about 50 μM CHIR99021 in the composition. The composition may contain about 1 μM to about 25 μM CHIR99021 in the composition. The composition may comprise about 2 μM to about 12.5 μM of CHIR99021 in the composition.The composition may comprise about 4 μM to about 6.25 μM of CHIR99021 in the composition.

[0102] The composition has 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 may be included within the composition. Compositions range up to approximately 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 may be included in the composition. The composition may include about 1 μM E-616452 in the composition. The composition may include about 2 μM E-616452 in the composition. The composition may include about 3 μM E-616452 in the composition. The composition may include about 4 μM E-616452 in the composition. The composition may include about 5 μM E-616452 in the composition. The composition may include about 6 μM E-616452 in the composition. The composition may include about 7 μM E-616452 in the composition. The composition may include about 8 μM E-616452 in the composition. The composition may include about 9 μM E-616452 in the composition. The composition may include about 10 μM E-616452 in the composition. The composition may comprise about 15 μM E-616452 in the composition.The composition may comprise about 20 μM E-616452 in the composition.The composition may comprise about 30 μM E-616452. The composition may comprise about 40 μM E-616452. The composition may comprise about 50 μM E-616452. The composition may comprise about 60 μM E-616452. The composition may comprise about 70 μM E-616452. The composition may comprise about 80 μM E-616452. The composition may comprise about 90 μM E-616452. The composition may comprise about 100 μM E-616452. The composition may comprise about 1 μM to about 100 μM E-616452. The composition may contain about 2 μM to about 75 μM of E-616452. The composition may contain about 3 μM to about 50 μM of E-616452. The composition may contain about 4 μM to about 40 μM of E-616452. The composition may contain about 5 μM to about 30 μM of E-616452. The composition may contain about 7.5 μM to about 20 μM of E-616452.

[0103] The composition may be 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 TTNPB may be included in 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 in the composition. The composition may comprise about 0.2 μM of TTNPB in the composition. The composition may include about 0.4 μM TTNPB in the composition. The composition may include about 0.6 μM TTNPB in the composition. The composition may include about 0.8 μM TTNPB in the composition. The composition may include about 1 μM TTNPB in the composition. The composition may include about 1.2 μM TTNPB in the composition. The composition may include about 1.4 μM TTNPB in the composition. The composition may include about 1.6 μM TTNPB in the composition. The composition may include about 1.8 μM TTNPB in the composition. The composition may include about 2 μM TTNPB in the composition. The composition may include about 4 μM TTNPB in the composition. The composition may include about 6 μM TTNPB in the composition. The composition may include about 8 μM TTNPB in the composition.The composition may contain about 10 μM TTNPB. The composition may contain about 12 μM TTNPB. The composition may contain about 14 μM TTNPB. The composition may contain about 16 μM TTNPB. The composition may contain about 18 μM TTNPB. The composition may contain about 20 μM TTNPB. The composition may contain about 0.2 μM to about 20 μM TTNPB. The composition may contain about 0.4 μM to about 15 μM TTNPB. The composition may contain about 0.6 μM to about 10 μM TTNPB. The composition may contain about 0.8 μM to about 8 μM TTNPB. The composition may contain about 1 μM to about 6 μM of TTNPB within the composition.The composition may contain about 1.5 μM to about 4 μM of TTNPB within the composition.

[0104] The composition may be 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 may be included within the composition. Compositions range up to approximately 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 may be included within the composition. The composition may include about 0.1 μM AKTi in the composition. The composition may include about 0.2 μM AKTi in the composition. The composition may include about 0.3 μM AKTi in the composition. The composition may include about 0.4 μM AKTi in the composition. The composition may include about 0.5 μM AKTi in the composition. The composition may include about 0.6 μM AKTi in the composition. The composition may include about 0.7 μM AKTi in the composition. The composition may include about 0.8 μM AKTi in the composition. The composition may include about 0.9 μM AKTi in the composition. The composition may include about 1 μM AKTi in the composition. The composition may include about 2 μM AKTi in the composition. The composition may include about 3 μM AKTi in the composition. The composition may include about 4 μM AKTi in the composition.The composition may contain about 5 μM AKTi. The composition may contain about 6 μM AKTi. The composition may contain about 7 μM AKTi. The composition may contain about 8 μM AKTi. The composition may contain about 9 μM AKTi. The composition may contain about 10 μM AKTi. The composition may contain about 0.1 μM to about 10 μM AKTi. The composition may contain about 0.2 μM to about 7.5 μM AKTi. The composition may contain about 0.3 μM to about 5 μM AKTi. The composition may contain about 0.4 μM to about 4 μM AKTi. The composition may contain about 0.5 μM to about 3 μM AKTi. The composition may comprise about 0.75 μM to about 2 μM of AKTi in the composition.

[0105] The composition may be 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 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 25 μM, 25 μM or more of SETD2-IN-1 may be included in the composition. Compositions range up to approximately 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 The composition may contain 25 μM or 25 μM of SETD2-in-1. The composition may contain about 0.05 μM of SETD2-in-1. The composition may contain about 0.1 μM of SETD2-in-1. The composition may contain about 0.15 μM of SETD2-in-1. The composition may contain about 0.2 μM of SETD2-in-1. The composition may contain about 0.25 μM of SETD2-in-1. The composition may contain about 0.3 μM of SETD2-in-1. The composition may contain about 0.35 μM of SETD2-in-1. The composition may contain about 0.4 μM of SETD2-in-1. The composition may comprise about 0.45 μM of SETD2-IN-1 in the composition.The composition may comprise about 0.5 μM SETD2-in-1. The composition may comprise about 1 μM SETD2-in-1. The composition may comprise about 1.5 μM SETD2-in-1. The composition may comprise about 2 μM SETD2-in-1. The composition may comprise about 2.5 μM SETD2-in-1. The composition may comprise about 3 μM SETD2-in-1. The composition may comprise about 3.5 μM SETD2-in-1. The composition may comprise about 4 μM SETD2-in-1. The composition may comprise about 4.5 μM SETD2-in-1. The composition may comprise about 5 μM SETD2-in-1. The composition may contain about 0.05 μM to about 2.5 μM of SETD2-IN-1. The composition may contain about 0.1 μM to about 1.875 μM of SETD2-IN-1. The composition may contain about 0.15 μM to about 1.25 μM of SETD2-IN-1. The composition may contain about 0.2 μM to about 1 μM of SETD2-IN-1. The composition may contain about 0.25 μM to about 0.75 μM of SETD2-IN-1. The composition may contain about 0.375 μM to about 0.5 μM of SETD2-IN-1.

[0106] The composition may be 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 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 25 μM or more of SAG may be included in the composition. Compositions range up to approximately 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 The composition may contain 25 μM or 25 μM of SAG. The composition may contain about 0.05 μM of SAG. The composition may contain about 0.1 μM of SAG. The composition may contain about 0.15 μM of SAG. The composition may contain about 0.2 μM of SAG. The composition may contain about 0.25 μM of SAG. The composition may contain about 0.3 μM of SAG. The composition may contain about 0.35 μM of SAG. The composition may contain about 0.4 μM of SAG. The composition may contain about 0.45 μM of SAG. The composition may contain about 0.5 μM of SAG. The composition may contain about 1 μM of SAG.The composition may contain about 1.5 μM SAG. The composition may contain about 2 μM SAG. The composition may contain about 2.5 μM SAG. The composition may contain about 3 μM SAG. The composition may contain about 3.5 μM SAG. The composition may contain about 4 μM SAG. The composition may contain about 4.5 μM SAG. The composition may contain about 5 μM SAG. The composition may contain about 0.05 μM to about 2.5 μM SAG. The composition may contain about 0.1 μM to about 1.875 μM SAG. The composition may contain about 0.15 μM to about 1.25 μM SAG. The composition may contain about 0.2 μM to about 1 μM of SAG in the composition. The composition may contain about 0.25 μM to about 0.75 μM of SAG in the composition. The composition may contain about 0.375 μM to about 0.5 μM of SAG in the composition.

[0107] The composition may be 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 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 25 μM or more of VTP50469 may be included in the composition. Compositions range up to approximately 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 The composition may comprise about 0.05 μM or 25 μM of VTP50469. The composition may comprise about 0.1 μM of VTP50469. The composition may comprise about 0.15 μM of VTP50469. The composition may comprise about 0.2 μM of VTP50469. The composition may comprise about 0.25 μM of VTP50469. The composition may comprise about 0.3 μM of VTP50469. The composition may comprise about 0.35 μM of VTP50469. The composition may comprise about 0.4 μM of VTP50469. The composition may comprise about 0.45 μM of VTP50469 in the composition.The composition may include about 0.5 μM VTP50469 in the composition. The composition may include about 1 μM VTP50469 in the composition. The composition may include about 1.5 μM VTP50469 in the composition. The composition may include about 2 μM VTP50469 in the composition. The composition may include about 2.5 μM VTP50469 in the composition. The composition may include about 3 μM VTP50469 in the composition. The composition may include about 3.5 μM VTP50469 in the composition. The composition may include about 4 μM VTP50469 in the composition. The composition may include about 4.5 μM VTP50469 in the composition. The composition may include about 5 μM VTP50469 in the composition. The composition may contain about 0.05 μM to about 2.5 μM of VTP50469. The composition may contain about 0.1 μM to about 1.875 μM of VTP50469. The composition may contain about 0.15 μM to about 1.25 μM of VTP50469. The composition may contain about 0.2 μM to about 1 μM of VTP50469. The composition may contain about 0.25 μM to about 0.75 μM of VTP50469. The composition may contain about 0.375 μM to about 0.5 μM of VTP50469.

[0108] The compositions 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 in the composition. Compositions range up to approximately 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 ruxolitinib may be included within the composition. The composition may comprise about 0.1 μM ruxolitinib in the composition. The composition may comprise about 0.2 μM ruxolitinib in the composition. The composition may comprise about 0.3 μM ruxolitinib in the composition. The composition may comprise about 0.4 μM ruxolitinib in the composition. The composition may comprise about 0.5 μM ruxolitinib in the composition. The composition may comprise about 0.6 μM ruxolitinib in the composition. The composition may comprise about 0.7 μM ruxolitinib in the composition. The composition may comprise about 0.8 μM ruxolitinib in the composition. The composition may comprise about 0.9 μM ruxolitinib in the composition. The composition may comprise about 1 μM of ruxolitinib in the composition. The composition may comprise about 2 μM of ruxolitinib in the composition.The composition may comprise about 3 μM ruxolitinib in the composition. The composition may comprise about 4 μM ruxolitinib in the composition. The composition may comprise about 5 μM ruxolitinib in the composition. The composition may comprise about 6 μM ruxolitinib in the composition. The composition may comprise about 7 μM ruxolitinib in the composition. The composition may comprise about 8 μM ruxolitinib in the composition. The composition may comprise about 9 μM ruxolitinib in the composition. The composition may comprise about 10 μM ruxolitinib in the composition. The composition may comprise about 0.1 μM to about 10 μM ruxolitinib in the composition. The composition may contain about 0.2 μM to about 7.5 μM of ruxolitinib. The composition may contain about 0.3 μM to about 5 μM of ruxolitinib. The composition may contain about 0.4 μM to about 4 μM of ruxolitinib. The composition may contain about 0.5 μM to about 3 μM of ruxolitinib. The composition may contain about 0.75 μM to about 2 μM of ruxolitinib.

[0109] The composition may be 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 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 The composition may contain 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM, 1 μM or more of DZNep. The composition is up to approximately 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 The composition may comprise 0.002 μM, 0.004 μM, 0.006 μM, 0.008 μM, 0.01 μM, 0.012 μM, 0.014 μM, 0.016 μM, or 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM, or 1 μM of DZNep. The composition may comprise about 0.002 μM of DZNep. The composition may comprise about 0.004 μM of DZNep. The composition may comprise about 0.006 μM of DZNep. The composition may comprise about 0.008 μM of DZNep. The composition may comprise about 0.01 μM of DZNep. The composition may comprise about 0.012 μM of DZNep. The composition may comprise about 0.014 μM of DZNep. The composition may comprise about 0.016 μM of DZNep.The composition may comprise about 0.018 μM DZNep in the composition. The composition may comprise about 0.02 μM DZNep in the composition. The composition may comprise about 0.04 μM DZNep in the composition. The composition may comprise about 0.06 μM DZNep in the composition. The composition may comprise about 0.08 μM DZNep in the composition. The composition may comprise about 0.1 μM DZNep in the composition. The composition may comprise about 0.12 μM DZNep in the composition. The composition may comprise about 0.14 μM DZNep in the composition. The composition may comprise about 0.16 μM DZNep in the composition. The composition may comprise about 0.18 μM DZNep in the composition. The composition may contain about 0.2 μM of DZNep. The composition may contain about 0.002 μM to about 0.2 μM of DZNep. The composition may contain about 0.0025 μM to about 0.15 μM of DZNep. The composition may contain about 0.005 μM to about 0.1 μM of DZNep. The composition may contain about 0.0075 μM to about 0.75 μM of DZNep. The composition may contain about 0.01 μM to about 0.5 μM of DZNep. The composition may contain about 0.015 μM to about 0.4 μM of DZNep.

[0110] The composition may be 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 EPZ5676 may be included in the composition. The composition may be 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 may be included within the composition. The composition may include about 0.2 μM EPZ5676 in the composition. The composition may include about 0.4 μM EPZ5676 in the composition. The composition may include about 0.6 μM EPZ5676 in the composition. The composition may include about 0.8 μM EPZ5676 in the composition. The composition may include about 1 μM EPZ5676 in the composition. The composition may include about 1.2 μM EPZ5676 in the composition. The composition may include about 1.4 μM EPZ5676 in the composition. The composition may include about 1.6 μM EPZ5676 in the composition. The composition may include about 1.8 μM EPZ5676 in the composition. The composition may include about 2 μM EPZ5676 in the composition. The composition may comprise about 4 μM EPZ5676 in the composition.The composition may comprise about 6 μM EPZ5676 in the composition.The composition may contain about 8 μM EPZ5676. The composition may contain about 10 μM EPZ5676. The composition may contain about 12 μM EPZ5676. The composition may contain about 14 μM EPZ5676. The composition may contain about 16 μM EPZ5676. The composition may contain about 18 μM EPZ5676. The composition may contain about 20 μM EPZ5676. The composition may contain about 0.2 μM to about 20 μM EPZ5676. The composition may contain about 0.4 μM to about 15 μM EPZ5676. The composition may contain about 0.6 μM to about 10 μM of EPZ5676. The composition may contain about 0.8 μM to about 8 μM of EPZ5676. The composition may contain about 1 μM to about 6 μM of EPZ5676. The composition may contain about 1.5 μM to about 4 μM of EPZ5676.

[0111] After contacting any group of stage 1 cells with any of the compositions described herein, the cells are incubated under hypoxic conditions. For example, stage 1 cells are 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 gas. The hypoxic conditions may include about 10% atmospheric oxygen gas. The hypoxic conditions may include about 9% atmospheric oxygen gas. The hypoxic conditions may include about 8% atmospheric oxygen gas. The hypoxic conditions may include about 7% atmospheric oxygen gas. The hypoxic conditions may include about 6% atmospheric oxygen gas. The hypoxic conditions may include about 5% atmospheric oxygen gas. The hypoxic conditions may include about 4% atmospheric oxygen gas. The hypoxic conditions may include about 3% atmospheric oxygen gas. The hypoxic conditions may include about 2% atmospheric oxygen gas. The hypoxic conditions may include about 1% atmospheric oxygen gas.

[0112] After contacting any population of stage 1 cells with any of the compositions described herein, the population of stage 1 cells may 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 population of stage 1 cells may be incubated with the composition for up to 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 population of stage 1 cells may be incubated with the composition for about 1 day. The population of stage 1 cells may be incubated with the composition for about 2 days. The population of stage 1 cells may be incubated with the composition for about 3 days. The population of stage 1 cells may be incubated with the composition for about 4 days. The population of stage 1 cells may be incubated with the composition for about 5 days. The population of stage 1 cells may be incubated with the composition for about 6 days. The population of stage 1 cells may be incubated with the composition for about 7 days. The population of stage 1 cells may be incubated with the composition for about 8 days. The population of stage 1 cells may be incubated with the composition for about 9 days. The population of stage 1 cells may be incubated with the composition for about 10 days. The population of stage 1 cells may be incubated with the composition for about 11 days. The population of stage 1 cells may be incubated with the composition for about 12 days. The population of stage 1 cells may be incubated with the composition for about 13 days. The population of stage 1 cells may be incubated with the composition for about 14 days. The population of stage 1 cells may be incubated with the composition for about 15 days. The population of stage 1 cells may be incubated with the composition for about 16 days. The population of stage 1 cells may be incubated with the composition for about 17 days. The population of stage 1 cells may be incubated with the composition for about 18 days.The population of stage 1 cells may be incubated with the composition for about 19 days. The population of stage 1 cells may be incubated with the composition for about 20 days. The population of stage 1 cells may be incubated with the composition for about 25 days.

[0113] Any of the compositions may be free of feeder cells or serum. Any of the compositions may be free of feeder cells and serum. Any of the compositions may be free of feeder cells. Any of the compositions may be free of serum. Any of the compositions may include feeder cells. Any of the compositions may include serum.

[0114] Phase 2 In some embodiments, the present invention provides second-stage methods and compositions for converting epithelial-like cells into cells with higher cellular differentiation potential (e.g., less differentiated cells), e.g., intermediate plasticity state cells. Such conversion processes are also referred to herein as "second stage." Second-stage methods may be part of a conversion process for reprogramming somatic cells or epithelial-like cells into pluripotent stem cells. Second-stage methods may be the second stage in a conversion process for reprogramming somatic cells into pluripotent stem cells.

[0115] The second-stage method may include contacting a first cell population with a first composition. The second-stage method may include converting a subset of the first cell population into different cells after or during the contact period. The cell population comprising different cells may include a second cell population. The second-stage method may include incubating the first cell population with the first composition for a predetermined period of time. A subset of the first cell population may be converted into different cells before, during, or after the incubation. In some cases, the second-stage method may include removing the first composition from the second cell population. In other cases, the second-stage method may include removing the first composition from the first cell population.

[0116] The population of cells in the second stage may comprise at least a subset of cells in the first stage. The population of cells in the second stage may comprise at most a subset of cells in the first stage. The population of cells in the second stage may comprise epithelial-like cells or somatic cells. The population of cells in the second stage may comprise epithelial-like cells. The population of cells in the second stage may comprise somatic cells. The population of cells in the second stage may comprise epithelial-like cells and somatic cells.

[0117] The first population of cells at the second stage may include any population of cells at the first stage. In some cases, the first population of cells at the second stage may include a second population of cells at the first stage.

[0118] The second population of cells in the second stage can include intermediate plasticity state cells. The first population of cells in the second stage can exclude intermediate plasticity state cells. The intermediate plasticity state cells can be non-naturally occurring cells. The intermediate plasticity state cells can express a combination of genes not expressed in naturally occurring cells. The intermediate plasticity state cells 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 more, higher than naturally occurring cells. The intermediate plasticity 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 than that of naturally occurring cells. The second population of second-stage cells may include somatic cells, epithelial-like cells, or intermediate plasticity state cells. The second population of second-stage cells may include somatic cells, epithelial-like cells, and intermediate plasticity state cells. The second population of second-stage cells may not include somatic cells or epithelial-like cells. In some cases, the second population of second-stage cells may include fewer somatic or epithelial-like cells than the first population of second-stage cells. For example, the second population of cells at the second stage 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 or epithelial-like cells than the first population of cells at the second stage. In some cases, the second population of cells at the second stage may include more intermediate plasticity state cells than the first population of cells at the second stage.For example, a second population of cells at the second stage 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 more intermediate plasticity state cells than a first population of cells at the second stage.

[0119] Intermediate plasticity state cells may exhibit reduced expression of genes expressed in somatic cells. Intermediate plasticity state cells may also exhibit increased expression of embryonic development-related genes, enhanced cell proliferation, and a reduced epigenetic methylation state. The promoter regions of genes related to embryonic development, cell cycle, and stem cell proliferation may be demethylated in intermediate plasticity state cells. Intermediate plasticity state cells may undergo dedifferentiation relative to somatic or epithelial-like cells. Genes upregulated in intermediate plasticity state cells may include those listed in Figure 16. In some cases, limb and appendage development-related genes may be upregulated, and intermediate plasticity state cells may have an open chromatin structure. Intermediate plasticity state cells can be reprogrammed to acquire characteristics of developing human limb bud cells (similar to limb regeneration in newts). Here, genes controlling embryonic limb development are reactivated during the dedifferentiation process. However, according to Guan (2002), dedifferentiation was not observed in frogs and mice, and no significant activation of the embryonic gene expression program was observed in limb tissue after injury.

[0120] Intermediate plasticity state cells may 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 plasticity state cells may express LIN28A. Intermediate plasticity state cells may express SALL4. Intermediate plasticity state cells may express MSX2. Intermediate plasticity state cells may express NMYC. Intermediate plasticity state cells may express WNT4. Intermediate plasticity state cells may express FGF19. Intermediate plasticity state cells may express TOP2A. Intermediate plasticity state cells may express MSX1. Intermediate plasticity state cells may express HOXB9. Intermediate plasticity state cells may express WT1. Intermediate plasticity state cells may express GATA2. Intermediate plasticity state cells may express HMGA2. Intermediate plasticity state cells may express LEF1. Intermediate plasticity state cells may express FGF9. Intermediate plasticity state cells may express HOXA9. Intermediate plasticity state cells may express HOZXA1. Intermediate plasticity state cells may express PTCH1. Intermediate plasticity state cells may express HOXA5. Intermediate plasticity state cells may express CCND2. Intermediate plasticity state cells may express SDC1. Intermediate plasticity state cells may express TBX3. Intermediate plasticity state cells may express BMP4. Intermediate plasticity state cells may express IGF2. Intermediate plasticity state cells may 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.

[0121] Intermediate plasticity state cells may express LIN28A or SALL4. Intermediate plasticity state cells may express LIN28A and SALL4. Intermediate plasticity state cells may 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 plasticity state cells may express LIN28A and SALL4; and MSX2. Intermediate plasticity state cells may express LIN28A and SALL4, and NMYC. Intermediate plasticity state cells may express LIN28A and SALL4, and WNT4. Intermediate plasticity state cells may express LIN28A, SALL4, and FGF19. Intermediate plasticity state cells may express LIN28A, SALL4, and TOP2A. Intermediate plasticity state cells may express LIN28A, SALL4, and MSX1. Intermediate plasticity state cells may express LIN28A, SALL4, and HOXB9. Intermediate plasticity state cells may express LIN28A, SALL4, and WT1. Intermediate plasticity state cells may express LIN28A, SALL4, and GATA2. Intermediate plasticity state cells may express LIN28A, SALL4, and HMGA2. Intermediate plasticity state cells may express LIN28A, SALL4, and LEF1. Intermediate plasticity state cells may express LIN28A, SALL4, and FGF9. Intermediate plasticity state cells may express LIN28A, SALL4, and HOXA9. Intermediate plasticity state cells may express LIN28A, SALL4, and HOZXA1. Intermediate plasticity state cells may express LIN28A, SALL4, and PTCH1. Intermediate plasticity state cells may express LIN28A, SALL4, and HOXA5. Intermediate plasticity state cells may express LIN28A, SALL4, and CCND2. Intermediate plasticity state cells may express LIN28A, SALL4, and SDC1.Intermediate plasticity state cells may express LIN28A and SALL4, and TBX3. Intermediate plasticity state cells may express LIN28A and SALL4, and BMP4. Intermediate plasticity state cells may express LIN28A and SALL4, and IGF2. Intermediate plasticity state cells may 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.

[0122] Intermediate plasticity state cells may express LIN28A and SALL4; a second gene; and a third gene. Epithelial-like cells may express LIN28A and SALL4; one or more second genes; and one or more third genes. The second genes expressed in intermediate plasticity state cells may 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. The 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 genes may include MSX2, NMYC, WNT4, FGF19, or TOP2A, or any combination thereof. The second genes may include MSX2. The second gene may include NMYC. The second gene may include WNT4. The second gene may include FGF19. The second gene may include TOP2A. The third gene may include MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1, or any combination thereof. The third gene may include MSX1. The third gene may include HOXB9. The third gene may include WT1. The third gene may include GATA2. The third gene may include HMGA2. The third gene may include LEF1. Intermediate plasticity state cells may 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 may include FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2, or any combination thereof. The fourth gene may include FGF9. The fourth gene may include HOXA9.The fourth gene may include HOZXA1. The fourth gene may include PTCH1. The fourth gene may include HOXA5. The fourth gene may include CCND2. The fourth gene may include SDC1. The fourth gene may include TBX3. The fourth gene may include BMP4. The fourth gene may include IGF2.

[0123] Figure 22 shows the gene expression profile of exemplary intermediate plasticity state cells at the second stage. In Figure 22, "A" indicates the expression of LIN28A and SALL4, "B" indicates the expression of a second gene, including MSX2, NMYC, WNT4, FGF19, or TOP2A, or any combination thereof, "C" indicates the expression of a third gene, including MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1, or any combination thereof, and "D" indicates the expression of a fourth gene, including FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2, or any combination thereof. For example, AB1C1D1 indicates an intermediate plasticity state cell expressing LIN28A, SALL4, MSX2, and MSX1. AB1C1 indicates intermediate plasticity state cells that express LIN28A, SALL4, MSX2, MSX1, and FGF9. These cells can express one or more of B, C, or D. For example, AB1B2C1C2D1D2 indicates intermediate plasticity state cells that express LIN28A, SALL4, MSX2, NMYC, MSX1, HOXB9, FGF9, and HOXA9.

[0124] The cells of the second population of cells in the second stage 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 the cells of the first population of cells in the second stage or either population of cells in the first stage. 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 population of second-stage cells may 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 in cells of the second population of second-stage cells compared to cells of either the first population of second-stage cells or the first population of first-stage cells. Relative to the cells of the second population of cells in the second stage, the cells of the first population of cells in the second stage 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.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 population of second-stage cells or any population of first-stage cells may 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 population of second-stage cells. The expression level may be measured by any method described herein. For example, gene expression may be measured by the method described in Example 2. Gene expression may be measured using any one of SEQ ID NOs: 1-83 (including controls).

[0125] In some embodiments, the present invention provides compositions comprising reprogramming factors for use in the second-stage conversion, or compositions comprising second-stage cells (first or second population of cells), or compositions comprising second-stage cells (first or second population of cells) and reprogramming factors for use in the second-stage conversion. In some cases, the composition comprises a medium containing the reprogramming factors for use in the second-stage conversion.

[0126] In some cases, the composition comprises a separated population of a second population of second-stage cells. In some cases, the composition comprises a separated population of a first population of second-stage cells. The separated population of second-stage cells is at least about 1 x 10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10The isolated population of cells in the second stage may contain up to about 1 x 10 cells or more. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 or 1×10 10 The isolated population of second-stage cells may comprise at least one intermediate plasticity state cell. In some cases, the isolated population of second-stage cells may comprise at least about 1 x 10 cells. 1 , 1×10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The isolated cell population may comprise up to about 1 x 10 cells or more intermediate plasticity state cells. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 or 1×10 10 In some cases, the isolated population of stage 3 cells may comprise at least about 1 x 10 intermediate plasticity state cells. 1 , 1×10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The isolated population of cells in the third stage may comprise up to about 1 x 10 cells, or more intermediate plasticity state cells, epithelial-like cells, or somatic cells, or any combination thereof. 2, 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 or 1×10 10 The cells may comprise intermediate plasticity state cells, epithelial-like cells or somatic cells, or any combination thereof.

[0127] The composition may comprise a chemical reprogramming factor. The composition may comprise multiple 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 up to 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 one chemical reprogramming factor. The composition may comprise two chemical reprogramming factors. The composition may comprise three chemical reprogramming factors. The composition may comprise four chemical reprogramming factors. The composition may comprise five chemical reprogramming factors. The composition may comprise six chemical reprogramming factors. The composition may include 7 chemical reprogramming factors. The composition may include 8 chemical reprogramming factors. The composition may include 9 chemical reprogramming factors. The composition may include 10 chemical reprogramming factors. The composition may include 11 chemical reprogramming factors. The composition may include 12 chemical reprogramming factors. The composition may include 13 chemical reprogramming factors. The composition may include 14 chemical reprogramming factors. The composition may include 15 chemical reprogramming factors. The composition may include 16 chemical reprogramming factors. The composition may include 17 chemical reprogramming factors. The composition may include 18 chemical reprogramming factors. The composition may include 19 chemical reprogramming factors. The composition may include 20 chemical reprogramming factors. The composition may include 21 chemical reprogramming factors. The composition may include 22 chemical reprogramming factors. The composition may include 23 chemical reprogramming factors. The composition may include 24 chemical reprogramming factors. The composition may include 25 chemical reprogramming factors.The chemical reprogramming factors in the composition may include any of the chemical reprogramming factors described herein.

[0128] 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 p38 MAPK inhibitor, an Akt inhibitor or a casein kinase 2 inhibitor. The composition may comprise up to 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 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.

[0129] The composition may include a GSK inhibitor. The composition may include a TGFβ receptor inhibitor. The composition may include a RAR agonist. The composition may include a c-Jun kinase inhibitor. The composition may include a CBP / p300 bromodomain inhibitor. The composition may include a SAH hydrolase inhibitor. The composition may include an adenosine kinase inhibitor. The composition may include a Dot1L inhibitor. The composition may include a Menin-MLL interaction inhibitor. The composition may include a SETD2 inhibitor. The composition may include an agonist of the G protein-coupled receptor Smoothened. The composition may include a ROCK inhibitor. The composition may include a BMP receptor / AMPK inhibitor. The composition may include a Jak1 / Jak2 inhibitor. The composition may include a p38 MAPK inhibitor. The composition may include an Akt inhibitor. The composition may include a casein kinase 2 inhibitor.

[0130] The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, 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 adenosine kinase inhibitor. The composition may comprise a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and an 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 an 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, an 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.

[0131] 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 one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen 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 up to 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.

[0132] 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 p38 MAPK 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.

[0133] 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 an 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 an 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 an 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. 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.

[0134] The composition may comprise intermediate plasticity state cells; 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 intermediate plasticity state cells and at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen 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 intermediate plasticity state cells and up to 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 intermediate plasticity state cells 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.

[0135] The composition may comprise intermediate plasticity state cells and a GSK inhibitor. The composition may comprise intermediate plasticity state cells and a TGFβ receptor inhibitor. The composition may comprise intermediate plasticity state cells and a RAR agonist. The composition may comprise intermediate plasticity state cells and a c-Jun kinase inhibitor. The composition may comprise intermediate plasticity state cells and a CBP / p300 bromodomain inhibitor. The composition may comprise intermediate plasticity state cells and a SAH hydrolase inhibitor. The composition may comprise intermediate plasticity state cells and an adenosine kinase inhibitor. The composition may comprise intermediate plasticity state cells and a Dot1L inhibitor. The composition may comprise intermediate plasticity state cells and a Menin-MLL interaction inhibitor. The composition may comprise intermediate plasticity state cells and a SETD2 inhibitor. The composition may comprise intermediate plasticity state cells and an agonist of the G protein-coupled receptor Smoothened. The composition may comprise intermediate plasticity state cells and a ROCK inhibitor. The composition may comprise intermediate plasticity state cells and a BMP receptor / AMPK inhibitor. The composition may comprise intermediate plasticity state cells and a Jak1 / Jak2 inhibitor. The composition may comprise intermediate plasticity state cells and a p38 MAPK inhibitor. The composition may comprise intermediate plasticity state cells and an Akt inhibitor. The composition may comprise intermediate plasticity state cells and a casein kinase 2 inhibitor.

[0136] The composition may comprise intermediate plasticity state cells; and a GSK inhibitor, a TGFβ receptor inhibitor, or a c-Jun kinase inhibitor, or any combination thereof. The composition may comprise intermediate plasticity state cells; and a GSK inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor. The composition may comprise intermediate plasticity state cells; 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 intermediate plasticity state cells; 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 intermediate plasticity state cells; 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 intermediate plasticity state cells, 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 intermediate plasticity state cells, and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and an SAH hydrolase inhibitor. The composition may comprise intermediate plasticity state cells, and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor, and an adenosine kinase inhibitor. The composition may comprise intermediate plasticity state cells; and a GSK inhibitor, a TGFβ receptor inhibitor, a c-Jun kinase inhibitor; and an SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise intermediate plasticity state cells, 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.

[0137] The intermediate plasticity state cells of the composition may express LIN28A, SALL4, MSX2, NMYC, WNT4, FGF19, or TOP2A, or any combination thereof. The intermediate plasticity state cells of the composition may express LIN28A and SALL4. The intermediate plasticity state cells of the composition may further express MSX2, NMYC, WNT4, FGF19, TOP2A, or a combination thereof. The intermediate plasticity state cells of the composition may express LIN28A, SALL4, and MSX2. The intermediate plasticity state cells of the composition may express LIN28A, SALL4, and NMYC. The intermediate plasticity state cells of the composition may express LIN28A, SALL4, and WNT4. The intermediate plasticity state cells of the composition may express LIN28A, SALL4, and FGF19. The intermediate plasticity state cells of the composition may express LIN28A, SALL4, and TOP2A. The intermediate plasticity state cells of the composition may further express any one or any combination of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1. Additionally, the intermediate plasticity state cells of the composition may further express any one or any combination of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2.

[0138] FIG. 23 shows an exemplary composition comprising chemical reprogramming factors and optional cells in the second stage. In Figure 23, "A" indicates a combination of a GSK inhibitor, a TGFβ receptor inhibitor, and a c-Jun kinase inhibitor; "B" indicates a combination of a CBP / p300 bromodomain inhibitor or one that does not contain a CBP / p300 bromodomain inhibitor; "C" indicates 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" indicates a Dot1L inhibitor, a Menin-MLL interaction inhibitor, a SETD2 inhibitor, a G protein-coupled receptor Smoothened agonist, 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; and "E" indicates epithelial-like cells, intermediate plasticity 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 comprising 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 plasticity state cells.

[0139] The composition may be 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, purmorphamine, 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 be 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, purmorphamine, 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 be 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, purmorphamine, 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 up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 of ellagic acid.The composition may be 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, purmorphamine, 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.

[0140] The composition may include CHIR99021 or CHIR98014. The composition may include E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine, or SB 525334. The composition may include TTNPB, Ch55, or AM580. The composition may include JNKIN8, JNKIN7, JNKIN5, or JNKIN12. The composition may include SGC-CBP30, I-CBP112, GNE272, or GNE409. The composition may include DZNep, NepA, Adox, or DZA. The composition may include 5-ITU or ABT 702. The composition may include EPZ004777 or EPZ5676. The composition may include VTP50469, MI3454, or WDR5-IN-4. The composition may include SETD2-IN-1, EPZ-719, or MMSET-IN-1. The composition may include SAG, purmorphamine, Hh-Ag1.5, or human SHH. The composition may include Y-27632 or thiazovivin. The composition may include dihydrodeoxymorphine. The composition may include ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib, or fedratinib. The composition may include BIRB796, SB203580, or SB202190. The composition may include AKTi. The composition may include CX-4945, TPP 22 or ellagic acid.

[0141] The composition may include 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 include CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; and a c-Jun kinase inhibitor. The composition may include 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; 5-ITU or ABT 702; or any combination thereof. The composition may include 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 include 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; and a SAH hydrolase inhibitor.The composition may include 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; and an adenosine kinase inhibitor. The composition may include CHIR99021 or CHIR98014; E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334; JNKIN8, JNKIN7, JNKIN5 or JNKIN12; and DZNep, NepA, Adox or DZA. The composition may include 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 include 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 include 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, purmorphamine, 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.

[0142] The composition may include 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 include 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 include up to 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 include 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.

[0143] The composition may include CHIR99021. The composition may include E-616452. The composition may include TTNPB. The composition may include JNKIN8. The composition may include SGC-CBP30. The composition may include DZNep. The composition may include 5-ITU. The composition may include EPZ004777. The composition may include VTP50469. The composition may include SETD2-IN-1. The composition may include SAG. The composition may include Y-27632. The composition may include dihydrodeoxymorphine. The composition may include ruxolitinib. The composition may include BIRB796. The composition may include AKTi. The composition may include CX-4945, TPP 22, or ellagic acid.

[0144] 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 an SAH hydrolase inhibitor or an adenosine kinase inhibitor. The composition may comprise CHIR99021; E-616452; JNKIN8; SGC-CBP30; and an 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 an 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 an 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.

[0145] The composition is 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 The composition may contain up to 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 μM, 3.5 μM, 4 μM, 4 μM, 4.5 μM, 5 μM, 5.5 μM, 6 μM, 6.5 μM, 7 μM, 7.5 μM, 8.5 μM, 9.5 μM, 10.5 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, 8.5 μM, 9.5 μM, 10 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 may be included in the composition. The composition may contain about 0.5 μM of CHIR99021 in the composition.The composition may comprise about 2 μM CHIR99021 in the composition. The composition may comprise about 3 μM CHIR99021 in the composition. The composition may comprise about 4 μM CHIR99021 in the composition. The composition may comprise about 5 μM CHIR99021 in the composition. The composition may comprise about 6 μM CHIR99021 in the composition. The composition may comprise about 7 μM CHIR99021 in the composition. The composition may comprise about 8 μM CHIR99021 in the composition. The composition may comprise about 9 μM CHIR99021 in the composition. The composition may comprise about 10 μM CHIR99021 in the composition. The composition may comprise about 15 μM CHIR99021 in the composition. The composition may comprise about 20 μM CHIR99021 in the composition. The composition may contain about 30 μM CHIR99021 in the composition. The composition may contain about 40 μM CHIR99021 in the composition. The composition may contain about 50 μM CHIR99021 in the composition. The composition may contain about 0.1 μM to about 100 μM CHIR99021 in the composition. The composition may contain about 0.2 μM to about 75 μM CHIR99021 in the composition. The composition may contain about 0.5 μM to about 50 μM CHIR99021 in the composition. The composition may contain about 1 μM to about 25 μM CHIR99021 in the composition. The composition may contain about 2 μM to about 12.5 μM CHIR99021 in the composition. The composition may comprise about 4 μM to about 6.25 μM of CHIR99021 in the composition.

[0146] The composition has 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 may be included within the composition. Compositions range up to approximately 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 may be included within the composition. The composition may comprise about 1 μM E-616452 in the composition. The composition may comprise about 2 μM E-616452 in the composition. The composition may comprise about 3 μM E-616452 in the composition. The composition may comprise about 4 μM E-616452 in the composition. The composition may comprise about 5 μM E-616452 in the composition. The composition may comprise about 6 μM E-616452 in the composition. The composition may comprise about 7 μM E-616452 in the composition. The composition may comprise about 8 μM E-616452 in the composition. The composition may comprise about 9 μM E-616452 in the composition. The composition may comprise about 10 μM E-616452 in the composition. The composition may comprise about 15 μM E-616452 in the composition. The composition may comprise about 20 μM E-616452 in the composition.The composition may comprise about 30 μM E-616452 in the composition. The composition may comprise about 40 μM E-616452 in the composition. The composition may comprise about 50 μM E-616452 in the composition. The composition may comprise about 60 μM E-616452 in the composition. The composition may comprise about 70 μM E-616452 in the composition. The composition may comprise about 80 μM E-616452 in the composition. The composition may comprise about 90 μM E-616452 in the composition. The composition may comprise about 100 μM E-616452 in the composition. The composition may comprise about 1 μM to about 100 μM E-616452 in the composition. The composition may contain about 2 μM to about 75 μM of E-616452. The composition may contain about 3 μM to about 50 μM of E-616452. The composition may contain about 4 μM to about 40 μM of E-616452. The composition may contain about 5 μM to about 30 μM of E-616452. The composition may contain about 7.5 μM to about 20 μM of E-616452.

[0147] The composition may be 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 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 25 μM, 25 μM or more of JNKIN8 may be included in the composition. Compositions range up to approximately 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 The composition may contain 25 μM or 25 μM JNKIN8. The composition may contain about 0.05 μM JNKIN8. The composition may contain about 0.1 μM JNKIN8. The composition may contain about 0.15 μM JNKIN8. The composition may contain about 0.2 μM JNKIN8. The composition may contain about 0.25 μM JNKIN8. The composition may contain about 0.3 μM JNKIN8. The composition may contain about 0.35 μM JNKIN8. The composition may contain about 0.4 μM JNKIN8. The composition may contain about 0.45 μM JNKIN8. The composition may contain about 0.5 μM JNKIN8.The composition may contain about 1 μM JNKIN8. The composition may contain about 1.5 μM JNKIN8. The composition may contain about 2 μM JNKIN8. The composition may contain about 2.5 μM JNKIN8. The composition may contain about 3 μM JNKIN8. The composition may contain about 3.5 μM JNKIN8. The composition may contain about 4 μM JNKIN8. The composition may contain about 4.5 μM JNKIN8. The composition may contain about 5 μM JNKIN8. The composition may contain about 0.05 μM to about 2.5 μM JNKIN8. The composition may contain about 0.1 μM to about 1.875 μM JNKIN8. The composition may contain about 0.15 μM to about 1.25 μM of JNKIN8. The composition may contain about 0.2 μM to about 1 μM of JNKIN8. The composition may contain about 0.25 μM to about 0.75 μM of JNKIN8. The composition may contain about 0.375 μM to about 0.5 μM of JNKIN8.

[0148] The composition may be 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 may be included within the composition. The composition may be 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 may be included in the composition. The composition may comprise about 0.2 μM SGC-CBP30 in the composition. The composition may comprise about 0.4 μM SGC-CBP30 in the composition. The composition may comprise about 0.6 μM SGC-CBP30 in the composition. The composition may comprise about 0.8 μM SGC-CBP30 in the composition. The composition may comprise about 1 μM SGC-CBP30 in the composition. The composition may comprise about 1.2 μM SGC-CBP30 in the composition. The composition may comprise about 1.4 μM SGC-CBP30 in the composition. The composition may comprise about 1.6 μM SGC-CBP30 in the composition. The composition may comprise about 1.8 μM SGC-CBP30 in the composition. The composition may comprise about 2 μM SGC-CBP30 in the composition. The composition may comprise about 4 μM SGC-CBP30 in the composition.The composition may comprise about 6 μM SGC-CBP30 in the composition. The composition may comprise about 8 μM SGC-CBP30 in the composition. The composition may comprise about 10 μM SGC-CBP30 in the composition. The composition may comprise about 12 μM SGC-CBP30 in the composition. The composition may comprise about 14 μM SGC-CBP30 in the composition. The composition may comprise about 16 μM SGC-CBP30 in the composition. The composition may comprise about 18 μM SGC-CBP30 in the composition. The composition may comprise about 20 μM SGC-CBP30 in the composition. The composition may comprise about 0.2 μM to about 20 μM SGC-CBP30 in the composition. The composition may contain about 0.4 μM to about 15 μM of SGC-CBP30. The composition may contain about 0.6 μM to about 10 μM of SGC-CBP30. The composition may contain about 0.8 μM to about 8 μM of SGC-CBP30. The composition may contain about 1 μM to about 6 μM of SGC-CBP30. The composition may contain about 1.5 μM to about 4 μM of SGC-CBP30.

[0149] The composition may be 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 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 The composition may contain 0.75 μM, 0.8 μM, 0.85 μM, 0.9 μM, 0.95 μM, 1 μM or more of DZNep. The composition is up to approximately 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 The composition may contain 0.002 μM, 0.004 μM, 0.006 μM, 0.008 μM, 0.01 μM, 0.012 μM, 0.014 μM, 0.016 μM, or 1 μM of DZNep. The composition may contain about 0.002 μM of DZNep. The composition may contain about 0.004 μM of DZNep. The composition may contain about 0.006 μM of DZNep. The composition may contain about 0.008 μM of DZNep. The composition may contain about 0.01 μM of DZNep. The composition may contain about 0.012 μM of DZNep. The composition may contain about 0.014 μM of DZNep. The composition may contain about 0.016 μM of DZNep.The composition may comprise about 0.018 μM DZNep in the composition. The composition may comprise about 0.02 μM DZNep in the composition. The composition may comprise about 0.04 μM DZNep in the composition. The composition may comprise about 0.06 μM DZNep in the composition. The composition may comprise about 0.08 μM DZNep in the composition. The composition may comprise about 0.1 μM DZNep in the composition. The composition may comprise about 0.12 μM DZNep in the composition. The composition may comprise about 0.14 μM DZNep in the composition. The composition may comprise about 0.16 μM DZNep in the composition. The composition may comprise about 0.18 μM DZNep in the composition. The composition may comprise about 0.2 μM DZNep in the composition. The composition may contain about 0.002 μM to about 0.2 μM of DZNep. The composition may contain about 0.0025 μM to about 0.15 μM of DZNep. The composition may contain about 0.005 μM to about 0.1 μM of DZNep. The composition may contain about 0.0075 μM to about 0.75 μM of DZNep. The composition may contain about 0.01 μM to about 0.5 μM of DZNep. The composition may contain about 0.015 μM to about 0.4 μM of DZNep.

[0150] The composition may be 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 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 5-ITU may be included in the composition. Compositions range up to approximately 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 The composition may contain 25 μM or 25 μM of 5-ITU. The composition may contain about 0.05 μM of 5-ITU. The composition may contain about 0.1 μM of 5-ITU. The composition may contain about 0.15 μM of 5-ITU. The composition may contain about 0.2 μM of 5-ITU. The composition may contain about 0.25 μM of 5-ITU. The composition may contain about 0.3 μM of 5-ITU. The composition may contain about 0.35 μM of 5-ITU. The composition may contain about 0.4 μM of 5-ITU. The composition may contain about 0.45 μM of 5-ITU. The composition may contain about 0.5 μM of 5-ITU.The composition may include about 1 μM 5-ITU in the composition. The composition may include about 1.5 μM 5-ITU in the composition. The composition may include about 2 μM 5-ITU in the composition. The composition may include about 2.5 μM 5-ITU in the composition. The composition may include about 3 μM 5-ITU in the composition. The composition may include about 3.5 μM 5-ITU in the composition. The composition may include about 4 μM 5-ITU in the composition. The composition may include about 4.5 μM 5-ITU in the composition. The composition may include about 5 μM 5-ITU in the composition. The composition may include about 0.05 μM to about 2.5 μM 5-ITU in the composition. The composition may contain about 0.1 μM to about 1.875 μM of 5-ITU. The composition may contain about 0.15 μM to about 1.25 μM of 5-ITU. The composition may contain about 0.2 μM to about 1 μM of 5-ITU. The composition may contain about 0.25 μM to about 0.75 μM of 5-ITU. The composition may contain about 0.375 μM to about 0.5 μM of 5-ITU.

[0151] The composition may be 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 TTNPB may be included in 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 in the composition. The composition may comprise about 0.2 μM of TTNPB in the composition. The composition may include about 0.4 μM TTNPB in the composition. The composition may include about 0.6 μM TTNPB in the composition. The composition may include about 0.8 μM TTNPB in the composition. The composition may include about 1 μM TTNPB in the composition. The composition may include about 1.2 μM TTNPB in the composition. The composition may include about 1.4 μM TTNPB in the composition. The composition may include about 1.6 μM TTNPB in the composition. The composition may include about 1.8 μM TTNPB in the composition. The composition may include about 2 μM TTNPB in the composition. The composition may include about 4 μM TTNPB in the composition. The composition may include about 6 μM TTNPB in the composition. The composition may include about 8 μM TTNPB in the composition.The composition may contain about 10 μM TTNPB. The composition may contain about 12 μM TTNPB. The composition may contain about 14 μM TTNPB. The composition may contain about 16 μM TTNPB. The composition may contain about 18 μM TTNPB. The composition may contain about 20 μM TTNPB. The composition may contain about 0.2 μM to about 20 μM TTNPB. The composition may contain about 0.4 μM to about 15 μM TTNPB. The composition may contain about 0.6 μM to about 10 μM TTNPB. The composition may contain about 0.8 μM to about 8 μM TTNPB. The composition may contain about 1 μM to about 6 μM TTNPB. The composition may comprise about 1.5 μM to about 4 μM TTNPB in the composition.

[0152] The composition may be 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 EPZ5676 may be included in the composition. The composition may be 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 may be included within the composition. The composition may include about 0.2 μM EPZ5676 in the composition. The composition may include about 0.4 μM EPZ5676 in the composition. The composition may include about 0.6 μM EPZ5676 in the composition. The composition may include about 0.8 μM EPZ5676 in the composition. The composition may include about 1 μM EPZ5676 in the composition. The composition may include about 1.2 μM EPZ5676 in the composition. The composition may include about 1.4 μM EPZ5676 in the composition. The composition may include about 1.6 μM EPZ5676 in the composition. The composition may include about 1.8 μM EPZ5676 in the composition. The composition may include about 2 μM EPZ5676 in the composition. The composition may include about 4 μM EPZ5676 in the composition. The composition may include about 6 μM EPZ5676 in the composition.The composition may contain about 8 μM EPZ5676. The composition may contain about 10 μM EPZ5676. The composition may contain about 12 μM EPZ5676. The composition may contain about 14 μM EPZ5676. The composition may contain about 16 μM EPZ5676. The composition may contain about 18 μM EPZ5676. The composition may contain about 20 μM EPZ5676. The composition may contain about 0.2 μM to about 20 μM EPZ5676. The composition may contain about 0.4 μM to about 15 μM EPZ5676. The composition may contain about 0.6 μM to about 10 μM EPZ5676. The composition may contain about 0.8 μM to about 8 μM of EPZ5676. The composition may contain about 1 μM to about 6 μM of EPZ5676. The composition may contain about 1.5 μM to about 4 μM of EPZ5676.

[0153] The composition may be 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 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 25 μM or more of VTP50469 may be included in the composition. Compositions range up to approximately 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 The composition may contain about 0.05 μM or 25 μM of VTP50469. The composition may contain about 0.1 μM of VTP50469. The composition may contain about 0.15 μM of VTP50469. The composition may contain about 0.2 μM of VTP50469. The composition may contain about 0.25 μM of VTP50469. The composition may contain about 0.3 μM of VTP50469. The composition may contain about 0.35 μM of VTP50469. The composition may contain about 0.4 μM of VTP50469. The composition may contain about 0.45 μM of VTP50469.The composition may comprise about 0.5 μM VTP50469 in the composition. The composition may comprise about 1 μM VTP50469 in the composition. The composition may comprise about 1.5 μM VTP50469 in the composition. The composition may comprise about 2 μM VTP50469 in the composition. The composition may comprise about 2.5 μM VTP50469 in the composition. The composition may comprise about 3 μM VTP50469 in the composition. The composition may comprise about 3.5 μM VTP50469 in the composition. The composition may comprise about 4 μM VTP50469 in the composition. The composition may comprise about 4.5 μM VTP50469 in the composition. The composition may comprise about 5 μM VTP50469 in the composition. The composition may contain about 0.05 μM to about 2.5 μM of VTP50469. The composition may contain about 0.1 μM to about 1.875 μM of VTP50469. The composition may contain about 0.15 μM to about 1.25 μM of VTP50469. The composition may contain about 0.2 μM to about 1 μM of VTP50469. The composition may contain about 0.25 μM to about 0.75 μM of VTP50469. The composition may contain about 0.375 μM to about 0.5 μM of VTP50469.

[0154] The composition may be 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 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 25 μM, 25 μM or more of SETD2-IN-1 may be included in the composition. Compositions range up to approximately 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 The composition may contain 25 μM or 25 μM of SETD2-in-1. The composition may contain about 0.05 μM of SETD2-in-1. The composition may contain about 0.1 μM of SETD2-in-1. The composition may contain about 0.15 μM of SETD2-in-1. The composition may contain about 0.2 μM of SETD2-in-1. The composition may contain about 0.25 μM of SETD2-in-1. The composition may contain about 0.3 μM of SETD2-in-1. The composition may contain about 0.35 μM of SETD2-in-1. The composition may contain about 0.4 μM of SETD2-in-1. The composition may comprise about 0.45 μM of SETD2-IN-1 in the composition.The composition may comprise about 0.5 μM SETD2-in-1. The composition may comprise about 1 μM SETD2-in-1. The composition may comprise about 1.5 μM SETD2-in-1. The composition may comprise about 2 μM SETD2-in-1. The composition may comprise about 2.5 μM SETD2-in-1. The composition may comprise about 3 μM SETD2-in-1. The composition may comprise about 3.5 μM SETD2-in-1. The composition may comprise about 4 μM SETD2-in-1. The composition may comprise about 4.5 μM SETD2-in-1. The composition may comprise about 5 μM SETD2-in-1. The composition may contain about 0.05 μM to about 2.5 μM of SETD2-IN-1. The composition may contain about 0.1 μM to about 1.875 μM of SETD2-IN-1. The composition may contain about 0.15 μM to about 1.25 μM of SETD2-IN-1. The composition may contain about 0.2 μM to about 1 μM of SETD2-IN-1. The composition may contain about 0.25 μM to about 0.75 μM of SETD2-IN-1. The composition may contain about 0.375 μM to about 0.5 μM of SETD2-IN-1.

[0155] The composition may be 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 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 25 μM or more of SAG may be included in the composition. Compositions range up to approximately 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 The composition may contain 25 μM or 25 μM SAG. The composition may contain about 0.05 μM SAG. The composition may contain about 0.1 μM SAG. The composition may contain about 0.15 μM SAG. The composition may contain about 0.2 μM SAG. The composition may contain about 0.25 μM SAG. The composition may contain about 0.3 μM SAG. The composition may contain about 0.35 μM SAG. The composition may contain about 0.4 μM SAG. The composition may contain about 0.45 μM SAG. The composition may contain about 0.5 μM SAG. The composition may contain about 1 μM SAG.The composition may contain about 1.5 μM SAG. The composition may contain about 2 μM SAG. The composition may contain about 2.5 μM SAG. The composition may contain about 3 μM SAG. The composition may contain about 3.5 μM SAG. The composition may contain about 4 μM SAG. The composition may contain about 4.5 μM SAG. The composition may contain about 5 μM SAG. The composition may contain about 0.05 μM to about 2.5 μM SAG. The composition may contain about 0.1 μM to about 1.875 μM SAG. The composition may contain about 0.15 μM to about 1.25 μM SAG. The composition may contain about 0.2 μM to about 1 μM of SAG in the composition. The composition may contain about 0.25 μM to about 0.75 μM of SAG in the composition. The composition may contain about 0.375 μM to about 0.5 μM of SAG in the composition.

[0156] The composition may be 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 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 1 μM, 25 μM or more dihydrodeoxymorphine may be included in the composition. Compositions range up to approximately 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 The composition may comprise 25 μM or 25 μM dihydrodeoxymorphine. The composition may comprise about 0.05 μM dihydrodeoxymorphine. The composition may comprise about 0.1 μM dihydrodeoxymorphine. The composition may comprise about 0.15 μM dihydrodeoxymorphine. The composition may comprise about 0.2 μM dihydrodeoxymorphine. The composition may comprise about 0.25 μM dihydrodeoxymorphine. The composition may comprise about 0.3 μM dihydrodeoxymorphine. The composition may comprise about 0.35 μM dihydrodeoxymorphine. The composition may comprise about 0.4 μM dihydrodeoxymorphine.The composition may comprise about 0.45 μM dihydrodeoxymorphine in the composition. The composition may comprise about 0.5 μM dihydrodeoxymorphine in the composition. The composition may comprise about 1 μM dihydrodeoxymorphine in the composition. The composition may comprise about 1.5 μM dihydrodeoxymorphine in the composition. The composition may comprise about 2 μM dihydrodeoxymorphine in the composition. The composition may comprise about 2.5 μM dihydrodeoxymorphine in the composition. The composition may comprise about 3 μM dihydrodeoxymorphine in the composition. The composition may comprise about 3.5 μM dihydrodeoxymorphine in the composition. The composition may comprise about 4 μM dihydrodeoxymorphine in the composition. The composition may comprise about 4.5 μM dihydrodeoxymorphine in the composition. The composition may contain about 5 μM dihydrodeoxymorphine. The composition may contain about 0.05 μM to about 2.5 μM dihydrodeoxymorphine. The composition may contain about 0.1 μM to about 1.875 μM dihydrodeoxymorphine. The composition may contain about 0.15 μM to about 1.25 μM dihydrodeoxymorphine. The composition may contain about 0.2 μM to about 1 μM dihydrodeoxymorphine. The composition may contain about 0.25 μM to about 0.75 μM dihydrodeoxymorphine. The composition may contain about 0.375 μM to about 0.5 μM dihydrodeoxymorphine.

[0157] The composition has 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 Y-27632 may be included in the composition. Compositions range up to approximately 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 may be included within the composition. The composition may comprise about 1 μM Y-27632 in the composition. The composition may comprise about 2 μM Y-27632 in the composition. The composition may comprise about 3 μM Y-27632 in the composition. The composition may comprise about 4 μM Y-27632 in the composition. The composition may comprise about 5 μM Y-27632 in the composition. The composition may comprise about 6 μM Y-27632 in the composition. The composition may comprise about 7 μM Y-27632 in the composition. The composition may comprise about 8 μM Y-27632 in the composition. The composition may comprise about 9 μM Y-27632 in the composition. The composition may comprise about 10 μM Y-27632 in the composition. The composition may comprise about 15 μM Y-27632 in the composition. The composition may comprise about 20 μM Y-27632 in the composition.The composition may comprise about 30 μM Y-27632 in the composition.The composition may contain about 40 μM Y-27632. The composition may contain about 50 μM Y-27632. The composition may contain about 60 μM Y-27632. The composition may contain about 70 μM Y-27632. The composition may contain about 80 μM Y-27632. The composition may contain about 90 μM Y-27632. The composition may contain about 100 μM Y-27632. The composition may contain about 1 μM to about 100 μM Y-27632. The composition may contain about 2 μM to about 75 μM Y-27632. The composition may contain about 3 μM to about 50 μM of Y-27632. The composition may contain about 4 μM to about 40 μM of Y-27632. The composition may contain about 5 μM to about 30 μM of Y-27632. The composition may contain about 7.5 μM to about 20 μM of Y-27632.

[0158] The compositions 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 in the composition. Compositions range up to approximately 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 ruxolitinib may be included within the composition. The composition may comprise about 0.1 μM ruxolitinib in the composition. The composition may comprise about 0.2 μM ruxolitinib in the composition. The composition may comprise about 0.3 μM ruxolitinib in the composition. The composition may comprise about 0.4 μM ruxolitinib in the composition. The composition may comprise about 0.5 μM ruxolitinib in the composition. The composition may comprise about 0.6 μM ruxolitinib in the composition. The composition may comprise about 0.7 μM ruxolitinib in the composition. The composition may comprise about 0.8 μM ruxolitinib in the composition. The composition may comprise about 0.9 μM ruxolitinib in the composition. The composition may comprise about 1 μM ruxolitinib in the composition.

[0159] The composition may be 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 may be included in the composition. The composition may be 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 may be included in the composition. The composition may comprise about 0.2 μM BIRB796 in the composition. The composition may comprise about 0.4 μM BIRB796 in the composition. The composition may comprise about 0.6 μM BIRB796 in the composition. The composition may comprise about 0.8 μM BIRB796 in the composition. The composition may comprise about 1 μM BIRB796 in the composition. The composition may comprise about 1.2 μM BIRB796 in the composition. The composition may comprise about 1.4 μM BIRB796 in the composition. The composition may comprise about 1.6 μM BIRB796 in the composition. The composition may comprise about 1.8 μM BIRB796 in the composition. The composition may comprise about 2 μM BIRB796 in the composition. The composition may comprise about 4 μM BIRB796 in the composition. The composition may include about 6 μM BIRB796 in the composition.The composition may contain about 8 μM BIRB796 in the composition. The composition may contain about 10 μM BIRB796 in the composition. The composition may contain about 12 μM BIRB796 in the composition. The composition may contain about 14 μM BIRB796 in the composition. The composition may contain about 16 μM BIRB796 in the composition. The composition may contain about 18 μM BIRB796 in the composition. The composition may contain about 20 μM BIRB796 in the composition. The composition may contain about 0.2 μM to about 20 μM BIRB796 in the composition. The composition may contain about 0.4 μM to about 15 μM BIRB796 in the composition. The composition may contain about 0.6 μM to about 10 μM BIRB796 in the composition. The composition may contain about 0.8 μM to about 8 μM of BIRB796. The composition may contain about 1 μM to about 6 μM of BIRB796. The composition may contain about 1.5 μM to about 4 μM of BIRB796.

[0160] The composition may be 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 may be included within the composition. Compositions range up to approximately 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 may be included within the composition. The composition may include about 0.1 μM AKTi in the composition. The composition may include about 0.2 μM AKTi in the composition. The composition may include about 0.3 μM AKTi in the composition. The composition may include about 0.4 μM AKTi in the composition. The composition may include about 0.5 μM AKTi in the composition. The composition may include about 0.6 μM AKTi in the composition. The composition may include about 0.7 μM AKTi in the composition. The composition may include about 0.8 μM AKTi in the composition. The composition may include about 0.9 μM AKTi in the composition. The composition may include about 1 μM AKTi in the composition. The composition may include about 2 μM AKTi in the composition. The composition may include about 3 μM AKTi in the composition. The composition may include about 4 μM AKTi in the composition.The composition may contain about 5 μM AKTi. The composition may contain about 6 μM AKTi. The composition may contain about 7 μM AKTi. The composition may contain about 8 μM AKTi. The composition may contain about 9 μM AKTi. The composition may contain about 10 μM AKTi. The composition may contain about 0.1 μM to about 10 μM AKTi. The composition may contain about 0.2 μM to about 7.5 μM AKTi. The composition may contain about 0.3 μM to about 5 μM AKTi. The composition may contain about 0.4 μM to about 4 μM AKTi. The composition may contain about 0.5 μM to about 3 μM AKTi. The composition may comprise about 0.75 μM to about 2 μM of AKTi in the composition.

[0161] The composition may be 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 may be included in the composition. The composition is up to approximately 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 The composition may comprise 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, or 8 μM of CX-4945. The composition may comprise about 0.08 μM of CX-4945. The composition may comprise about 0.1 μM of CX-4945. The composition may comprise about 0.2 μM of CX-4945. The composition may comprise about 0.3 μM of CX-4945.The composition may comprise about 0.4 μM CX-4945 in the composition. The composition may comprise about 0.5 μM CX-4945 in the composition. The composition may comprise about 0.6 μM CX-4945 in the composition. The composition may comprise about 0.7 μM CX-4945 in the composition. The composition may comprise about 0.8 μM CX-4945 in the composition. The composition may comprise about 0.9 μM CX-4945 in the composition. The composition may comprise about 1 μM CX-4945 in the composition. The composition may comprise about 1.5 μM CX-4945 in the composition. The composition may comprise about 2 μM CX-4945 in the composition. The composition may comprise about 3 μM CX-4945 in the composition. The composition may contain about 4 μM CX-4945. The composition may contain about 5 μM CX-4945. The composition may contain about 6 μM CX-4945. The composition may contain about 7 μM CX-4945. The composition may contain about 8 μM CX-4945. The composition may contain about 0.08 μM to about 8 μM CX-4945. The composition may contain about 0.1 μM to about 4 μM CX-4945. The composition may contain about 0.15 μM to about 2 μM CX-4945. The composition may contain about 0.25 μM to about 1.5 μM CX-4945. The composition may comprise about 0.5 μM to about 1 μM of CX-4945 in the composition.

[0162] After contacting any group of second-stage cells with any of the compositions described herein, the cells may be incubated under normoxic conditions. For example, second-stage cells may be incubated in up to 23%, 22%, 21%, 20%, or 19% atmospheric oxygen gas. Normoxic conditions may include about 22% atmospheric oxygen gas. Normoxic conditions may include about 21% atmospheric oxygen gas. Normoxic conditions may include about 20% atmospheric oxygen gas.

[0163] After contacting any population of second-stage cells with any of the compositions described herein, the population of second-stage cells may 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 population of second-stage cells may be incubated with the composition for up to 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 population of second-stage cells may be incubated with the composition for about 1 day. The population of second-stage cells may be incubated with the composition for about 2 days. The population of stage two cells may be incubated with the composition for about 3 days. The population of stage two cells may be incubated with the composition for about 4 days. The population of stage two cells may be incubated with the composition for about 5 days. The population of stage two cells may be incubated with the composition for about 6 days. The population of stage two cells may be incubated with the composition for about 7 days. The population of stage two cells may be incubated with the composition for about 8 days. The population of stage two cells may be incubated with the composition for about 9 days. The population of stage two cells may be incubated with the composition for about 10 days. The population of stage two cells may be incubated with the composition for about 11 days. The population of stage two cells may be incubated with the composition for about 12 days. The population of stage two cells may be incubated with the composition for about 13 days. The population of stage two cells may be incubated with the composition for about 14 days. The population of stage two cells may be incubated with the composition for about 15 days. The population of stage two cells may be incubated with the composition for about 16 days. The population of stage 2 cells may be incubated with the composition for about 17 days. The population of stage 2 cells may be incubated with the composition for about 18 days.The population of stage 2 cells may be incubated with the composition for about 19 days. The population of stage 2 cells may be incubated with the composition for about 20 days. The population of stage 2 cells may be incubated with the composition for about 25 days.

[0164] Any of the compositions may be free of feeder cells or serum. Any of the compositions may be free of feeder cells and serum. Any of the compositions may be free of feeder cells. Any of the compositions may be free of serum. Any of the compositions may include feeder cells. Any of the compositions may include serum.

[0165] Phase 3 In some embodiments, the present invention provides third-stage methods and compositions for converting intermediate plasticity state cells into cells with higher cellular differentiation potential (e.g., less differentiated cells), such as pluripotent stem cells. Such conversion processes are also referred to as "third stage" herein. The third stage method may be part of a conversion process for reprogramming intermediate plasticity state cells into pluripotent stem cells. The third stage method may be the third stage in a conversion process for reprogramming intermediate plasticity state cells into pluripotent stem cells.

[0166] The third-stage method may include contacting a first cell population with a first composition. The third-stage method may include converting a subset of the first cell population into different cells after or during the contact period. The cell population comprising different cells may include a second cell population. The third-stage method may include incubating the first cell population with the first composition for a predetermined period of time. A subset of the first cell population may be converted into different cells before, during, or after the incubation. In some cases, the third-stage method may include removing the first composition from the second cell population. In other cases, the third-stage method may include removing the first composition from the first cell population.

[0167] The first population of cells at the third stage may include any population of cells at stage 1 or stage 2. In some cases, the first population of cells at the third stage may include a second population of cells at stage 1 or stage 2. In some cases, the first population of cells at the third stage may include a composition wherein the second population of cells at stage 2 and the chemical reprogramming factors at stage 2 are separated or removed.

[0168] The second population of stage 3 cells may comprise pluripotent stem cells. The pluripotent stem cells obtained after contacting the population of cells with the composition may be referred to as chemically induced pluripotent stem cells (CiPSCs). The CiPSCs may comprise human CiPSCs (hCiPSCs). The first population of stage 3 cells may comprise pluripotent stem cells.

[0169] CiPSCs are not naturally occurring cells. CiPSCs may express combinations of genes that are not expressed in naturally occurring cells. In some cases, CiPSCs 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 more, higher than naturally occurring cells. In some cases, the CiPSCs 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 population of stage three cells may comprise somatic cells, epithelial-like cells, intermediate plasticity state cells, or CiPSCs. The second population of stage three cells may comprise somatic cells, epithelial-like cells, intermediate plasticity state cells, and CiPSCs. The second population of stage three cells may not comprise somatic cells, epithelial-like cells, or intermediate plasticity state cells. In some cases, the second population of stage 3 cells may include fewer somatic, epithelial-like, or intermediate plasticity state cells than the first population of stage 3 cells. For example, the second population of stage 3 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, epithelial-like, or intermediate plasticity state cells than the first population of stage 3 cells. In some cases, the second population of stage 3 cells may include more CiPSCs than the first population of stage 3 cells.For example, the second population of stage 3 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 CiPSCs than the first population of stage 3 cells.

[0170] CiPSCs may 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 may express OCT4. CiPSCs may express SOX2. CiPSCs may express NANOG. CiPSCs may express FGF4. CiPSCs may express ZFP57. CiPSCs may express DPPA5. CiPSCs may express REX1. CiPSCs may express DPPA4. CiPSCs may express TDGF1. CiPSCs may express TRA-1-60. CiPSCs may express TRA-1-81. CiPSCs may express SSEA4. CiPSCs may express KLF4. The CiPSCs may express KLF17. The CiPSCs may express DPPA3. The CiPSCs may express DNMT3L. The CiPSCs may express UTF1. The CiPSCs may 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.

[0171] CiPSCs may express OCT4, SOX2, or NANOG. CiPSCs may express OCT4, SOX2, and NANOG. CiPSCs may express OCT4 or SOX2. CiPSCs may express OCT4 or NANOG. CiPSCs may express SOX2 or NANOG. CiPSCs may express OCT4 and SOX2. CiPSCs may express OCT4 and NANOG. CiPSCs may express SOX2 and NANOG. CiPSCs may 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 may express OCT4, SOX2, and NANOG; and FGF4. CiPSCs may express OCT4, SOX2, and NANOG; and ZFP57. CiPSCs may express OCT4, SOX2, and NANOG; and DPPA5. CiPSCs may express OCT4, SOX2, and NANOG; and REX1. CiPSCs may express OCT4, SOX2, and NANOG; and DPPA4. CiPSCs may express OCT4, SOX2, and NANOG; and TDGF1. CiPSCs may express OCT4, SOX2, and NANOG; and TRA-1-60. CiPSCs may express OCT4, SOX2, and NANOG; and TRA-1-81. CiPSCs may express OCT4, SOX2, and NANOG; and SSEA4. CiPSCs may express OCT4, SOX2, and NANOG; and KLF4. The CiPSCs may express OCT4, SOX2, and NANOG; and KLF17. The CiPSCs may express OCT4, SOX2, and NANOG; and DPPA3. The CiPSCs may express OCT4, SOX2, and NANOG; and DNMT3L. The CiPSCs may express OCT4, SOX2, and NANOG; and UTF1.The CiPSCs may express one or more of OCT4, SOX2 and NANOG; and FGF4, ZFP57, DPPA5, REX1, DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DPPA5, DNMT3L, REX1 or UTF1.

[0172] The CPISCs may express OCT4, SOX2, and NANOG; a second gene; and a third gene. The epithelial-like cells may express OCT4, SOX2, and NANOG; one or more second genes; and one or more third genes. The second genes expressed by the CPISCs may include FGF4, ZFP57, DPPA5, or REX1, or any combination thereof. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express OCT4. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express SOX2. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express NANOG. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express OCT4, SOX2, or NANOG. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express OCT4, SOX2, or NANOG. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express OCT4, SOX2, or NANOG; a second gene; or a third gene. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express a second gene. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express a third gene. The somatic cells, epithelial-like cells, or intermediate plasticity state cells may not express OCT4, SOX2, or NANOG; one or more second genes; and one or more third genes.

[0173] The second gene may include FGF4, ZFP57, DPPA5, or REX1, or any combination thereof. The second gene may include FGF4. The second gene may include ZFP57. The second gene may include DPPA5. The second gene may include REX1. The third gene may include DPPA4, TDGF1, TRA-1-60, TRA-1-81, SSEA4, KLF4, KLF17, DPPA3, DNMT3L, or UTF1, or any combination thereof. The third gene may include DPPA4. The third gene may include TDGF1. The third gene may include TRA-1-60. The third gene may include TRA-1-81. The third gene may include SSEA4. The third gene may include KLF4. The third gene may include KLF17. The third gene may include DPPA3. The third gene may include DNMT3L. The third gene may include UTF1. Figure 24 shows exemplary CiPSCs expressing OCT4, SOX2, and NANOG shown in a heatmap. The x-axis and y-axis in the heatmap indicate the second gene and the third gene, respectively. Each pixel in 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 third genes (e.g., TRA-1-60 and TRA-1-81). Cell 243 expresses OCT4, SOX2, NANOG, KLF17, or any combination of second genes (e.g., DNMT3L and UTF1).

[0174] Compared to the cells of the first population of cells in the third stage or any population of cells in the first or second stage, the cells of the second population of cells in the third stage 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. A higher expression level of any one of OC4, 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, in cells of the second population of cells at a third stage means 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 cells of the first population of cells at a third stage or any population of cells at a first or second stage. Compared to cells of a second population of cells in a third stage, cells of a first population of cells in a third stage or any population of cells in a first or second stage 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.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 population of stage 3 cells or any population of stage 1 or stage 2 cells may 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 population of stage 3 cells. Expression levels may be measured by any method described herein. For example, gene expression may be measured by the method described in Example 2. Any one of SEQ ID NOs: 1-83 (including controls) may be used to measure gene expression.

[0175] In some embodiments, the present invention provides a composition comprising reprogramming factors for use in the third stage conversion, or a composition comprising cells at the third stage (first cell population or second cell population), or a composition comprising cells at the third stage (first cell population or second cell population) and reprogramming factors for use in the third stage conversion. In some cases, the composition comprises a medium containing the reprogramming factors for use in the third stage conversion.

[0176] In some cases, the composition may include an isolated population of a second population of stage three cells. In some cases, the composition may include an isolated population of a first population of stage three cells. The isolated population of stage three cells may be at least about 1 x 10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10The isolated population of cells in the third stage may contain up to about 1 x 10 cells or more. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The dissociated population of stage 3 cells may comprise at least one CiPSC. In some cases, the dissociated population of stage 3 cells may comprise at least about 1, 1 x 10 1 , 1×10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The isolated cell population may contain up to about 1 x 10 CiPSCs or more. 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 In some cases, the isolated population of stage 3 cells may comprise at least about 1 x 10 CiPSCs. 1 , 1×10 2 , 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The isolated population of stage 3 cells may comprise up to about 1 x 10 CiPSCs, intermediate plasticity state cells, epithelial-like cells, or somatic cells, or any combination thereof. 2 , 1×103 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 The cells may comprise CiPSCs, intermediate plasticity state cells, epithelial-like cells or somatic cells, or any combination thereof.

[0177] The composition may comprise a chemical reprogramming factor. The composition may comprise multiple 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 up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 chemical reprogramming factors. The composition may comprise one chemical reprogramming factor. The composition may comprise two chemical reprogramming factors. The composition may comprise three chemical reprogramming factors. The composition may comprise four chemical reprogramming factors. The composition may comprise five chemical reprogramming factors. The composition may comprise six chemical reprogramming factors. The composition may comprise seven chemical reprogramming factors. The composition may comprise eight chemical reprogramming factors. The composition may comprise nine chemical reprogramming factors. The composition may comprise ten chemical reprogramming factors. The composition may comprise eleven 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.

[0178] 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 demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor, or any combination thereof. The composition may comprise at least one, two, three, four, five, six, seven, or eight of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor. The composition may comprise up to one, two, three, four, five, six, seven, or eight of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor. 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 deacetylase inhibitor, a Dot1L inhibitor, and a SAH hydrolase inhibitor. The composition may comprise a MEK inhibitor. The composition may comprise a B-Raf inhibitor. The composition may comprise a histone deacetylase inhibitor. The composition may comprise a Wnt inhibitor. The composition may comprise a GSK inhibitor. The composition may comprise a ROCK inhibitor. The composition may comprise a histone demethylase inhibitor. The composition may comprise a Dot1L inhibitor. The composition may comprise a SAH hydrolase inhibitor.

[0179] The composition may comprise a MEK inhibitor, a B-Raf inhibitor or a histone deacetylase inhibitor. The composition may comprise a MEK inhibitor or a B-Raf inhibitor. The composition may comprise a MEK inhibitor or a histone deacetylase inhibitor. The composition may comprise a B-Raf inhibitor or a histone deacetylase inhibitor. The composition may comprise a MEK inhibitor, a B-Raf inhibitor and a histone deacetylase inhibitor.

[0180] The composition may comprise a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a Wnt inhibitor. The composition may comprise a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a GSK inhibitor. The composition may comprise a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a ROCK inhibitor. The composition may comprise a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a histone demethylase inhibitor. The composition may comprise a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a Dot1L inhibitor. The composition may comprise a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a SAH hydrolase inhibitor. The composition may comprise a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor; and one or more of a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

[0181] The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor, or any combination thereof. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and at least one, two, three, four, five, six, seven, or eight of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and up to one, two, three, four, five, six, seven, or eight of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, and a SAH hydrolase inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a B-Raf inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a histone deacetylase inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a Wnt inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a GSK inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a ROCK inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a histone demethylation inhibitor.The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a Dot1L inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a SAH hydrolase inhibitor. The intermediate plasticity state cells may further express one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A. The intermediate plasticity state cells may also further express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4, or IGF2.

[0182] The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, or a histone deacetylase inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor or a B-Raf inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor or a histone deacetylase inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a B-Raf inhibitor or a histone deacetylase inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, and a histone deacetylase inhibitor.

[0183] The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a Wnt inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a GSK inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a ROCK inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a histone demethylation inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a Dot1L inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a SAH hydrolase inhibitor. The composition may comprise intermediate plasticity state cells expressing LIN28A and SALL4; a MEK inhibitor, a B-Raf inhibitor, and a histone deacetylase inhibitor; and one or more of a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

[0184] The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor, or any combination thereof. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and at least one, two, three, four, five, six, seven, or eight of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and up to one, two, three, four, five, six, seven, or eight of a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, a Wnt inhibitor, a GSK inhibitor, a ROCK inhibitor, a histone demethylase inhibitor, a Dot1L inhibitor, and a SAH hydrolase inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a B-Raf inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a histone deacetylase inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a Wnt inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a GSK inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a ROCK inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a histone demethylation inhibitor.The composition may comprise CiPSCs expressing OCT4, SOX2 or NANOG; and a Dot1L inhibitor.

[0185] The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor, a B-Raf inhibitor, or a histone deacetylase inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor or a B-Raf inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor or a histone deacetylase inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a B-Raf inhibitor or a histone deacetylase inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor, a B-Raf inhibitor, and a histone deacetylase inhibitor.

[0186] The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor, a B-Raf inhibitor, a histone deacetylase inhibitor, and a Wnt inhibitor. The composition may comprise CiPSCs expressing OCT4, SOX2, or NANOG; and a MEK inhibitor...

Claims

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

2. 2. The method of claim 1, wherein converting 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 of claim 1 or 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 to 3, wherein the composition further comprises an 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) epithelial-like cells or their progeny; (i) a CBP / p300 bromodomain inhibitor or an adenosine kinase inhibitor; (ii) a glycogen kinase inhibitor, (iii) a TGFβ receptor inhibitor, and (iv) converting the epithelial-like cells or their progeny into intermediate plasticity state cells that express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A, by contacting the cells with a c-Jun kinase inhibitor; (c) converting the intermediate plastic state cell or its progeny into a pluripotent stem cell.

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

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

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

9. 9. The method of any one of claims 1 to 8, wherein the intermediate plasticity 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. 10. The method of claim 9, wherein the intermediate plasticity state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, or LEF1.

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

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

13. 13. The method of any one of claims 1 to 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. 14. The method of claim 13, wherein the pluripotent cells express one or more of FGF4, ZFP57, DPPA5, or REX1.

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

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

18. 17. The method of claim 16, wherein the somatic cells comprise fibroblasts.

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

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

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

22. 22. The method of any one of claims 16 to 21, wherein the method produces up to one pluripotent stem cell for every 1,000 somatic cells in a population of somatic cells.

23. 23. The method of claim 22, wherein the method produces up to one pluripotent stem cell for every 200 somatic cells in a population of somatic cells.

24. 24. The method of claim 23, wherein the method produces up to one pluripotent stem cell for every 50 somatic cells in a population of somatic cells.

25. The method further comprises culturing cells in a cell culture area per square centimeter (cm ２ ) Maximum of about 1 x 10 ６ 25. The method of any one of claims 16 to 24, comprising seeding somatic cells at a cell density of 0.1 to 0.

5.

26. Cell culture area 1cm ２ Maximum of about 5 x 10 ５ 26. The method of claim 25, wherein the somatic cells are seeded at a cell density of .

27. Cell culture area 1cm ２ Maximum of about 2.5 x 10 ５ 27. The method of claim 26, wherein the somatic cells are seeded at a cell density of .

28. A method for producing pluripotent stem cells, comprising: (a) obtaining a first cell population comprising epithelial-like cells that express LIN28A; (b) obtaining a second population of cells by 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; (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.

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

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

31. 31. The method of claim 30, wherein CHIR99021 is present in the second composition in an amount from about 0.5 micromolar (μM) to about 50 μM.

32. 32. The method of claim 31, wherein CHIR99021 is present in the second composition in an amount from about 1 μM to about 25 μM.

33. 33. The method of claim 32, wherein CHIR99021 is present in the second composition in an amount from about 2 μM to about 12.5 μM.

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

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

36. 36. The method of claim 35, wherein the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334, optionally wherein the TGFβ receptor inhibitor comprises E-616452.

37. 37. The method of claim 36, wherein E-616452 is present in the second composition in an amount of from about 1 μM to about 100 μM.

38. 38. The method of claim 37, wherein E-616452 is present in the second composition in an amount of from about 2 μM to about 50 μM.

39. 39. The method of claim 38, wherein E-616452 is present in the second composition in an amount of from about 4 μM to about 25 μM.

40. 40. The method of claim 39, wherein the amount of E-616452 present in the second composition is about 10 μM.

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

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

43. 43. The method of claim 42, wherein the amount of JNKIN8 present in the second composition is from about 0.05 μM to about 5 μM.

44. 44. The method of claim 43, wherein the amount of JNKIN8 present in the second composition is from about 0.1 μM to about 2.5 μM.

45. 45. The method of claim 44, wherein the amount of JNKIN8 present in the second composition is from about 0.2 μM to about 1.25 μM.

46. 46. ​​The method of claim 45, wherein the amount of JNKIN8 present in the second composition is about 0.5 μM.

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

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

49. 49. The method of claim 48, wherein PD0325901 is present in the third composition in an amount from about 0.1 μM to about 10 μM.

50. 50. The method of claim 49, wherein PD0325901 is present in the third composition in an amount from about 0.2 μM to about 5 μM.

51. 51. The method of claim 50, wherein PD0325901 is present in the third composition in an amount from about 0.4 μM to about 2.5 μM.

52. 52. The method of claim 51 , wherein PD0325901 is present in the third composition in an amount of about 1 μM.

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

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

55. 55. The method of claim 54, wherein SB590885 is present in the third composition in an amount from about 0.05 μM to about 5 μM.

56. 56. The method of claim 55, wherein SB590885 is present in the third composition in an amount from about 0.1 μM to about 2.5 μM.

57. 57. The method of claim 56, wherein SB590885 is present in the third composition in an amount from about 0.2 μM to about 1.25 μM.

58. 58. The method of claim 57, wherein SB590885 is present in the third composition in an amount of about 0.5 μM.

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

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

61. 61. The method of claim 60, wherein VPA is present in the third composition in an amount from about 0.1 millimolar (mM) to about 10 mM.

62. 62. The method of claim 61, wherein VPA is present in the third composition in an amount from about 0.2 mM to about 5 mM.

63. 63. The method of claim 62, wherein VPA is present in the third composition in an amount from about 0.4 mM to about 2.5 mM.

64. 64. The method of claim 63, wherein the amount of VPA present in the third composition is about 1 mM.

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

66. The method of any one of claims 28 to 64, wherein 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.

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

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

69. 69. The method of claim 68, wherein TTNPB is present in the composition in an amount of about 0.2 μM to about 20 μM.

70. 70. The method of claim 69, wherein TTNPB is present in the composition in an amount of about 0.4 μM to about 10 μM.

71. 71. The method of claim 70, wherein TTNPB is present in the composition in an amount of about 0.8 μM to about 5 μM.

72. 72. The method of claim 71, wherein the amount of TTNPB present in the composition is about 2 μM.

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

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

75. 75. The method of claim 74, wherein the amount of DZNep present in the second composition is from about 0.02 μM to about 2 μM.

76. 76. The method of claim 75, wherein DZNep is present in the second composition in an amount of about 0.04 μM to about 1 μM.

77. 77. The method of claim 76, wherein DZNep is present in the second composition in an amount of about 0.08 μM to about 0.5 μM.

78. 78. The method of claim 77, wherein the amount of DZNep present in the second composition is about 0.2 μM.

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

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

81. 81. The method of claim 80, wherein the amount of SGC-CBP30 present in the second composition is from about 0.2 μM to about 20 μM.

82. 82. The method of claim 81, wherein the amount of SGC-CBP30 present in the second composition is from about 0.4 μM to about 10 μM.

83. 83. The method of claim 82, wherein the amount of SGC-CBP30 present in the second composition is from about 0.8 μM to about 5 μM.

84. 84. The method of claim 83, wherein the amount of SGC-CBP30 present in the second composition is about 2 μM.

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

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

87. 87. The method of claim 86, wherein 5-ITU is present in the composition in an amount of about 0.05 μM to about 5 μM.

88. 88. The method of claim 87, wherein 5-ITU is present in the composition in an amount of from about 0.1 micromolar μM to about 2.5 μM.

89. 89. The method of claim 88, wherein 5-ITU is present in the composition in an amount of from about 0.2 micromolar μM to about 1 μM.

90. 90. The method of claim 89, wherein the amount of 5-ITU present in the composition is about 0.5 μM.

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

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

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

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

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

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

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

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

99. 99. The method of claim 98, wherein the pluripotent stem cell or its progeny comprises a genetic modification.

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

101. 101. The method of claim 100, wherein the foreign nucleic acid sequence encodes a polypeptide.

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

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

104. 104. The method of any one of claims 98 to 103, wherein the genetic modification reduces the immunogenicity of the pluripotent stem cell or its progeny.

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

106. 106. The method of claim 105, wherein the cell population is incubated with about 21% atmospheric oxygen gas during the contact period.

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

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

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

110. 110. The method of claim 109, wherein 5-ITU is present in the composition in an amount from about 0.05 micromolar (μM) to about 5 μM.

111. 111. The method of claim 110, wherein 5-ITU is present in the composition in an amount of from about 0.1 micromolar μM to about 2.5 μM.

112. 112. The method of claim 111, wherein the amount of 5-ITU present in the composition is from about 0.2 micromolar μM to about 1 μM.

113. 113. The method of claim 112, wherein the amount of 5-ITU present in the composition is about 0.5 μM.

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

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

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

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

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

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

120. 120. The method of claim 119, wherein the amount of DZNep present in the second composition is about 0.2 micromolar (μM).

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

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

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

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

125. 125. The method of claim 124, wherein CHIR99021 is present in the composition in an amount of from about 1 μM to about 25 μM.

126. 126. The method of claim 125, wherein CHIR99021 is present in the composition in an amount of from about 2 μM to about 12.5 μM.

127. 127. The method of claim 126, wherein CHIR99021 is present in the composition in an amount of about 5 μM.

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

129. 129. The method of claim 128, wherein the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334, optionally wherein the TGFβ receptor inhibitor comprises E-616452.

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

131. 131. The method of claim 130, wherein E-616452 is present in the composition in an amount of about 2 μM to about 50 μM.

132. 132. The method of claim 131, wherein E-616452 is present in the composition in an amount of about 4 μM to about 25 μM.

133. 133. The method of claim 132, wherein the amount of E-616452 present in the composition is about 10 μM.

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

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

136. 136. The method of claim 135, wherein JNKIN8 is present in the composition in an amount of from about 0.05 micromolar (μM) to about 50 μM.

137. The method of claim 136, wherein the amount of JNKIN8 present in the composition is from about 0.1 μM to about 2.5 μM.

138. The method of claim 137, wherein the amount of JNKIN8 present in the composition is from about 0.2 μM to about 1.25 μM.

139. The method of claim 138, wherein the amount of JNKIN8 present in the composition is about 0.5 μM.

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

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

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

143. 143. The method of claim 142, wherein the amount of SGC-CBP30 present in the composition is from about 0.2 micromolar (μM) to about 20 μM.

144. The method of claim 143, wherein the amount of SGC-CBP30 present in the composition is from about 0.4 μM to about 10 μM.

145. The method of claim 144, wherein the amount of SGC-CBP30 present in the composition is from about 0.8 μM to about 5 μM.

146. The method of claim 145, wherein the amount of SGC-CBP30 present in the composition is about 2 μM.

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

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

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

150. 150. The method of claim 149, wherein SETD2-IN-1 is present in the composition in an amount of about 0.05 μM to about 5 μM.

151. 151. The method of claim 150, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

152. 152. The method of claim 151, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

153. 153. The method of claim 152, wherein SETD2-IN-1 is present in the composition at an amount of about 0.4 μM.

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

155. 155. The method of claim 154, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.1 μM to about 10 μM.

156. 156. The method of claim 155, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.2 μM to about 5 μM.

157. 157. The method of claim 156, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.4 μM to about 2.5 μM.

158. 158. The method of claim 157, wherein the amount of AKT kinase inhibitor present in the composition is about 1 μM.

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

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

161. 161. The method of claim 160, wherein CX-4945 is present in the composition in an amount of from about 0.08 μM to about 8 μM.

162. 162. The method of claim 161, wherein CX-4945 is present in the composition in an amount of from about 0.16 μM to about 4 μM.

163. 163. The method of claim 162, wherein CX-4945 is present in the composition in an amount of from about 0.32 μM to about 2 μM.

164. 164. The method of claim 163, wherein CX-4945 is present in the composition in an amount of about 0.8 μM.

165. The method of any one of claims 105 to 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 of claim 165, wherein the Menin-MLL interaction inhibitor comprises VTP50469, MI3454 or WDR5-IN-4.

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

168. 168. The method of claim 167, wherein VTP50469 is present in the composition in an amount from about 0.05 micromolar (μM) to about 5 μM.

169. 169. The method of claim 168, wherein VTP50469 is present in the composition in an amount of about 0.1 μM to about 2.5 μM.

170. 170. The method of claim 169, wherein VTP50469 is present in the composition in an amount of about 0.2 μM to about 1.25 μM.

171. 171. The method of claim 170, wherein VTP50469 is present in the composition in an amount of about 0.5 μM.

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

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

174. 174. The method of claim 173, wherein the amount of SAG present in the composition is from about 0.05 micromolar (μM) to about 5 μM.

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

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

177. The method of claim 176, wherein the amount of SAG present in the composition is about 0.5 μM.

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

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

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

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

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

183. The method of claim 182, wherein the amount of Y-27632 present in the composition is about 10 μM.

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

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

186. 186. The method of claim 185, wherein the amount of dihydrodeoxymorphine present in the composition is from about 0.1 μM to about 2.5 μM.

187. The method of claim 186, wherein the amount of dihydrodeoxymorphine present in the composition is from about 0.2 μM to about 1.25 μM.

188. The method of claim 187, wherein the amount of dihydrodeoxymorphine present in the composition is about 0.5 μM.

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

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

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

192. 192. The method of claim 191, wherein the amount of TTNPB present in the composition is from about 0.2 μM to about 20 μM.

193. 193. The method of claim 192, wherein the amount of TTNPB present in the composition is from about 0.4 μM to about 10 μM.

194. The method of claim 193, wherein the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM.

195. The method of claim 194, wherein the amount of TTNPB present in the composition is about 2 μM.

196. 196. The method of any one of claims 105 to 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 of claim 196, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

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

199. 200. The method of claim 198, wherein EPZ5676 is present in the composition in an amount of about 0.2 μM to about 20 μM.

200. 200. The method of claim 199, wherein EPZ5676 is present in the composition in an amount of from about 0.4 μM to about 10 μM.

201. The method of claim 200, wherein EPZ5676 is present in the composition in an amount of from about 0.8 μM to about 5 μM.

202. The method of claim 201, wherein the amount of EPZ5676 present in the composition is about 2 μM.

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

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

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

206. The method of claim 205, wherein ruxolitinib is present in the composition in an amount of from about 0.2 μM to about 5 μM.

207. The method of claim 206, wherein ruxolitinib is present in the composition in an amount of from about 0.4 μM to about 2.5 μM.

208. The method of claim 207, wherein the amount of ruxolitinib present in the composition is about 1 μM.

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

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

211. The method of claim 210, wherein BIRB796 is present in the composition in an amount of from about 0.2 μM to about 20 μM.

212. The method of claim 211, wherein BIRB796 is present in the composition in an amount of about 0.4 μM to about 10 μM.

213. The method of claim 212, wherein BIRB796 is present in the composition in an amount of from about 0.8 μM to about 5 μM.

214. The method of claim 213, wherein the amount of BIRB796 present in the composition is about 2 μM.

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

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

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

218. 218. The method of any one of claims 105 to 217, wherein the method converts epithelial-like cells into intermediate plasticity state cells that express LIN28A and SALL4 and one or more of MSX2, NMYC, SDC1, WNT4, FGF19 or TOP2A.

219. The method of claim 218, wherein the intermediate plasticity state cells express one or more of MSX1, HOXB9, WT1, GATA2, HMGA2, LEF1, FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2.

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

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

222. 222. The method of any one of claims 105 to 221, wherein the intermediate plasticity state cell or a progeny thereof comprises a genetic modification.

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

224. 224. The method of claim 223, wherein the foreign nucleic acid sequence encodes a polypeptide.

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

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

227. The method of any one of claims 222 to 226, wherein the genetic modification reduces the immunogenicity of the intermediate plasticity state cell or its progeny.

228. 1. A method for reprogramming somatic cells, comprising: contacting a population of cells, including somatic cells, with a composition; The composition comprises: (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, (c) an RAR agonist, and (d) comprising one or more of an Akt inhibitor or a SETD2 inhibitor; method.

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

230. 229. The method of claim 228, wherein the somatic cells comprise fibroblasts.

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

232. 232. The method of claim 231, wherein the cell population is incubated with up to about 5% atmospheric oxygen gas during the contact period.

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

234. The method of claim 233, wherein CHIR99021 is present in the composition in an amount of from about 0.5 μM to about 50 μM.

235. 235. The method of claim 234, wherein CHIR99021 is present in the composition in an amount of from about 1 μM to about 25 μM.

236. 236. The method of claim 235, wherein CHIR99021 is present in the composition in an amount of from about 2 μM to about 12.5 μM.

237. 237. The method of claim 236, wherein CHIR99021 is present in the composition in an amount of about 5 μM.

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

239. The method of claim 238, wherein the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334, and optionally, the TGFβ receptor inhibitor comprises E-616452.

240. The method of claim 239, wherein the amount of E-616452 present in the composition is from about 1 μM to about 100 μM.

241. The method of claim 240, wherein the amount of E-616452 present in the composition is from about 2 μM to about 50 μM.

242. The method of claim 241, wherein the amount of E-616452 present in the composition is from about 4 μM to about 25 μM.

243. The method of claim 242, wherein the amount of E-616452 present in the composition is about 10 μM.

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

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

246. The method of claim 245, wherein the amount of TTNPB present in the composition is from about 0.2 μM to about 20 μM.

247. The method of claim 246, wherein the amount of TTNPB present in the composition is from about 0.4 μM to about 10 μM.

248. The method of claim 247, wherein the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM.

249. The method of claim 248, wherein the amount of TTNPB present in the composition is about 2 μM.

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

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

252. 252. The method of claim 251, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.1 μM to about 10 μM.

253. 253. The method of claim 252, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.2 μM to about 5 μM.

254. 254. The method of claim 253, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.4 μM to about 2.5 μM.

255. 255. The method of claim 254, wherein the amount of AKT kinase inhibitor present in the composition is about 1 μM.

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

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

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

259. 259. The method of claim 258, wherein SETD2-IN-1 is present in the composition in an amount of about 0.05 μM to about 5 μM.

260. 260. The method of claim 259, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

261. 261. The method of claim 260, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

262. 262. The method of claim 261, wherein the amount of SETD2-IN-1 present in the composition is about 0.4 μM.

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

264. 264. The method of any one of claims 228-263, wherein the composition does not comprise feeder cells.

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

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

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

268. The method of claim 267, wherein the amount of SAG present in the composition is from about 0.05 μM to about 5 μM.

269. The method of claim 268, wherein the amount of SAG present in the composition is from about 0.1 μM to about 2.5 μM.

270. The method of claim 269, wherein the amount of SAG present in the composition is from about 0.2 μM to about 1.25 μM.

271. The method of claim 270, wherein the amount of SAG present in the composition is about 0.5 μM.

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

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

274. The method of claim 273, wherein VTP50469 is present in the composition in an amount of about 0.05 μM to about 5 μM.

275. The method of claim 274, wherein VTP50469 is present in the composition in an amount of about 0.1 μM to about 2.5 μM.

276. The method of claim 275, wherein VTP50469 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

277. The method of claim 276, wherein the amount of VTP50469 present in the composition is about 0.5 μM.

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

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

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

281. The method of claim 280, wherein ruxolitinib is present in the composition in an amount of from about 0.1 μM to about 10 μM.

282. The method of claim 281, wherein the amount of ruxolitinib present in the composition is from about 0.2 μM to about 5 μM.

283. The method of claim 282, wherein the amount of ruxolitinib present in the composition is from about 0.4 μM to about 2.5 μM.

284. The method of claim 283, wherein the amount of ruxolitinib present in the composition is about 1 μM.

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

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

287. The method of claim 286, wherein the amount of DZNep present in the second composition is from about 0.02 μM to about 2 μM.

288. The method of claim 287, wherein the amount of DZNep present in the second composition is from about 0.04 μM to about 1 μM.

289. The method of claim 288, wherein the amount of DZNep present in the second composition is from about 0.08 μM to about 0.5 μM.

290. The method of claim 299, wherein the amount of DZNep present in the second composition is about 0.2 μM.

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

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

293. 293. The method of claim 292, wherein the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM.

294. 294. The method of claim 293, wherein the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM.

295. 295. The method of claim 294, wherein the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM.

296. The method of claim 295, wherein the amount of EPZ5676 present in the composition is about 2 μM.

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

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

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

300. 300. The method of any one of claims 228 to 299, wherein said method converts somatic cells into epithelial-like cells that express LIN28A.

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

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

304. The method of claim 303, wherein the epithelial-like cells or their progeny comprise a genetic modification.

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

306. 306. The method of claim 305, wherein the foreign nucleic acid sequence encodes a polypeptide.

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

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

309. The method of any one of claims 228 to 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: producing pluripotent stem cells by contacting a cell population comprising intermediate plasticity state cells or their progeny with a composition comprising (a) a MEK inhibitor, (b) a B-Raf inhibitor, and (c) a histone deacetylase inhibitor; the intermediate plasticity state cells express LIN28A and SALL4, and one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A; method.

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

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

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

314. 314. The method of claim 313, wherein PD0325901 is present in the third composition in an amount of from about 0.1 μM to about 10 μM.

315. The method of claim 314, wherein PD0325901 is present in the third composition in an amount of from about 0.2 μM to about 5 μM.

316. The method of claim 315, wherein PD0325901 is present in the third composition in an amount of from about 0.4 μM to about 2.5 μM.

317. The method of claim 316, wherein the amount of PD0325901 present in the third composition is about 1 μM.

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

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

320. 320. The method of claim 319, wherein SB590885 is present in the composition in an amount of about 0.05 μM to about 5 μM.

321. 321. The method of claim 320, wherein SB590885 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

322. 322. The method of claim 321, wherein SB590885 is present in the composition in an amount of about 0.2 μM to about 1.25 μM.

323. The method of claim 322, wherein SB590885 is present in the composition in an amount of about 0.5 μM.

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

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

326. 326. The method of claim 325, wherein VPA is present in the composition in an amount of about 0.1 millimolar (mM) to 10 mM.

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

328. The method of claim 327, wherein the amount of VPA present in the composition is between about 0.4 mM and 2.5 mM.

329. The method of claim 328, wherein the amount of VPA present in the composition is about 1 mM.

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

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

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

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

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

335. The method of claim 334, wherein the amount of IWP-2 present in the composition is from about 0.2 μM to about 20 μM.

336. The method of claim 335, wherein the amount of IWP-2 present in the composition is from about 0.4 μM to about 10 μM.

337. The method of claim 336, wherein the amount of IWP-2 present in the composition is from about 0.8 μM to about 5 μM.

338. The method of claim 337, wherein the amount of IWP-2 present in the composition is about 2 μM.

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

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

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

342. 342. The method of claim 341, wherein CHIR99021 is present in the composition in an amount from about 0.1 micromolar (μM) to about 10 μM.

343. The method of claim 342, wherein CHIR99021 is present in the composition in an amount of about 0.2 μM to about 5 μM.

344. The method of claim 343, wherein CHIR99021 is present in the composition in an amount of about 0.4 μM to about 2.5 μM.

345. The method of claim 344, wherein the amount of CHIR99021 present in the composition is about 1 μM.

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

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

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

349. The method of claim 348, wherein the amount of Y-27632 present in the composition is from about 1 μM to about 100 μM.

350. The method of claim 349, wherein the amount of Y-27632 present in the composition is from about 2 μM to about 50 μM.

351. The method of claim 350, wherein the amount of Y-27632 present in the composition is from about 4 μM to about 25 μM.

352. The method of claim 351, wherein the amount of Y-27632 present in the composition is about 10 μM.

353. 353. The method of 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 of claim 353, wherein the composition further comprises a histone demethylation inhibitor.

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

356. The method of claim 355, wherein the amount of tranylcypromine present in the composition is from about 1 μM to about 100 μM.

357. The method of claim 356, wherein the amount of tranylcypromine present in the composition is from about 2 μM to about 50 μM.

358. The method of claim 357, wherein the amount of tranylcypromine present in the composition is from about 4 μM to about 25 μM.

359. The method of claim 358, wherein the amount of tranylcypromine present in the composition is about 10 μM.

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

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

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

363. The method of claim 362, wherein the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM.

364. The method of claim 363, wherein the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM.

365. The method of claim 364, wherein the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM.

366. The method of claim 365, wherein the amount of EPZ5676 present in the composition is about 2 μM.

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

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

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

370. The method of claim 369, wherein the amount of DZNep present in the composition is from about 0.02 μM to about 20 μM.

371. The method of claim 370, wherein the amount of DZNep present in the composition is from about 0.04 μM to about 10 μM.

372. The method of claim 371, wherein the amount of DZNep present in the composition is from about 0.08 μM to about 5 μM.

373. The method of claim 372, wherein the amount of DZNep present in the composition is about 0.2 μM.

374. 374. The method of any one of claims 310 to 373, wherein said contacting comprises culturing a population of cells in said composition.

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

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

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

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

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

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

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

383. 383. The method of any one of claims 310 to 382, ​​wherein the method converts an intermediate plasticity state cell or its progeny into a pluripotent stem cell.

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

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

387. The method of 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. 388. The method of any one of claims 310 to 387, wherein the pluripotent stem cell or its progeny comprises a genetic modification.

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

390. 390. The method of claim 389, wherein the foreign nucleic acid sequence encodes a polypeptide.

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

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

393. 393. The method of any one of claims 310 to 392, wherein the genetic modification reduces the immunogenicity of the pluripotent stem cell or its progeny.

394. 1. An isolated population of cells comprising intermediate plasticity state cells, The intermediate plasticity state cells are (a) LIN28A and SALL4; (b) one or more of MSX2, NMYC, WNT4, FGF19, or TOP2A; and (c) An isolated population of cells expressing one or more of MSX1, HOXB9, WT1, GATA2, HMGA2 or LEF1.

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

396. 396. The isolated population of cells of claim 394 or claim 395, wherein the intermediate plasticity state cells comprise a genetic modification.

397. 397. The isolated population of cells of any one of claims 394-396, wherein said genetic modification comprises an exogenous nucleic acid sequence.

398. 398. The isolated population of cells of claim 397, wherein said exogenous nucleic acid sequence encodes a polypeptide.

399. 399. The isolated population of cells of claim 397 or claim 398, wherein said exogenous nucleic acid sequence comprises a sequence of a non-coding nucleic acid molecule.

400. 400. The isolated population of cells of any one of claims 396 to 399, wherein the genetic modification comprises an alteration of a genomic sequence.

401. 401. The isolated population of cells of any one of claims 396-400, wherein said genetic modification reduces the immunogenicity of said intermediate plasticity state cells.

402. intermediate plasticity state cells expressing LIN28A and SALL4 and one or more of MSX2, NMYC, WNT4, FGF19 or TOP2A; and A composition comprising one or more of a glycogen kinase inhibitor, a TGFβ receptor inhibitor, an 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, and a casein kinase 2 inhibitor.

403. The composition of claim 402, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

404. The composition of claim 403, wherein the glycogen kinase inhibitor comprises CHIR99021.

405. The composition of any one of claims 402 to 404, wherein the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334.

406. The composition of claim 405, wherein the TGFβ receptor inhibitor comprises E-616452.

407. The composition of claim 406, wherein the RAR agonist comprises TTNPB, Ch55 or AM580.

408. The composition of claim 407, wherein the RAR agonist comprises TTNPB.

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

410. The composition of claim 409, wherein the c-Jun kinase inhibitor comprises JNKIN8.

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

412. The composition of claim 411, wherein the CBP / p300 bromodomain inhibitor comprises SGC-CBP30.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

435. 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; composition.

436. The composition of claim 435, wherein the composition further comprises a CBP / p300 bromodomain inhibitor.

437. (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, composition.

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

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

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

441. The composition of claim 440, wherein the amount of 5-ITU present in the composition is from about 0.05 micromolar (μM) to about 5 μM.

442. The composition of claim 441, wherein the amount of 5-ITU present in the composition is from about 0.1 micromolar μM to about 2.5 μM.

443. The composition of claim 442, wherein the amount of 5-ITU present in the composition is from about 0.2 micromolar μM to about 1 μM.

444. The composition of claim 443, wherein the amount of 5-ITU present in the composition is about 0.5 μM.

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

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

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

448. The composition of claim 447, wherein the amount of DZNep present in the composition is from about 0.02 μM to about 20 μM.

449. The composition of claim 448, wherein the amount of DZNep present in the composition is from about 0.04 μM to about 10 μM.

450. The composition of claim 449, wherein the amount of DZNep present in the composition is from about 0.08 μM to about 5 μM.

451. The composition of claim 450, wherein the amount of DZNep present in the composition is about 0.2 μM.

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

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

454. The composition of claim 453, wherein CHIR99021 is present in the composition in an amount of from about 0.5 micromolar (μM) to about 50 μM.

455. The composition of claim 454, wherein CHIR99021 is present in the composition in an amount of from about 1 μM to about 25 μM.

456. The composition of claim 455, wherein CHIR99021 is present in the composition in an amount of from about 2 μM to about 12.5 μM.

457. The composition of claim 456, wherein CHIR99021 is present in the composition in an amount of about 5 μM.

458. The composition of any one of claims 435 to 457, wherein the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334.

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

460. The composition of claim 459, wherein E-616452 is present in the composition in an amount of from about 1 micromolar (μM) to about 100 μM.

461. The composition of claim 460, wherein the amount of E-616452 present in the composition is from about 2 μM to about 50 μM.

462. The composition of claim 461, wherein the amount of E-616452 present in the composition is from about 4 μM to about 25 μM.

463. The composition of claim 462, wherein the amount of E-616452 present in the composition is about 10 μM.

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

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

466. The composition of claim 465, wherein the amount of JNKIN present in said composition is from about 0.05 micromolar (μM) to about 50 μM.

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

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

469. The composition of claim 468, wherein the amount of JNKIN present in the composition is about 0.5 μM.

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

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

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

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

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

475. The composition of claim 474, wherein the amount of SGC-CBP30 present in the composition is about 2 μM.

476. The composition of any one of claims 435 to 475, wherein the composition further comprises one or more of a SETD2 inhibitor, an Akt inhibitor, or a casein kinase 2 inhibitor.

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

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

479. The composition of claim 478, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.05 μM to about 5 μM.

480. The composition of claim 479, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

481. The composition of claim 480, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

482. The composition of claim 481, wherein the amount of SETD2-IN-1 present in the composition is about 0.4 μM.

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

484. The composition of claim 483, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.1 μM to about 10 μM.

485. The composition of claim 484, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.2 μM to about 5 μM.

486. The composition of claim 485, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.4 μM to about 2.5 μM.

487. The composition of claim 486, wherein the amount of the AKT kinase inhibitor present in the composition is about 1 μM.

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

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

490. The composition of claim 489, wherein CX-4945 is present in the composition in an amount of from about 0.08 μM to about 8 μM.

491. The composition of claim 490, wherein CX-4945 is present in the composition in an amount of from about 0.16 μM to about 4 μM.

492. The composition of claim 491, wherein CX-4945 is present in the composition in an amount of from about 0.32 μM to about 2 μM.

493. The composition of claim 492, wherein the amount of CX-4945 present in the composition is about 0.8 μM.

494. The composition of any one of claims 435 to 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 of claim 494, wherein the Menin-MLL interaction inhibitor comprises VTP50469, MI3454 or WDR5-IN-4.

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

497. The composition of claim 496, wherein VTP50469 is present in the composition in an amount of from about 0.05 micromolar (μM) to about 5 μM.

498. The composition of claim 497, wherein VTP50469 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

499. The composition of claim 498, wherein VTP50469 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

500. The composition of claim 499, wherein the amount of VTP50469 present in the composition is about 0.5 μM.

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

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

503. The composition of claim 502, wherein the SAG is present in the composition in an amount of from about 0.05 micromolar (μM) to about 5 μM.

504. The composition of claim 503, wherein the amount of SAG present in the composition is from about 0.1 μM to about 2.5 μM.

505. The composition of claim 504, wherein the amount of SAG present in the composition is from about 0.2 μM to about 1.25 μM.

506. The composition of claim 505, wherein the amount of SAG present in the composition is about 0.5 μM.

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

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

509. The composition of claim 508, wherein the amount of Y27632 present in the composition is from about 1 μM to about 100 μM.

510. The composition of claim 509, wherein the amount of Y27632 present in the composition is from about 2 μM to about 50 μM.

511. The composition of claim 510, wherein the amount of Y27632 present in the composition is from about 4 μM to about 25 μM.

512. The composition of claim 511, wherein the amount of Y27632 present in the composition is about 10 μM.

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

514. The composition of claim 513, wherein the amount of dihydrodeoxymorphine present in the composition is from about 0.05 μM to about 5 μM.

515. The composition of claim 514, wherein the amount of dihydrodeoxymorphine present in the composition is from about 0.1 μM to about 2.5 μM.

516. The composition of claim 515, wherein the amount of dihydrodeoxymorphine present in the composition is from about 0.2 μM to about 1.25 μM.

517. The composition of claim 516, wherein the amount of dihydrodeoxymorphine present in the composition is about 0.5 μM.

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

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

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

521. The composition of claim 520, wherein EPZ5676 is present in the composition in an amount of from about 0.2 μM to about 20 μM.

522. The composition of claim 521, wherein EPZ5676 is present in the composition in an amount of from about 0.4 μM to about 10 μM.

523. The composition of claim 522, wherein EPZ5676 is present in the composition in an amount of from about 0.8 μM to about 5 μM.

524. The composition of claim 523, wherein the amount of EPZ5676 present in the composition is about 2 μM.

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

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

527. The composition of claim 526, wherein ruxolitinib is present in the composition in an amount of from about 0.1 μM to about 10 μM.

528. The composition of claim 527, wherein the amount of ruxolitinib present in the composition is from about 0.2 μM to about 5 μM.

529. The composition of claim 528, wherein the amount of ruxolitinib present in the composition is from about 0.4 μM to about 2.5 μM.

530. The composition of claim 529, wherein the amount of ruxolitinib present in the composition is about 1 μM.

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

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

533. The composition of claim 532, wherein BIRB796 is present in the composition in an amount of from about 0.2 μM to about 20 μM.

534. The composition of claim 533, wherein BIRB796 is present in the composition in an amount of from about 0.4 μM to about 10 μM.

535. The composition of claim 534, wherein BIRB796 is present in the composition in an amount of from about 0.8 μM to about 5 μM.

536. The composition of claim 535, wherein the amount of BIRB796 present in the composition is about 2 μM.

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

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

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

540. The composition of claim 539, wherein the amount of TTNPB present in the composition is from about 0.2 μM to about 20 μM.

541. The composition of claim 540, wherein the amount of TTNPB present in the composition is from about 0.4 μM to about 10 μM.

542. The composition of claim 541, wherein the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM.

543. The composition of claim 542, wherein the amount of TTNPB present in the composition is 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. 545. The isolated cell population of 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 described in 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. Epithelial-like cells expressing LIN28A, and (a) a glycogen kinase inhibitor, (b) a TGFβ receptor inhibitor, (c) an RAR agonist, and (d) A composition comprising an Akt inhibitor or a SETD2 inhibitor.

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

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

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

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

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

553. 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 composition comprising an RAR agonist.

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

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

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

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

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

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

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

561. The composition of any one of claims 547-560, wherein the composition does not comprise feeder cells.

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

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

564. The composition of any one of claims 547 to 563, wherein the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334.

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

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

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

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

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

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

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

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

573. The composition of any one of claims 547 to 572, wherein the composition further comprises a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Dot1L inhibitor.

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

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

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

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

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

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

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

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

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

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

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

585. The composition of any one of claims 580 to 584, wherein the composition does not comprise feeder cells.

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

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

588. The composition of claim 587, wherein CHIR99021 is present in the composition in an amount from about 0.5 micromolar (μM) to about 50 μM.

589. The composition of claim 588, wherein CHIR99021 is present in the composition in an amount of from about 1 μM to about 25 μM.

590. The composition of claim 589, wherein CHIR99021 is present in the composition in an amount of from about 2 μM to about 12.5 μM.

591. The composition of claim 590, wherein the amount of CHIR99021 present in the composition is about 5 μM.

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

593. The composition of claim 592, wherein the TGFβ receptor inhibitor comprises E-616452, A 83-01, SB431542, SB 505124, GW 788388, dihydrodeoxymorphine or SB 525334, and optionally, the TGFβ receptor inhibitor comprises E-616452.

594. The composition of claim 593, wherein the amount of E-616452 present in the composition is from about 1 μM to about 100 μM.

595. The composition of claim 594, wherein the amount of E-616452 present in the composition is from about 2 μM to about 50 μM.

596. The composition of claim 595, wherein the amount of E-616452 present in the composition is from about 4 μM to about 25 μM.

597. The composition of claim 596, wherein the amount of E-616452 present in the composition is about 10 μM.

598. The composition of any one of claims 580 to 597, wherein the RAR agonist comprises TTNPB, Ch55 or AM580.

599. The composition of claim 598, wherein the RAR agonist comprises TTNPB.

600. The composition of claim 599, wherein TTNPB is present in the composition in an amount of about 0.2 μM to about 20 μM.

601. The composition of claim 600, wherein TTNPB is present in the composition in an amount of about 0.4 μM to about 10 μM.

602. The composition of claim 601, wherein the amount of TTNPB present in the composition is from about 0.8 μM to about 5 μM.

603. The composition of claim 602, wherein the amount of TTNPB present in the composition is about 2 μM.

604. The composition of any one of claims 580 to 603, wherein the composition comprises an Akt inhibitor.

605. The composition of claim 604, wherein the Akt inhibitor comprises an AKT kinase inhibitor.

606. The composition of claim 605, wherein the AKT kinase inhibitor is present in the composition in an amount from about 0.1 μM to about 10 μM.

607. The composition of claim 606, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.2 μM to about 5 μM.

608. The composition of claim 607, wherein the AKT kinase inhibitor is present in the composition in an amount of from about 0.4 μM to about 2.5 μM.

609. The composition of claim 608, wherein the amount of AKT kinase inhibitor present in the composition is about 1 μM.

610. The composition of any one of claims 580 to 609, wherein the composition comprises a SETD2 inhibitor.

611. The composition of claim 610, wherein the SETD2 inhibitor comprises SETD2-IN-1, EPZ-719 or MMSET-IN-1.

612. The composition of claim 611, wherein the SETD2 inhibitor comprises SETD2-IN-1.

613. The composition of claim 612, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.05 μM to about 5 μM.

614. The composition of claim 613, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

615. The composition of claim 614, wherein SETD2-IN-1 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

616. The composition of claim 615, wherein SETD2-IN-1 is present in the composition in an amount of about 0.4 μM.

617. The composition of any one of claims 580 to 616, further comprising an agonist of the G protein-coupled receptor Smoothened or an inhibitor of Menin-MLL interaction.

618. The composition of claim 617, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG, purmorphamine, Hh-Ag1.5 or human SHH.

619. The composition of claim 618, wherein the agonist of the G protein-coupled receptor Smoothened comprises SAG.

620. The composition of claim 619, wherein the SAG is present in the composition in an amount of from about 0.05 micromolar (μM) to about 5 μM.

621. The composition of claim 620, wherein the amount of SAG present in the composition is from about 0.1 μM to about 2.5 μM.

622. The composition of claim 621, wherein the amount of SAG present in the composition is from about 0.2 μM to about 1.25 μM.

623. The composition of claim 622, wherein the amount of SAG present in the composition is about 0.5 μM.

624. The composition of any one of claims 617 to 623, wherein the Menin-MLL interaction inhibitor comprises VTP50469, MI3454 or WDR5-IN-4.

625. The composition of claim 624, wherein the Menin-MLL interaction inhibitor comprises VTP50469.

626. The composition of claim 625, wherein VTP50469 is present in the composition in an amount from about 0.05 micromolar (μM) to about 5 μM.

627. The composition of claim 626, wherein VTP50469 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

628. The composition of claim 627, wherein VTP50469 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

629. The composition of claim 628, wherein the amount of VTP50469 present in the composition is about 0.5 μM.

630. The composition of any one of claims 580 to 629, wherein the composition further comprises a Jak1 / Jak2 inhibitor, a SAH hydrolase inhibitor, or a Dot1L inhibitor.

631. The composition of claim 630, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib, tofacitinib, AZD1480, baricitinib, S-ruxolitinib or fedratinib.

632. The composition of claim 631, wherein the Jak1 / Jak2 inhibitor comprises ruxolitinib.

633. The composition of claim 632, wherein ruxolitinib is present in the composition in an amount of from about 0.1 μM to about 10 μM.

634. The composition of claim 633, wherein the amount of ruxolitinib present in the composition is from about 0.2 μM to about 5 μM.

635. The composition of claim 634, wherein the amount of ruxolitinib present in the composition is from about 0.4 μM to about 2.5 μM.

636. The composition of claim 635, wherein the amount of ruxolitinib present in the composition is about 1 μM.

637. 637. The composition of any one of claims 630 to 636, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox, or DZA.

638. The composition of claim 637, wherein the SAH hydrolase inhibitor comprises DZNep.

639. The composition of claim 638, wherein the amount of DZNep present in the composition is from about 0.002 μM to about 0.2 μM.

640. The composition of claim 639, wherein the amount of DZNep present in the composition is from about 0.004 μM to about 0.1 μM.

641. The composition of claim 640, wherein the amount of DZNep present in the composition is from about 0.008 μM to about 0.05 μM.

642. The composition of claim 641, wherein the amount of DZNep present in the composition is about 0.02 μM.

643. The composition of any one of claims 630 to 642, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

644. The composition of claim 643, wherein the Dot1L inhibitor comprises EPZ5676.

645. The composition of claim 644, wherein the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM.

646. The composition of claim 645, wherein EPZ5676 is present in the composition in an amount of from about 0.4 μM to about 10 μM.

647. The composition of claim 646, wherein the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM.

648. The composition of claim 647, wherein the amount of EPZ5676 present in the composition is about 2 μM.

649. intermediate plasticity state cells expressing LIN28A and SALL4 and one or more of MSX2, NMYC, WNT4, FGF19 or TOP2A; and A composition comprising 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 of claim 649, wherein the intermediate plasticity state cells express one or more of FGF9, HOXA9, HOZXA1, PTCH1, HOXA5, CCND2, SDC1, TBX3, BMP4 or IGF2.

651. The composition of claim 649 or claim 650, wherein the MEK inhibitor comprises PD0325901, AZD8330 or TAK-733.

652. The composition of claim 651, wherein the MEK inhibitor comprises PD0325901.

653. The composition of claim 652, wherein PD0325901 is present in the third composition in an amount of from about 0.1 μM to about 10 μM.

654. The composition of claim 653, wherein PD0325901 is present in the third composition in an amount of from about 0.2 μM to about 5 μM.

655. The composition of claim 654, wherein PD0325901 is present in the third composition in an amount of from about 0.4 μM to about 2.5 μM.

656. The composition of claim 655, wherein the amount of PD0325901 present in the third composition is about 1 μM.

657. The composition of any one of claims 649 to 656, wherein the B-Raf inhibitor comprises SB590885, vemurafenib, RAF265, or PLX4720.

658. The composition of claim 657, wherein the B-Raf inhibitor comprises SB590885.

659. The composition of claim 658, wherein SB590885 is present in the composition in an amount of from about 0.05 μM to about 5 μM.

660. The composition of claim 659, wherein SB590885 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

661. The composition of claim 660, wherein SB590885 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

662. The composition of claim 661, wherein the amount of SB590885 present in the composition is about 0.5 μM.

663. The composition of any one of claims 649 to 662, wherein the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275, or HDACi IV.

664. The composition of claim 663, wherein the histone deacetylase inhibitor comprises valproic acid (VPA).

665. The composition of claim 664, wherein the amount of VPA present in the composition is from about 0.1 millimolar (mM) to 10 mM.

666. The composition of claim 665, wherein the amount of VPA present in the composition is about 0.2 mM to 5 mM.

667. The composition of claim 666, wherein the amount of VPA present in the composition is between about 0.4 mM and 2.5 mM.

668. The composition of claim 667, wherein the amount of VPA present in the composition is about 1 mM.

669. The composition of any one of claims 649 to 668, wherein the histone demethylation inhibitor comprises tranylcypromine.

670. The composition of claim 669, wherein the amount of tranylcypromine present in the composition is from about 1 μM to about 100 μM.

671. The composition of claim 670, wherein the amount of tranylcypromine present in the composition is from about 2 μM to about 50 μM.

672. The composition of claim 671, wherein the amount of tranylcypromine present in the composition is from about 4 μM to about 25 μM.

673. The composition of claim 672, wherein the amount of tranylcypromine present in the composition is about 10 μM.

674. The composition of any one of claims 649 to 673, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

675. The composition of claim 674, wherein the Dot1L inhibitor comprises EPZ5676.

676. The composition of claim 675, wherein the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM.

677. The composition of claim 676, wherein the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM.

678. The composition of claim 677, wherein the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM.

679. The composition of claim 678, wherein the amount of EPZ5676 present in the composition is about 2 μM.

680. 679. The composition of any one of claims 649 to 679, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox, or DZA.

681. The composition of claim 680, wherein the SAH hydrolase inhibitor comprises DZNep.

682. The composition of claim 681, wherein the amount of DZNep present in the composition is from about 0.02 μM to about 20 μM.

683. The composition of claim 682, wherein the amount of DZNep present in the composition is from about 0.04 μM to about 10 μM.

684. The composition of claim 683, wherein the amount of DZNep present in the composition is from about 0.08 μM to about 5 μM.

685. The composition of claim 684, wherein the amount of DZNep present in the composition is about 0.2 μM.

686. The composition of any one of claims 649 to 685, wherein the Wnt inhibitor comprises IWR-1 or IWP-2.

687. The composition of claim 686, wherein the Wnt inhibitor comprises IWR-1.

688. The composition of claim 686 or claim 687, wherein the Wnt inhibitor comprises IWP-2.

689. The composition of claim 688, wherein the amount of IWP-2 present in the composition is from about 0.2 μM to about 20 μM.

690. The composition of claim 689, wherein the amount of IWP-2 present in the composition is from about 0.4 μM to about 10 μM.

691. The composition of claim 690, wherein the amount of IWP-2 present in the composition is from about 0.8 μM to about 5 μM.

692. The composition of claim 691, wherein the amount of IWP-2 present in the composition is about 2 μM.

693. The composition of any one of claims 649 to 692, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

694. The composition of claim 693, wherein the glycogen kinase inhibitor comprises CHIR99021.

695. The composition of claim 694, wherein CHIR99021 is present in the composition in an amount from about 0.1 micromolar (μM) to about 10 μM.

696. The composition of claim 695, wherein CHIR99021 is present in the composition in an amount of from about 0.2 μM to about 5 μM.

697. The composition of claim 696, wherein CHIR99021 is present in the composition in an amount of from about 0.4 μM to about 2.5 μM.

698. The composition of claim 697, wherein the amount of CHIR99021 present in the composition is about 1 μM.

699. The composition of any one of claims 649 to 698, wherein the ROCK inhibitor comprises Y-27632 or thiazovivin.

700. The composition of claim 699, wherein the ROCK inhibitor comprises Y-27632.

701. The composition of claim 700, wherein the amount of Y-27632 present in the composition is from about 1 μM to about 100 μM.

702. The composition of claim 701, wherein the amount of Y-27632 present in the composition is from about 2 μM to about 50 μM.

703. The composition of claim 702, wherein the amount of Y-27632 present in the composition is from about 4 μM to about 25 μM.

704. The composition of claim 703, wherein the amount of Y-27632 present in the composition is about 10 μM.

705. (a) MEK inhibitors, B-Raf inhibitors and histone deacetylase inhibitors, and (b) a composition comprising a histone demethylation inhibitor, a Dot1L inhibitor, or a SAH hydrolase inhibitor.

706. The composition of claim 705, wherein the composition further comprises pluripotent stem cells expressing OCT4, SOX2 and NANOG.

707. The composition of claim 705 or claim 706, wherein the pluripotent cells express one or more of FGF4, ZFP57, DPPA5 or REX1.

708. The composition of any one of claims 705 to 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 of any one of claims 705 to 708, wherein the MEK inhibitor comprises PD0325901, AZD8330, or TAK-733.

710. The composition of claim 709, wherein the MEK inhibitor comprises PD0325901.

711. The composition of any one of claims 705 to 710, wherein the B-Raf inhibitor comprises SB590885, vemurafenib, RAF265, or PLX4720.

712. The composition of claim 711, wherein the B-Raf inhibitor comprises SB590885.

713. The composition of any one of claims 705 to 712, wherein the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275 or HDACi IV.

714. The composition of claim 713, wherein the histone deacetylase inhibitor comprises VPA.

715. The composition of any one of claims 705 to 714, wherein the composition comprises a histone demethylation inhibitor.

716. The composition of claim 715, wherein the histone demethylation inhibitor comprises tranylcypromine.

717. The composition of any one of claims 705 to 716, wherein the composition comprises a Dot1L inhibitor.

718. The composition of claim 717, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

719. The composition of claim 718, wherein the Dot1L inhibitor comprises EPZ5676.

720. The composition of any one of claims 705 to 719, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

721. The composition of claim 720, wherein the SAH hydrolase inhibitor comprises DZNep.

722. The composition of any one of claims 705 to 721, further comprising a Wnt inhibitor, a glycogen kinase inhibitor, or a ROCK inhibitor.

723. The composition of claim 722, wherein the composition comprises a Wnt inhibitor.

724. The composition of claim 723, wherein the Wnt inhibitor comprises IWR-1 or IWP-2.

725. The composition of claim 724, wherein the Wnt inhibitor comprises IWR-1.

726. The composition of claim 724 or claim 725, wherein the Wnt inhibitor comprises IWP-2.

727. The composition of any one of claims 722 to 726, wherein the composition comprises a glycogen kinase inhibitor.

728. The composition of claim 727, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

729. The composition of claim 728, wherein the glycogen kinase inhibitor comprises CHIR99021.

730. The composition of claim 729, wherein the glycogen kinase inhibitor comprises CHIR98014.

731. The composition of any one of claims 722 to 730, wherein the composition comprises a ROCK inhibitor.

732. The composition of claim 731, wherein the ROCK inhibitor comprises Y-27632 or thiazovivin.

733. The composition of claim 732, wherein the ROCK inhibitor comprises Y-27632.

734. The composition of any one of claims 706-733, wherein the pluripotent stem cells comprise a genetic modification.

735. The composition of claim 734, wherein the genetic modification comprises an exogenous nucleic acid sequence.

736. The composition of claim 735, wherein the foreign nucleic acid sequence encodes a polypeptide.

737. The composition of claim 735 or claim 736, wherein the foreign nucleic acid sequence comprises a sequence of a non-coding nucleic acid molecule.

738. The composition of any one of claims 734 to 737, wherein the genetic modification comprises an alteration of a genomic sequence.

739. The composition of any one of claims 734-738, wherein the genetic modification reduces the immunogenicity of the pluripotent stem cells.

740. The composition of claim 705, wherein the MEK inhibitor comprises PD0325901, AZD8330 or TAK-733.

741. The composition of claim 740, wherein the MEK inhibitor comprises PD0325901.

742. The composition of claim 741, wherein PD0325901 is present in the third composition in an amount of from about 0.1 μM to about 10 μM.

743. The composition of claim 742, wherein PD0325901 is present in the third composition in an amount of from about 0.2 μM to about 5 μM.

744. The composition of claim 743, wherein PD0325901 is present in the third composition in an amount of from about 0.4 μM to about 2.5 μM.

745. The composition of claim 744, wherein the amount of PD0325901 present in the third composition is about 1 μM.

746. The composition of any one of claims 705 and 740-745, wherein the B-Raf inhibitor comprises SB590885, vemurafenib, RAF265 or PLX4720.

747. The composition of claim 746, wherein the B-Raf inhibitor comprises SB590885.

748. The composition of claim 747, wherein SB590885 is present in the composition in an amount of from about 0.05 μM to about 5 μM.

749. The composition of claim 748, wherein SB590885 is present in the composition in an amount of from about 0.1 μM to about 2.5 μM.

750. The composition of claim 749, wherein SB590885 is present in the composition in an amount of from about 0.2 μM to about 1.25 μM.

751. The composition of claim 750, wherein SB590885 is present in the composition in an amount of about 0.5 μM.

752. The composition of any one of claims 705 and 740 to 751, wherein the histone deacetylase inhibitor comprises valproic acid (VPA), LMK235, MS275 or HDACi IV.

753. The composition of claim 752, wherein the histone deacetylase inhibitor comprises valproic acid (VPA).

754. The composition of claim 753, wherein VPA is present in the composition in an amount of about 0.1 millimolar (mM) to 10 mM.

755. The composition of claim 754, wherein the amount of VPA present in the composition is about 0.2 mM to 5 mM.

756. The composition of claim 755, wherein the amount of VPA present in the composition is between about 0.4 mM and 2.5 mM.

757. The composition of claim 756, wherein the amount of VPA present in the composition is about 1 mM.

758. The composition of any one of claims 705 and 740 to 757, wherein the histone demethylation inhibitor comprises tranylcypromine.

759. The composition of claim 758, wherein the amount of tranylcypromine present in the composition is from about 1 μM to about 100 μM.

760. The composition of claim 759, wherein the amount of tranylcypromine present in the composition is from about 2 μM to about 50 μM.

761. The composition of claim 760, wherein the amount of tranylcypromine present in the composition is from about 4 μM to about 25 μM.

762. The composition of claim 761, wherein the amount of tranylcypromine present in the composition is about 10 μM.

763. The composition of any one of claims 705 and 740 to 762, wherein the Dot1L inhibitor comprises EPZ004777 or EPZ5676.

764. The composition of claim 763, wherein the Dot1L inhibitor comprises EPZ5676.

765. The composition of claim 764, wherein the amount of EPZ5676 present in the composition is from about 0.2 μM to about 20 μM.

766. The composition of claim 765, wherein the amount of EPZ5676 present in the composition is from about 0.4 μM to about 10 μM.

767. The composition of claim 766, wherein the amount of EPZ5676 present in the composition is from about 0.8 μM to about 5 μM.

768. The composition of claim 767, wherein the amount of EPZ5676 present in the composition is about 2 μM.

769. The composition of any one of claims 705 and 740-768, wherein the SAH hydrolase inhibitor comprises DZNep, NepA, Adox or DZA.

770. The composition of claim 769, wherein the SAH hydrolase inhibitor comprises DZNep.

771. The composition of claim 770, wherein the amount of DZNep present in the composition is from about 0.02 μM to about 20 μM.

772. The composition of claim 771, wherein the amount of DZNep present in the composition is from about 0.04 μM to about 10 μM.

773. The composition of claim 772, wherein the amount of DZNep present in the composition is from about 0.08 μM to about 5 μM.

774. The composition of claim 773, wherein the amount of DZNep present in the composition is about 0.2 μM.

775. The composition of any one of claims 705 and 740 to 774, wherein the Wnt inhibitor comprises IWR-1 or IWP-2.

776. The composition of claim 775, wherein the Wnt inhibitor comprises IWR-1.

777. The composition of claim 775 or claim 776, wherein the Wnt inhibitor comprises IWP-2.

778. The composition of claim 777, wherein the amount of IWP-2 present in the composition is from about 0.2 μM to about 20 μM.

779. The composition of claim 778, wherein the amount of IWP-2 present in the composition is from about 0.4 μM to about 10 μM.

780. The composition of claim 779, wherein the amount of IWP-2 present in the composition is from about 0.8 μM to about 5 μM.

781. The composition of claim 780, wherein the amount of IWP-2 present in the composition is about 2 μM.

782. The composition of any one of claims 705 and 740 to 781, wherein the glycogen kinase inhibitor comprises CHIR99021 or CHIR98014.

783. The composition of claim 782, wherein the glycogen kinase inhibitor comprises CHIR99021.

784. The composition of claim 783, wherein CHIR99021 is present in the composition in an amount of from about 0.1 micromolar (μM) to about 10 μM.

785. The composition of claim 784, wherein CHIR99021 is present in the composition in an amount of from about 0.2 μM to about 5 μM.

786. The composition of claim 785, wherein CHIR99021 is present in the composition in an amount of from about 0.4 μM to about 2.5 μM.

787. The composition of claim 786, wherein the amount of CHIR99021 present in the composition is about 1 μM.

788. The composition of any one of claims 705 and 740 to 787, wherein the ROCK inhibitor comprises Y-27632 or thiazovivin.

789. The composition of claim 788, wherein the ROCK inhibitor comprises Y-27632.

790. The composition of claim 789, wherein the amount of Y-27632 present in the composition is from about 1 μM to about 100 μM.

791. The composition of claim 790, wherein the amount of Y-27632 present in the composition is from about 2 μM to about 50 μM.

792. The composition of claim 791, wherein the amount of Y-27632 present in the composition is from about 4 μM to about 25 μM.

793. The composition of claim 792, wherein the amount of Y-27632 present in the composition is about 10 μM.

794. The composition of any one of claims 473-543, 580, 584-705, 709-733, or 740-793, wherein the composition is a medium for culturing cells.

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