Extracellular vesicle composition for use in the treatment of graft-versus-host disease

Abstract

Disclosed are methods of treating patients receiving an organ transplant by administering extracellular vesicle composition.

Description

TREATMENT FOR SOLID ABDOMINAL ORGAN TRANSPLANTATION WITH EXTRACELLULAR VESICLE COMPOSITIONCROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 596,952, filed on November 7, 2023, and U.S. Provisional Patent Application No. 63 / 712,072, filed on October 25, 2024, each of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Over the last decade there has been increased utilization of mesenchymal stem cells (MSCs) for the treatment of severe inflammatory disorders including graft-versus-host disease (GvHD), systemic lupus erythematosus, myocardial infarction, multiple sclerosis, Crohn’s disease, and solid abdominal organ rejection. These studies have highlighted the desirable therapeutic benefit of the anti-inflammatory and immunomodulatory characteristics of MSCs. MSCs have been shown suppress T- cell proliferation in response to alloantigenic and mitogenic stimulation while increasing the regulatory T cell (Treg) population which is useful for the treatment of acute cellular rejection. Specific to GVHD, MSCs have been shown to drive T-cell mediated immunosuppressive activity in GVHD specific animal models and have been successfully used to treat GVHD in both pediatric and adult patient populations.

[0003] Unfortunately, cell therapy has several logistical limitations including scalability and reproducibility of product, temperature control on transportation, need for cryorecovery, alloimmune response, pulmonary trapping with intravenous delivery, and access to product source.SUMMARY OF THE INVENTION

[0004] In some aspects, provided herein is a method of treating graft-versus-host disease in a subject in need thereof, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-.

[0005] In some aspects, provided herein is a method of treating graft-versus-host disease in a subject in need thereof, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a- 3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. miRNA sequences may be obtained from https: / / www.mirbase.org / .

[0006] In some aspects, provided herein is a method of treating graft-versus-host disease in a subject in need thereof, the method comprising administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocytemacrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein- glutamine gamma-glutamyltransf erase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0007] In some embodiments, the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145- 5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa- miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a- 3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa- miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some embodiments, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL- 1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), blG- H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein- coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activatorinhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein- 2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf- related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0008] In some embodiments, the subject has received an organ transplant or allograft. In some embodiments, the subject has received a modified multivisceral allograft, an isolated intestine allograft, or an isolated liver allograft. In some embodiments, the subject exhibits one or more signs or symptoms of graft-versus-host disease and / or allograft rejection. In some embodiments, the subject exhibits one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.

[0009] In some embodiments, the subject is receiving corticosteroids. In some embodiments, the subject is receiving high dose corticosteroids. In some embodiments, the subject experiences improvement after treatment in one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite, jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.

[0010] In some embodiments, the dosage of the therapeutic MSC secretome composition administered to the subject is a cell-equivalent dosage of 0.7 to 7 million cells / kg. In some embodiments, administering comprises intravenous administration. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of thecomposition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0011] In some embodiments, the composition is prepared by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

[0012] In some embodiments, the method comprising preparing the composition prior to the administering, wherein preparing the composition occurs by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

[0013] In some embodiments, the culture media is serum-free. In some embodiments, the culture media has a glucose concentration below 4.5 g / L. In some embodiments, formulating the MSC conditioned media comprises exchanging the conditioned media for a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutically acceptable formulation comprises saline. In some embodiments, the composition comprises at least 6xlO10to 8xl010extracellular vesicles per ml and is administered at a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0014] In some embodiments, disclosed herein are methods of treating a patient undergoing organ transplantation by administering extracellular vesicle compositions derived from bone marrow mesenchymal stem cells. An aspect of the present disclosure is a method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome compositionmade by a method comprising: (a) culturing bone marrow-derived MSCs under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a). In some embodiments, the subject has received an organ transplant or allograft. In some embodiments, the subject has received a modified multivisceral allograft, an isolated intestine allograft, an isolated liver allograft. In some embodiments, the subject exhibits one or more signs or symptoms of graft-versus-host disease and / or allograft rejection. In some embodiments, the subject exhibits one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof. In some embodiments, the subject is receiving corticosteroids. In some embodiments, the subject is receiving high dose corticosteroids.

[0015] In some embodiments, the subject experiences improvement after treatment in one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite aundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof. In some embodiments, the dosage of the therapeutic MSC secretome composition administered to the subject is a cell-equivalent dosage of 0.7 to 7 million cells / kg. In some embodiments, the culture media is serum-free. In some embodiments, the culture media has a glucose concentration below 4.5 g / L. In some embodiments, at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-. In some embodiments, the therapeutic MSC secretome composition comprises one or more of the following proteins: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ,Cathepsin L, RBP4, Serpin A4, JAM- A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref- 1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl3O, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF- 23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin- 1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B,HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL- 17 RC, MIP-3b, Cy statin C, Cy statin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cy statin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA I3, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha- 1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP- 2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmogl ein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmogl ein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1,TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 F0LR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.1, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP- 10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3 A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cy statin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13. In some embodiments, the therapeutic MSC secretome composition comprises one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let- 7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR- 106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa- miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR- 132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa- miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR- 15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR- 181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR- 199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a- 5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21- 5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a- 3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR- 29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa- miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR- 376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa- mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p.

[0016] An aspect of the present disclosure is a method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic MSC secretome composition comprising extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9-CD81-. In some embodiments, the therapeutic MSC secretome composition further comprises one or more of the following proteins: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM- C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7 A, NKp80, Cy statin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan- 4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD 109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP -A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD- L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP- 1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD- ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1,APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL- 19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA I3, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM- 1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL- 28 A, FGF- 12, METAP2, AS AHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL- 10 Rb, XEDAR, IL-22, PILR-alpha, NRG1- 131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2,LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R- Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL- 1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, R0B03, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP- 2, PU.l, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13. In some embodiments, the extracellular vesicles comprise one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR- 10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR- 139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa- miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa- miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa- miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214- 3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24- 2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR- 3Ob-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa- miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p,hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa- miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a- 3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR- 99b-5p. In some embodiments, the subject has received an organ transplant or allograft. In some embodiments, the subject has received a modified multivisceral allograft, an isolated intestine allograft, an isolated liver allograft. In some embodiments, the subject exhibits one or more signs or symptoms of graft-versus-host disease and / or allograft rejection. In some embodiments, the subject exhibits one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof. In some embodiments, the subject is receiving corticosteroids. In some embodiments, the subject is receiving high dose corticosteroids. In some embodiments, the subject experiences improvement after treatment in one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite aundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof. In some embodiments, subject exhibits the improvement within 24 hours of administration of the therapeutic product.

[0017] An aspect of the present disclosure is a method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles (EVs), wherein the therapeutic MSC secretome comprises (i) Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL- 20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM- A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA,IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref- 1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl3O, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF- 23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin- 1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1,Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL- 17 RC, MIP-3b, Cy statin C, Cy statin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cy statin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA I3, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha- 1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP- 2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmogl ein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmogl ein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin,Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.1, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP- 10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3 A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cy statin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let- 7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR- 1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR- 140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa- miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR- 20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa- miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa- miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa- miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir- 30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR- 320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir- 486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa- miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa- miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p, or a combination of two or more thereof; or (iii) both (i) and (ii). Another aspect of the present disclosure is a method of treating graft-versus-host disease, the method comprising administering to the subject a therapeutic MSC secretome composition. Another aspect of the present disclosure is a method of treating allograft rejection, the method comprising administering to the subject a therapeutic MSC secretome composition. Another aspect of the present disclosure is a method of reducing symptoms associated with graft-versus host disease in a subject, the method comprising administering to the subject a therapeutic MSC secretome composition. Another aspect of the present disclosureis a method of improving one or more signs or symptoms of graft-versus-host disease and / or allograft rejection selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof. In some embodiments, extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-. In some embodiments, the therapeutic MSC secretome comprises (i) Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL- 20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM- A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, P0N1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref- 1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4,TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF- 23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p27, Siglec-6, Dectin- 1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL- 17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA I3, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha- 1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP- 2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmogl ein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NT AL, EGF R,TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, IAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.1, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, S0X15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP- 10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3 A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cy statin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let- 7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR- 1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR- 140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa- miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR- 20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa- miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa- miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir- 30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR- 320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir- 486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa- miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa- miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p, or a combination of two or more thereof; or (iii) both (i) and (ii). In some embodiments, the therapeutic MSC secretome composition is made by a method comprising: (a) culturing bone marrow-derived MSCs under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii)culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a). In some embodiments, the subject has received an organ transplant or allograft. In some embodiments, the subject has received a modified multivisceral allograft, an isolated intestine allograft, an isolated liver allograft. In some embodiments, the subject has exhibits one or more signs or symptoms of graft-versus-host disease and / or allograft rejection. In some embodiments, the subject exhibits one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof. In some embodiments, the composition comprises 15 mL of the therapeutic MSC secretome composition. In some embodiments, the composition is administered intravenously.

[0018] The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The numberof EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0019] An aspect of the present disclosure is a method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles (EVs), wherein the composition comprises 15 mL of the therapeutic MSC secretome composition. An aspect of the present disclosure is a method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition extracellular vesicles (EVs), wherein the administering improves one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetitejaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof. In some embodiments, the administering improves inflammation.

[0020] An aspect of the present disclosure is the use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles in treating graft-versus-host disease in a subject, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-.

[0021] An aspect of the present disclosure is the use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles (EVs) in treating graft-versus-host disease in a subject in need thereof, wherein the therapeutic mesenchymal stem cell (MSC) secretome composition comprises (i) Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL- 20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM- A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C,IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, P0N1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref- 1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF- 23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin- 1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR,Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL- 17 RC, MIP-3b, Cy statin C, Cy statin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cy statin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA I3, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha- 1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP- 2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmogl ein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmogl ein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.1, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl,CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP- 10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3 A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cy statin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let- 7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR- 1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR- 140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa- miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR- 20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa- miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa- miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa- miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir- 30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR- 320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir- 486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa- miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa- miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p, or a combination of two or more thereof; or (iii) both (i) and (ii).

[0022] An aspect of the present disclosure is the use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles (EVs) in treating graft-versus-host disease in a subject, wherein the composition comprises 15 mL of the therapeutic MSC secretome composition. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. Theintravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0024] FIG. 1 shows histological images showing improvement in allograft inflammation and resolution of acute cellular rejection following therapeutic product administration.DETAILED DESCRIPTION OF THE INVENTIONTherapeutic Compositions

[0025] Extracellular vesicles (EV) are small membrane bound spheres containing proteins and RNA (of which exosomes are a subset). Exosomes are small (e.g., 30 - 170 nm) diameter lipid bilayer vesicles secreted by cells to enable paracrine communication. Other EV populations are derived directly from the plasma membrane or are formed during apoptosis (apoptotic bodies). Disclosed herein are compositions comprising a therapeutically effective amount of an MSC secretome (such as, for example, including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions).

[0026] Example compositions herein comprise therapeutic compositions comprising a secreted biomolecule (which may include proteins, lipids, and / or ribonucleic acids) and / or extracellular vesicle comprising a biomolecule, originating from mesenchymal lineage cells. In one aspect, therapeutic compositions comprise a therapeutically effective amount of components secreted from a MSC (i.e. a MSC secretome), for example, including, but not limited to, MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions. In an exemplary embodiment, the MSC is a bone marrow MSC. The MSC secretome may be purified or otherwise separated from the MSC growth and / or culturing condition. For example, the MSC secretome may comprise exosomes separated from the MSC culture. As such, reference to MSC secretome is inclusive of purified secretome components, e.g., exosomes or extracellular vesicles. The purified secretome components may be a therapeutic composition. Partially purified secretome components may be a therapeutic composition. For instance, the therapeutic composition may comprise extracellular vesicles and one or more growth factors from the MSCsecretome. The therapeutic composition may comprise reconstituted extracellular vesicles e.g., reconstituted from a lyophilized or otherwise powdered or dry composition. The therapeutic composition may comprise reconstituted extracellular vesicles and one or more growth factors, e.g., reconstituted from a lyophilized or otherwise powdered or dry composition.

[0027] In some embodiments, the MSC secretome comprises a MSC growth factor composition. In some embodiments, the MSC secretome is a MSC growth factor composition. The MSC growth factor composition may comprise one or more growth factors secreted from the MSC. One or more of the one or more growth factors secreted from the MSC may be present in an exosome secreted from the MSC. One or more of the one or more growth factors secreted from the MSC may be present in an extracellular vesicle secreted from the MSC. One or more of the one or more growth factors secreted from the MSC may not be present in an exosome or extracellular vesicle secreted from the MSC. In an exemplary embodiment, the MSC is a bone marrow MSC.

[0028] In some embodiments, the MSC secretome comprises a MSC exosome composition. In some embodiments, the MSC secretome is a MSC exosome composition. The MSC exosome composition may comprise one or more exosomes secreted from the MSC. The MSC exosome may comprise one or more biomolecules, for example, a peptide, polypeptide, protein, siRNA, shRNA, and / or microRNA (miRNA). The MSC exosome may comprise a growth factor. The growth factor may be present within the one or more exosomes secreted from the MSC. The growth factor may not be present within the one or more exosomes secreted from the MSC. The MSC exosome may comprise a nucleic acid such as a miRNA. The nucleic acid may be present within the one or more exosomes secreted from the MSC. The nucleic acid may not be present within the one or more exosomes secreted from the MSC. In an exemplary embodiment, the MSC is a bone marrow MSC.

[0029] In some embodiments, the MSC secretome comprises a MSC extracellular vesicle composition. In some embodiments, the MSC secretome is a MSC extracellular vesicle composition. The MSC extracellular vesicle composition may comprise one or more extracellular vesicles secreted from the MSC. The MSC extracellular vesicle composition may comprise one or more biomolecules, for example, a peptide, polypeptide, protein, siRNA, shRNA, and / or microRNA (miRNA). The MSC extracellular vesicle may comprise a growth factor. The growth factor may be present within the one or more extracellular vesicles secreted from the MSC. The growth factor may not be present within the one or more extracellular vesicle secreted from the MSC. The MSC extracellular vesicle may comprise a nucleic acid, such as a miRNA. The nucleic acid may be present within the one or more extracellular vesicles secreted from the MSC. The nucleic acid may not be present within the one or moreextracellular vesicle secreted from the MSC. In an exemplary embodiment, the MSC is a bone marrow MSC.

[0030] In some embodiments, the MSC secretome comprises a MSC extract composition. In an exemplary embodiment, the MSC is a bone marrow MSC. In some embodiments, the MSC secretome is a MSC extract composition. The MSC extract composition may comprise one or more biomolecules, for example, a peptide, polypeptide, protein, siRNA, shRNA, and / or microRNA (miRNA). The MSC extract composition may comprise an exosome and one or more biomolecules, where the exosome is secreted from the MSC and the one or more biomolecules are secreted from the MSC. One or more of the one or more biomolecules may be present within the exosome. One or more of the one or more biomolecules may not be present in the exosome. The MSC extract composition may comprise an extracellular vesicle and one or more biomolecules, where the extracellular vesicle is secreted from the MSC and the one or more biomolecules are secreted from the MSC. One or more of the one or more biomolecules may be present within the extracellular vesicle. One or more of the one or more biomolecules may not be present in the extracellular vesicle. One of the one or more biomolecules may be a growth factor. One of the one or more biomolecules may be a nucleic acid, such as miRNA.

[0031] In some embodiments, the MSC secretome comprises a MSC growth factor composition and a MSC exosome composition. In an exemplary embodiment, the MSC is a bone marrow MSC. The MSC growth factor composition may comprise one or more growth factors secreted from the MSC. One or more of the one or more growth factors secreted from the MSC may be present in the MSC exosome composition. One or more of the one or more growth factors secreted from the MSC may not be present in the exosome. The MSC exosome composition may comprise one or more exosomes secreted from the MSC. The MSC exosome may comprise one or more biomolecules, for example, a peptide, polypeptide, protein, siRNA, shRNA, and / or microRNA (miRNA). One of the one or more biomolecules may be a nucleic acid, such as miRNA.

[0032] In some embodiments, the MSC secretome comprises a MSC growth factor composition and a MSC extracellular vesicle composition. In an exemplary embodiment, the MSC is a bone marrow MSC. The MSC growth factor composition may comprise one or more growth factors secreted from the MSC. One or more of the one or more growth factors secreted from the MSC may be present in the MSC extracellular vesicle composition. One or more of the one or more growth factors secreted from the MSC may not be present in the extracellular vesicle. The MSC extracellular vesicle composition may comprise one or more extracellular vesicles secreted from the MSC. The MSC extracellular vesicle may comprise one or more biomolecules, for example,a peptide, polypeptide, protein, siRNA, shRNA, and / or microRNA (miRNA). One of the one or more biomolecules may be a nucleic acid, such as miRNA.

[0033] In some embodiments, the therapeutic composition, e.g., MSC secretome composition, comprises one or more peptide biomolecules. At least one of the one or more peptide biomolecules may be a growth factor. For instance, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more proteins may be present in the MSC secretome. Nonlimiting example growth factors or growth factor-associated proteins that may be present in the MSC secretome include: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF RI, htPAPP- A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM- A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, and Syndecan-4. Non-limiting example proteins that may be present in the MSC secretome include: Ferritin, IGFBP-4 IL-1 R6 GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP- A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL- 18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP- 1, TC-PTP, IL-24, gp!30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNabR2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM- 1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP- 3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL- 17B, IL- 17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, LTAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3,Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desm oglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt- 3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4- 1BB, HO-1, SOST, S100A13, Kallikrein 7, and IL-13. Non-limiting examples of a selection of growth factors or growth factor proteins is shown in Table 1 below.Table 1

[0034] In some embodiments, the therapeutic composition, e.g., MSC secretome composition, comprises one or more nucleic acid biomolecules. At least one of the one or more nucleic acid biomolecules may be a miRNA. For instance, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more nucleic acids may be present in the MSC secretome. Nonlimiting example miRNA that may be present in the MSC secretome include: hsa-let-7a-5p, hsa- let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR- 10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR- 139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa- miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa- miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa- miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214- 3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24- 2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR- 30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa- miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa- miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a- 3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR- 99b-5p.

[0035] Exemplary microRNA that may be present within the therapeutic composition, e.g., MSC secretome, include hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-214-3p, and hsa-miR-27a-3p, and combinations of two or more thereof, each of which all have binding sites in mRNA for TMPRSS2.

[0036] In some embodiments, the therapeutic composition, e.g., MSC secretome, comprises an extracellular vesicle with a phenotype of CD63+CD9 CD81". In some embodiments, at least 70, 75, 80, 85, 90, 91, 92, 93, 94, or 95% of the extracellular vesicles in the therapeutic composition are CD63+CD9 CD81". In some embodiments, at least 50, 60, 70, 80, 85, 90, 91, 92, 93, 94, or 95% of the extracellular vesicles in the therapeutic composition are CD9 . In some embodiments, at least 50, 60, 70, 80, 85, 90, 91, 92, 93, 94, or 95% of the extracellular vesicles in the therapeutic composition are CD81". In an exemplary embodiment, the MSC is a bone marrow MSC.

[0037] In some embodiments, the MSCs cultured to produce the therapeutic composition have the capacity to undergo trilineage differentiation in vitro toward adipocyte, osteoblast, and chondrocyte phenotypes. In some embodiments, the MSCs are positive for CD73, CD105, CD166, and CD90 and are negative for CD14, CD31, CD34, and CD45. In an exemplary embodiment, the MSC is a bone marrow MSC.

[0038] Therapeutic compositions herein may comprise one or more exosomes and one or more growth factors. The growth factors and / or exosomes can be allogenic or autogenic. The growth factors and / or exosomes can be derived from any cell in the human body, such as from ectodermal cells, endodermal cells, or mesodermal cells. For example, the therapeutic compositions may comprise mesenchymal stem cell (MSC) derived growth factors, MSC derived exosomes, or both MSC derived growth factors and exosomes. In some embodiments, the therapeutic composition comprises one or more components from a MSC secretome and an additive that is not a component from a MSC secretome. In one aspect, disclosed herein are therapeutic compositions comprising a MSC secretome and one more additional additives, wherein the one or more additional additive comprises prostaglandin E2 (PGE2), transforming growth factor 131 (TGF-131), hepatocyte growth factor (HGF), stromal cell derived factor-1 (SDF-1), nitric oxide, indoleamine 2,3 -dioxygenase, interleukin-4 (IL-4), IL-6, interleukin- 10 (IL-10), IL-1 receptor antagonist and soluble TNF-a receptor, insulin-like growth factors, fibroblast growth factors (FGF) 1-23 (especially, FGF1 and FGF2), bone morphogenetic proteins (BMPs) 1-15, epidermal growth factor (EGF), transforming growth factor-a (TGF-a) macrophage-stimulating protein (MSP), platelet derived growth factor (PLGF), vascular endothelial growth factor (VEGF), macrophage colony stimulating factor (M-CSF), insulin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), estrogen, or a thyroid hormone, or a combination of two or more thereof.

[0039] Embodiments of a therapeutic composition described herein may comprise proteins and microRNAs, some of which may be embedded in or surrounded by a lipid membrane to create vesicles in the size range of about >20nm to about 200 nm in size. The number of vesicles within the composition may be between about 1 million to about 100 billion vesicles per mL when suspended or about 10 million to about 1 trillion when formulated as a lyophilized powder. The vesicles may be extracellular vesicles. The extracellular vesicles may be components of a MSC secretome. The vesicles may be exosomes. The exosomes may be components of a MSC secretome. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into anintravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.Mesenchymal Stem Cells

[0040] Example therapeutic compositions herein comprise MSC secretome compositions and / or components derived from mesenchymal stem cells (MSCs) (e.g., biomolecules such as nucleic acids like miRNA and peptides like growth factors). In one aspect, disclosed herein are MSC secretome compositions (including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions)for the treatment, inhibition, decrease, reduction, amelioration, and / or prevention of conditions such as, for example, graft- versus-host disease.

[0041] MSCs are multipotent cells that have the ability to differentiate into a multitude of cell types including myocytes, chondrocytes, adipocytes, and osteoblasts. Typically, these cells can be found in the placenta, umbilical cord blood, adipose tissue, bone marrow, or amniotic fluid, including perivascular tissue. As used herein, "MSC" refers to non-terminally differentiated cells including but not limited to multipotential stem cell, multipotential stromal cell, stromal vascular cells, pericytes, perivascular cells, stromal cells, pluripotent cells, multipotent cells, adipose- derived fibroblast-like cells, adipose-derived stromal vascular fraction, adipose-derived MSC, bone marrow-derived fibroblast-like cells, bone marrow-derived stromal vascular fraction, bone marrow-derived MSC, tissue-derived fibroblast-like cells, adult stem cells, adult stromal cells, keratinocytes, and / or melanocytes.

[0042] In some embodiments, a MSC secretome composition comprises a MSC growth factor, MSC exosome, extracellular vesicle, extracellular vesicle isolate product (EVIP), acellular extract of MSC or a MSC lysate, or a combination of two or more thereof, obtained from a MSC. The MSC may be a human MSCs, fibroblast-like cells, or a non-human animal MSC including, but not limited to a MSC from horses, cows, pigs, sheep, non-human primates, dogs, cats, rabbits, rats, or mice. In embodiments, the MSC may be derived from the patient to which the composition will be applied (autologous) or derived from another individual (allogeneic). The MSC may be culture expanded to collect the conditioned media and / or to increase the quantity of cells for the lysate or used freshly prior to incorporation into a therapeutic composition of the present disclosure.

[0043] The MSC secretome compositions (including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions) maycomprise about 0.00001 to about 20 wt.%, such as from about 0.01 to about 10 wt.%, of a mesenchymal stem cell (MSC) extract, MSC exosome, or MSC growth factor preparation.

[0044] MSC secretome compositions, or components of the MSC secretome compositions, may be obtained by culturing MSCs under normal hyperoxic culturing conditions or under artificial wound healing conditions.

[0045] MSCs can be selectively stimulated to produce the MSC secretome compositions or components of the MSC secretome compositions disclosed herein. The stimulated MSCs may product MSC growth factors, secretomes, cytokines, chemokines, mesenchymal stem cell proteins, peptides, glycosaminoglycans, extracellular matrix (ECM), proteoglycans, or extracellular vesicles (e.g., exosomes), or a combination of two or more thereof. MSC growth factors include, but are not limited to, prostaglandin E2 (PGE2), transforming growth factor 131 (TGF-131), hepatocyte growth factor (HGF), stromal cell derived factor-1 (SDF-1), nitric oxide, indoleamine 2,3-dioxygenase, interleukin-4 (IL-4), IL-6, interleukin- 10 (IL-10), IL-1 receptor antagonist and soluble TNF-a receptor, insulin-like growth factors, fibroblast growth factors (FGF) 1-23 (especially, FGF1 and FGF2), bone morphogenetic proteins (BMPs) 1-15, epidermal growth factor (EGF), transforming growth factor-a (TGF-a) macrophage-stimulating protein (MSP), platelet derived growth factor (PLGF), vascular endothelial growth factor (VEGF), macrophage colony stimulating factor (M-CSF), insulin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), as well as hormones including estrogen, and thyroid hormones.

[0046] Culturing the MSCs may occur under wound healing and / or hypoxic conditions. Wound healing conditions may comprise about 1% to about 5% oxygen, reduced or no serum, reduced glucose, or these elements in various combinations. The combined reduced nutrient and metabolite environment may trigger the cultured cells to produce wound healing and antiinflammatory ECM proteins and growth factors to direct tissue healing. In one aspect, the MSC secretome composition comprises MSC growth factors, MSC exosomes, and / or cellular extracts of MSCs or MSC lysates obtained from MSCs cultured under standard hyperoxic culturing conditions (for example, 21% oxygen) or MSCs cultured under artificial wound healing conditions (such as, for example, 0.1% to about 5% oxygen).

[0047] Artificial wound healing conditions used to culture MSCs may include one or more of the following growth conditions reduction in glucose availability, reduction in oxygen tension, reduction in pH, and increased temperature.

[0048] In some embodiments, the glucose availability can be reduced relative to normal control (e.g., 4.5 g / L). Modified culture media to reduce glucose, but not damage the cells can be between 0 and 50% reduction in glucose, more preferably between about 5% and 40% reductionin glucose. For example, MSC artificial wound healing culture conditions can comprise glucose reduction of about 5% to about 15%, from about 10% to about 20%, from about 15% to about 25%, from about 20% to about 30%, or from about 25% to about 35%. In some embodiments, glucose is present at a concentration of about 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 g / L, or a range between any two of these values. In some embodiments, glucose is present at a concentration of less than or no more than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5 g / L.

[0049] In some embodiments, oxygen tension can be reduced to oxygen levels to hypoxic conditions. Normal atmospheric oxygen is approximately 21% and any reduction is considered hypoxic. Thus, in one aspect, MSCs can be cultured at between 0.0% and 20.9% oxygen, from about 0.1% to about 0.5% oxygen, from about 0.1% to about 2.0%, from about 0.1% to about 5.0% oxygen, from about 0.5% to 5.0%, from about 1.0% to about 10% oxygen, about 5.0% to about 10.0% oxygen; and from about 10.0% to about 15.0%. The hypoxic oxygen conditions may be an aspect of artificial wound healing conditions. Oxygen tension may be between about 0.5% and 20.5% oxygen when culturing MSCs to produce a therapeutic secretome composition comprising extracellular vesicles and / or MSC-secreted growth factors, such as, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7,7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3,9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2,11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13,13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7,14.8, 14.9, 15, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16, 16.1, 16.2, 16.3, 16.4, 16.5,16.6, 16.7, 16.8, 16.9, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18, 18.1, 18.2, 18.3,18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, or20.0% oxygen, or a range between any two of these values.

[0050] The pH can also be reduced during MSC culturing. The pH can be from about 6.0 to about 7.4, for example, from 6.0 to about 6.4, from about 6.2 to about 6.4, from about 6.2 to about 6.6, from about 6.4 to about 6.6, from about 6.4 to about 6.8, or from about 6.6 to about 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 or 7.4.

[0051] The temperature of the culture environment may be raised relative to physiologic homeostasis temperature (e.g., 37°C). In one aspect, the culture conditions for the MSCs can comprise from about 35°C to about 39°C, from about 35°C to about 36°C, from about 36°C toabout 37°C, from about 37°C to about 38°C, from about 38°C to about 39°C, from about 39°C to about 40°C. In one aspect, the temperature of the culture can be 35.0, 35.1, 35.2, 35.3, 36.4,35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, .37.1,37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8,38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0°C.

[0052] In some embodiments, the culture media is serum free. In some embodiments, the serum free culture media comprises platelet lysate. In some embodiments, the platelet lysate is human platelet lysate (HPL). In some embodiments, the serum free culture media comprises at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of HPL by volume, or a range between any two of these values. In some embodiments, the culture media comprises from 8% to 12%, 5% to 15%, or 9% to 11% of HPL by volume.

[0053] In one aspect, the therapeutic composition, e.g., MSC secretome compositions (including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions) comprise an additive. The additive can serve as a protective coating. The additive can reduce degradation of components within the composition, such as a growth factor. The additive may be a cryoprotectant. The cryoprotectant may be an oligosaccharide. The additive may be a polymer. Polymers include a relatively high molecular weight organic compound, natural or synthetic, whose structure can be represented by a repeated small unit, the monomer. Non-limiting examples of polymers include polyethylene, rubber, cellulose. Synthetic polymers are typically formed by addition or condensation polymerization of monomers. The term copolymer may refer to a polymer formed from two or more different repeating units (monomer residues). By way of example and without limitation, a copolymer can be an alternating copolymer, a random copolymer, a block copolymer, or a graft copolymer. The polymer may be a natural polymer, synthetic polymer, homopolymer, heteropolymer or copolymer. In one aspect, the polymer can comprise a copolymer, block copolymer, diblock copolymer, and / or triblock copolymer. In one aspect, the additive may comprise a biocompatible polymer. In one aspect, the biocompatible polymer is crosslinked. Biocompatible polymers include, but are not limited to, polysaccharides; hydrophilic polypeptides; poly(amino acids) such as poly-L-glutamic acid (PGS), gamma-polyglutamic acid, poly-L-aspartic acid, poly-L- serine, or poly-L-lysine; polyalkylene glycols and polyalkylene oxides such as polyethylene glycol (PEG), polypropylene glycol (PPG), and poly(ethylene oxide) (PEO); poly(oxyethylated polyol); poly(olefinic alcohol); polyvinylpyrrolidone); poly(hydroxyalkylmethacrylamide); poly(hydroxyalkylmethacrylate); poly(saccharides); poly(hydroxy acids); poly(vinyl alcohol), polyhydroxyacids such as poly(lactic acid), poly (gly colic acid), and poly (lactic acid-co- glycolic acids); polyhydroxyalkanoates such as poly 3 -hydroxybutyrate or poly4-hydroxybutyrate; polycaprolactones; poly(orthoesters); polyanhydrides; poly(phosphazenes); poly(lactide-co-caprolactones); polycarbonates such as tyrosine polycarbonates; polyamides (including synthetic and natural polyamides), polypeptides, and poly(amino acids); polyesteramides; polyesters; poly(dioxanones); poly(alkylene alkylates); hydrophobic polyethers; polyurethanes; polyetheresters; polyacetals; polycyanoacrylates; polyacrylates; polymethylmethacrylates; polysiloxanes; poly(oxyethylene) / poly(oxypropylene) copolymers; polyketals; polyphosphates; polyhydroxyvalerates; polyalkylene oxalates; polyalkylene succinates; poly(maleic acids), as well as copolymers thereof. Biocompatible polymers can also include polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols (PVA), methacrylate PVA(m-PVA), polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly (methyl methacrylate), poly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutylmethacrylate), poly(hexlmethacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly (phenyl methacrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl alcohols), poly(vinyl acetate, poly vinyl chloride polystyrene and polyvinylpryrrolidone, derivatives thereof, linear and branched copolymers and block copolymers thereof, and blends thereof. Exemplary biodegradable polymers include polyesters, poly(ortho esters), poly(ethylene amines), poly(caprolactones), poly(hydroxybutyrates), poly(hydroxyvalerates), polyanhydrides, poly(acrylic acids), polyglycolides, poly(urethanes), polycarbonates, polyphosphate esters, polyphospliazenes, derivatives thereof, linear and branched copolymers and block copolymers thereof, and blends thereof.

[0054] In some embodiments the protective coating comprises carbohydrate construction of monosaccharides as well as carbohydrate polymers such as di saccharides or polysaccharides including but not limited to non-reducing poly or disaccharides as well as any combination thereof. Examples of carbohydrates that can be used in the protective coating comprise Glucose, Aldoses (D-Allose, D-Altrose, D-Mannose, etc.), Glucopyranose, Pentahydroxyhexanal, a-D- Glucopyranosyl-D-glucose, a-D-Glucopyranosyl-dihydrate, Polymer of P-D-Glycopyranosyl units, P-D-Fructofuranosyl a-D-glucopyranoside (anhydrous / dihydrate), f3-D-Galactopyranosyl-D-glucose, a-D-Glucopyranosyl-a-D-glucopyranoside (anhydrous / dihydrate), Galactose, Pentoses (Ribose, xylose, lyxose), Dextrose, Dodecacarbon monodecahydrate, Fructose, Sucrose, Lactose, Maltose, Trehalose, Agarose, D-galactosyl-0-(l- 4)-anhydro-L-galactosyl, Cellulose, Polymer of P-D-Glycopyranosyl units, and Starch, as well as, Polyhydric alcohols, Polyalcohols, Alditols, Erythritol, Glycitols, Glycerol, Xylitol, and Sorbitol.

[0055] In some embodiments the protective coating contains biocompatible and / or biodegradable polyesters or polyanhydrides such as poly(lactic acid), poly(glycolic acid), and poly(lactic-co-gly colic acid). The particles can contain one more of the following polyesters: homopolymers including glycolic acid units, referred to herein as "PGA", and lactic acid units, such as poly-L-lactic acid, poly-D-lactic acid, poly-D,L-lactic acid, poly-L-lactide, poly-D- lactide, and poly-D,L-lactide5 collectively referred to herein as "PLA", and caprolactone units, such as poly(e-caprolactone), collectively referred to herein as "PCL"; and copolymers including lactic acid and glycolic acid units, such as various forms of poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide) characterized by the ratio of lactic acid:gly colic acid, collectively referred to herein as "PLGA"; and polyacrylates, and derivatives thereof. Exemplary polymers also include copolymers of polyethylene glycol (PEG) and the aforementioned polyesters, such as various forms of PLGA-PEG or PLA-PEG copolymers, collectively referred to herein as "PEGylated polymers". In certain embodiments, the PEG region can be covalently associated with polymer to yield "PEGylated polymers" by a cleavable linker. In one aspect, the polymer comprises at least 60, 65, 70, 75, 80, 85, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent acetal pendant groups.

[0056] The triblock copolymers disclosed herein comprise a core polymer such as, example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO), poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic) acid, poly(lactic co-glycolic) acid (PLGA), cellulose derivatives, such as hydroxymethylcellulose, hydroxypropylcellulose and the like. Examples of diblock copolymers that can be used in the protective coatings disclosed herein comprise a polymer such as, example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO), poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic) acid, poly(lactic co- glycolic) acid (PLGA).

[0057] In one aspect, the protective coating contains (i.e., the encapsulated, the encapsulated compositions can further comprise lecithin or hydrolyzed lecithin as a carrier or as encapsulation material. As used herein, lecithin and / or hydrolyzed lecithin coatings include coatings comprising phosphatidyl choline, phosphatidyl inositol, phosphatidyl ethanolamine, phosphatidyl serine, and phosphatidic acid. Sources of the lecithin can be plant or animal sources.

[0058] In one aspect, any of the polymers, monosaccharides, disaccharides, or polysaccharides used to form the protective coating formed by placing the MSC additive in an encapsulating solution can be at an appropriate concentration for form the protective coating. For example, polymers, monosaccharides, disaccharides, or polysaccharides can be at any concentration between 0.01 mM and 10.0 M concentration, for example, from about 0.01 M to about 0.1 M, from about 0.1 mM to about 1.0 M, from about 1.0 M to about 10.0 M.

[0059] In one aspect, the MSC secretome compositions (including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions) disclosed herein may comprise any known ingredients typically found pharmaceutical fields such as agents for combating free radicals; bactericides; sequestering agents; preservatives; basifying or acidifying agents; fragrances; surfactants; fillers; natural products or extracts of natural product, such as aloe or green tea extract; vitamins; or coloring materials. Other ingredients that may be combined with the powder may include an antioxidant, which can be selected from a variety of antioxidants. Suitable antioxidants include vitamins, such as Vitamin C (L-Ascorbate, Ascorbate-2 Phosphate magnesium salt, Ascorbyl Palmitate, Tetrahexyl decyl Ascorbate), Vitamin E (Tocotrienol), Vitamin A (retinol, retinal, retinoic acid, provitamin A carotenoids, such as beta-carotene), N-acetyl glucosamine, or other derivatives of glucosamine. Other ingredients may include at least one essential fatty acid, such as S2-3, S2-6, and S2-9 polyunsaturated fatty acids, such as linoleic acid (LA), gamma-linoleic acid (GLA), alpha-linoleic acid (ALA), dihomo-y-linolenic acid (DGLA), arachidonic acid (ARA), and others. The fatty acids may be derived from various sources including evening primrose oil, black currant oil, borage oil, or GLA modified safflower seeds. Other ingredients may include a platelet rich fibrin matrix, at least one ingredient to support ECM production and production of hyaluronic acid, such as N-acetyl glucosamine or other derivatives of glucosamine, ultra-low molecular weight (ULMW) hyaluronic acid, chondroitin sulfate, or keratin sulfate.

[0060] The MSC secretome compositions may be produced by a method comprising culturing MSCs collected from a donor under stimulation conditions; collecting and combining the secretome with an additive, and freezing the combination, wherein the combination is formulated into a therapeutic composition. The frozen combination may be a dry powder. Thetherapeutic composition may comprise the dry powder reconstituted into a delivery vehicle suitable for human administration, e.g., saline. The therapeutic composition may comprise exosomes, peptides, proteins, cytokines, growth factors, extracellular matrix (ECM), proteoglycans, glycosaminoglycans, chemokines, or a combination of two or more thereof. The MSCs may be bone marrow MSCs. The MSCs may be human MSCs, animal MSCs, multipotential stromal cells, fibroblasts, or fibroblast cellsThe MSC secretome compositions may be produced by a method comprising culturing MSCs collected from a donor under stimulation conditions, lysing the MSCs to generate an extracted lysate, concentrating the extracted lysate, and combining the extracted lysate with an additive, and freezing the mixture to generate a dry powder. In example embodiments, the additive is a saccharide. In some embodiments, freezing includes lyophilization. The powder may comprise a concentrated collection of analgesic MSC secretomes components (e.g., exosomes, extracellular matrix) that are specific to anti-inflammation.

[0061] The methods may also include filter-sterilizing, concentrating, freezing, or freeze drying the MSC culture medium, e.g., after culturing under wound healing conditions. Additionally, the MSC culture medium may be combined with a cryoprotectant prior to freezing. The cryoprotectant may be the additive, such as an oligosaccharide.

[0062] Lysing may be achieved by the addition of a hypotonic solution or repeated freeze-thaw processes to disrupt the cell membranes. The cells may be lysed while attached to the culture surface or in suspension. The cells may be enzymatically released and / or lysed by mechanical homogenization.

[0063] Stimulation conditions include stimulating the MSC to selectively secrete desired antiinflammatory proteins, peptides, glycosaminoglycans, proteoglycans, exosomes and / or secretomes. Stimulation may be achieved by adjusting the cell growth conditions, such as cell confluency, culture media supplements, nutritional supplements, oxygen levels, length of culture in those conditions, cell passage number or combinations of those, and the like. Stimulation may comprise growth under wound healing conditions. Wound healing conditions may comprise about 1% to about 5% oxygen, reduced or no serum, reduced glucose, or these elements in various combinations.Pharmaceutical carriers / Delivery of pharmaceutical products

[0064] Therapeutic compositions, such as MSC secretome compositions, may be administered in vivo in a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject, along with the nucleic acid or vector, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of thepharmaceutical composition in which it is contained. The carrier may be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject. The compositions may be administered parenterally (e.g., intravenously).

[0065] Parenteral administration of the composition, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. Parenteral administration may involve use of a slow release or sustained release system such that a constant dosage is maintained.

[0066] Preparations for parenteral administration may include a sodium chloride solution. Therapeutic Uses

[0067] Provided herein are methods of treating graft-versus-host disease in a subject. The subject may have received an organ transplant or allograft. The subject may have received a modified multivisceral allograft, an isolated intestine allograft, or an isolated liver allograft. The subject may exhibit one or more signs or symptoms of graft-versus-host disease and / or allograft rejection. For example, the subject may exhibit one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetitejaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.

[0068] In some embodiments, the subject may be receiving corticosteroids. For example, the subject may be receiving high dose corticosteroids. In some embodiments, the subject may experience improvement after treatment in one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite aundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.

[0069] Methods of treating graft-versus-host disease in a subject may comprise administering to the subject a composition comprising a protein, wherein the protein comprises one or more proteins selected from Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine3-0-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocytemacrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein- glutamine gamma-glutamyltransf erase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, TIMP-2 (Tissue Inhibitor of MMPs 2), and the proteins of Table 1. Methods of treating graft-versus-host disease in a subject may comprise administering to the subject a composition an extracellular vesicle (EV), the EV comprising one or more nucleic acids selected from hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR- 27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, and hsa-miR-940, and combinations of two or more thereof. In some methods, at least 80% of the EVs are CD63+ CD9- CD81-.The composition may have an EV concentration of at least about 60 billion EVs. The composition may have an EV concentration of at least about 60 billion EVs per mL. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0070] Methods of treating graft-versus-host disease in a subject may comprise administering to the subject a composition comprising an extracellular vesicle (EV), wherein the composition comprises at least about 60 billion EVs. The at least about 60 billion EVs may be about 60 to about 80 billion EVs. The at least about 60 billion EVs may be at least about 60 billion EVs per mL of composition. The at least about 60 billion EVs may be about 60 billion to 80 billion EVs per mL of composition. In some methods, at least 80% of the EVs are CD63+CD9 CD8 I .Thecomposition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0071] Methods of treating graft-versus-host disease in a subject may comprise administering to the subject a composition comprising extracellular vesicles (EVs), wherein at least 80% of the EVs are CD63+CD9 CD8 I .The composition may have an EV concentration of at least about 60 billion EVs. The composition may have an EV concentration of at least about 60 billion EVs per mL. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0072] Methods of treating graft-versus-host disease in a subject may comprise administering to the subject a composition comprising a protein and an extracellular vesicle (EV), wherein the protein comprises one or more proteins selected from Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin,TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin- 4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, TIMP-2 (Tissue Inhibitor of MMPs 2), and the proteins of Table 1; and the EV comprising one or more nucleic acids selected from hsa-miR- 125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR- 27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa- miR-423-3p, hsa-miR-424-5p, and hsa-miR-940, and combinations of two or more thereof. miRNA sequences may be obtained from https: / / www.mirbase.org / . In some methods, at least 80% of the EVs are CD63+ CD9- CD81-.The composition may have an EV concentration of at least about 60 billion EVs. The composition may have an EV concentration of at least about 60 billion EVs per mL. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a nonlimiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0073] The protein administered to the subject may be prepared from a method comprising: (a) culturing bone marrow-derived mesenchymal stem cell (MSC) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition, wherein the composition comprises the protein produced by the bone marrow-derived MSCs in step (a), and formulating comprises formulating the protein into a pharmaceutically acceptable formulation for injection into the subject. The culture media may be serum-free. The culture media may have a glucose concentration below 4.5 g / L or no glucose. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million toabout 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0074] The EV administered to the subject may be prepared from a method comprising: (a) culturing bone marrow-derived mesenchymal stem cell (MSC) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition, wherein the composition comprises the EV produced by the bone marrow-derived MSCs in step (a), and formulating comprises formulating the EV into a pharmaceutically acceptable formulation for injection into the subject. The culture media may be serum-free. The culture media may have a glucose concentration below 4.5 g / L or no glucose. In some methods, at least 80% of the EVs are CD63+CD9 CD8 I .The composition may have an EV concentration of at least about 60 billion EVs. The composition may have an EV concentration of at least about 60 billion EVs per mL. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0075] Methods of treating graft-versus-host disease in a subject may comprise administering to the subject a composition comprising a protein, the method comprising: (a) culturing bone marrow-derived mesenchymal stem cell (MSC) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition, wherein the composition comprises the protein produced by the bone marrow-derived MSCs in step (a), and formulating comprises formulating the protein into a pharmaceutically acceptable formulation for injection into the subject; and (d) administering the pharmaceutically acceptable formulation to the subject. The culture media may be serum-free. The culture media may have a glucose concentration below 4.5 g / L or no glucose.

[0076] Methods of treating graft-versus-host disease in a subject may comprise administering to the subject a composition comprising an EV, the method comprising: (a) culturing bone marrow-derived mesenchymal stem cell (MSC) under the following conditions to produce anMSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition, wherein the composition comprises the EV produced by the bone marrow-derived MSCs in step (a), and formulating comprises formulating the EV into a pharmaceutically acceptable formulation for injection into the subject; and (d) administering the pharmaceutically acceptable formulation to the subject. The culture media may be serum-free. The culture media may have a glucose concentration below 4.5 g / L or no glucose. In some methods, at least 80% of the EVs are CD63+CD9 CD8 I .The composition may have an EV concentration of at least about 60 billion EVs. The composition may have an EV concentration of at least about 60 billion EVs per mL. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within the composition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0077] Methods of treating graft-versus-host disease in a subject may comprise administering to the subject a composition comprising a protein and an EV, the method comprising: (a) culturing bone marrow-derived mesenchymal stem cell (MSC) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition, wherein the composition comprises the protein and the EV produced by the bone marrow-derived MSCs in step (a), and formulating comprises formulating the protein and the EV into a pharmaceutically acceptable formulation for injection into the subject; and (d) administering the pharmaceutically acceptable formulation to the subject. The culture media may be serum-free. The culture media may have a glucose concentration below 4.5 g / L or no glucose. In some methods, at least 80% of the EVs are CD63+CD9 CD8 I .The composition may have an EV concentration of at least about 60 billion EVs. The composition may have an EV concentration of at least about 60 billion EVs per mL. The composition may have an EV concentration of at least about 60 billion EVs per mL, for instance, about 60 billion to about 250 billion per mL, or about 60 billion to about 80 billion per mL. Optionally about 5, 10, 15 or 20 mL is administered. As a non-limiting example, the about 5, 10, 15, or 20 mL of the composition is diluted into an intravenous solution such as saline, and administered to the subject. The intravenous solution may be about 100 mL. The number of EVs within thecomposition may be about 10 million to about 1 trillion. The number of EVs within the composition may be about 1 trillion. The number of EVs within the composition may be about 10 billion to about 1 trillion.

[0078] In some embodiments, therapeutic compositions herein, such as MSC secretome compositions comprise a growth factor and / or exosome. The growth factor and / or exosome may induce cell proliferation, and angiogenesis. The therapeutic compositions herein may comprise mitogenic proteins such as transforming growth factor-alpha (TGF-a), TGFP, hepatocyte growth factor (HGF), epithelial growth factor (EGF), basic fibroblast growth factor (FGF-2) and / or insulin-like growth factor-1 (IGF-1). These increase fibroblast, epithelial and endothelial cell division. The therapeutic compositions herein may comprise vascular endothelial growth factor (VEGF), IGF-1, EGF and / or angiopoietin-1, which recruit endothelial lineage cells and initiate vascularization. The therapeutic compositions herein may comprise components that are antiinflammatory. The therapeutic compositions herein may comprise components that are immunomodulatory. Non-limiting example anti-inflammatory proteins include prostaglandin 2, TGF-131, HGF, SDF-1, nitrous oxide, indoleamine 2, 3 -dioxygenase, IL-4, IL-10, IL-1 receptor antagonist and soluble tumor necrosis factor-a receptor. The therapeutic compositions herein may comprise components that prevent proliferation and function of inflammatory immune cells, including T-cells, natural killer cells, B-cells, monocytes, macrophages, and dendritic cells.

[0079] A characteristic of chronically inflamed environments is a persistent imbalance in the types of helper T-cells and macrophages. In some embodiments, therapeutic compositions, e.g., MSC secretome compositions, indirectly promote the transition of TH1 to TH2 cells by reducing INF-y and increasing IL-4 and IL- 10. The restored TH1 / TH2 balance may improve tissue regeneration in cartilage, muscle, and other soft tissue. The reduction in INF-y and secretion of IL-4 may promote a shift in macrophages from Ml (proinflammatory, anti-angiogenic and tissue growth inhibition) to M2 (anti-inflammatory, pro-remodeling and tissue healing) type, for skeletal, muscular, and neural healing and regeneration.Methods of Treating Graft-versus-Host Disease (GVHD)

[0080] In some embodiments, the therapeutic compositions, e.g., MSC secretome compositions, disclosed herein are used in methods of treating graft-versus-host disease (GVHD) in a subject. Any of the therapeutic compositions described herein may be used in such a method. In some embodiments, the subject is taking immunosuppressive medication. In some embodiments, the subject has a modified multivisceral allograft. In some embodiments, the subject has an isolated intestine allograft. In some embodiments, the subject has an isolated liver allograft. In some embodiments, the subject exhibits signs or symptoms of graft-versus-host disease. In someembodiments, the subject exhibits signs or symptoms of allograft rejection. In some embodiments, signs or symptoms of graft-versus-host disease and / or allograft rejection include but are not limited to crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetitejaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, and / or ulcers.

[0081] In some embodiments, the subject is receiving high dose corticosteroids. In some embodiments, the subject exhibits signs or symptoms of graft-versus-host disease and / or allograft rejection despite receiving high dose corticosteroids. In some embodiments, the subject exhibits improvement in one or more signs or symptoms of graft-versus-host disease and / or allograft rejection after administration of one or more doses of the therapeutic product. In some embodiments, the subject exhibits the improvement within 24 hours of administration of the therapeutic product. In some embodiments, the subject exhibits improvement in pulmonary symptoms and / or dermatologic manifestations of graft-vs-host disease after administration of the therapeutic product. In some embodiments, the subject exhibits improvement in pulmonary symptoms and / or dermatologic manifestations of graft-vs-host disease within 24 hours after administration of the therapeutic product. In some embodiments, the subject exhibits improvement in one or more signs or symptoms of graft-versus-host disease and / or allograft rejection within 7 days of the administration of the initial dose of the therapeutic product. In some embodiments, the subject exhibits improved serologic laboratory evaluation with regard to graft function within 7 days of the administration of the initial therapeutic dose. In some embodiments, the subject exhibits complete histologic resolution of graft inflammation and / or rejection within 7 days of administration of the therapeutic product.

[0082] In some embodiments, the therapeutic product is administered intravenously. In some embodiments, 15 mL of the therapeutic product is administered per dose. In some embodiments, one dose, two doses, or three doses are administered to a subject. In some embodiments, one, two, or three doses are administered over the course of seven days. In some embodiments, 15 mL of the therapeutic product is suspended in 100 mL total volume of saline and administered intravenously over the course of one hour. In some embodiments, 15 mL of the therapeutic product is suspended in 100 mL total volume of saline and administered intravenously over the course of one hour one days 0, 2, and 4. In some embodiments, the administration is repeated one, two, three, four, or five times.

[0083] Disclosed herein in some embodiments is the treatment of solid abdominal organ transplant recipients who presented with either evidence of GVHD or solid abdominal graft rejection despite conventional immunosuppression who were treated with a bone marrow MSCderived EV therapeutic product (Direct Biologies, Austin TX). In some embodiments, EVs derived from MSCs as disclosed herein are comprised in an easy to store, off the shelf product, which is easy to administer with a high safety profile. As described herein, EVs derived from MSCs were used to successfully treat seven transplant patients presenting with evidence of acute intestinal graft rejection and GVHD. There were no adverse or serious adverse events, and all patients made complete clinical and histologic recovery following delivery of the therapeutic product. Embodiments of EVs derived from MSCs as disclosed herein represent a novel and safe therapeutic, with potential for effectiveness as indicated here, for patients who present with allograft rejection in the setting of concurrent infectious complications or GVHD. Embodiments of extracellular vesicles derived from mesenchymal stem cells cultured under hypoxic, low glucose, low pH conditions disclosed herein provide an anti-inflammatory, immunomodulatory product for the transplant patient population.

[0084] Definition

[0085] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise. The terms “and / or” and “any combination thereof’ and their grammatical equivalents as used herein, can be used interchangeably.

[0086] The term “about” or “approximately” can mean within an acceptable error range for the particular value, which may depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0087] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0088] The terms “individual,” “patient,” or “subject” are used interchangeably. None of the terms require or are limited to situation characterized by the supervision (e.g. constant orintermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly, or a hospice worker).

[0089] Non-Limiting Numbered Embodiments1. A method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition made by a method comprising:(a) culturing bone marrow-derived MSCs under the following conditions to produce an MSC conditioned media:(i) oxygen tension below 5%; and(ii) culture media having a pH below 7;(b) harvesting the MSC conditioned media; and(c) formulating the MSC conditioned media to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).2. The method of embodiment 1, wherein the subject has received an organ transplant or allograft.3. The method of embodiment 2, wherein the subject has received a modified multivisceral allograft, an isolated intestine allograft, or an isolated liver allograft.4. The method of any one of embodiments 1 to 3, wherein the subject exhibits one or more signs or symptoms of graft-versus-host disease and / or allograft rejection.5. The method of any one of embodiments 1 to 4, wherein the subject exhibits one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.6. The method of any one of embodiments 1 to 5, wherein the subject is receiving corticosteroids.7. The method of embodiment 6, wherein the subject is receiving high dose corticosteroids.8. The method of any one of embodiments 1 to 7, wherein the subject experiences improvement after treatment in one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite aundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.9. The method of any one of embodiments 1 to 8, wherein the dosage of the therapeutic MSC secretome composition administered to the subject is a cell-equivalent dosage of 0.7 to 7 million cells / kg.10. The method of any one of embodiments 1 to 9, wherein the culture media is serum-free.11. The method of any one of embodiments 1 to 10, wherein the culture media has a glucose concentration below 4.5 g / L.12. The method of any one of embodiments 1 to 11, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-.13. The method of any one of embodiments 1 to 12, wherein the therapeutic MSC secretome composition comprises one or more of the following proteins: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL- 20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM- A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref- 1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24,gpl30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF- 23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin- 1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL- 17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA I3, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha- 1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cy statin SA, Galectin-4, Pepsinogen II, Desmogl ein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmogl ein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.1, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, S0X15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP- 10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3 A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cy statin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13. 14. The method of any one of embodiments 1 to 13, wherein the therapeutic MSC secretome composition comprises one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100- 5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa- mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa- mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa- miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR- 30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR- 3 l-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa- miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b- 3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p.15. A method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic MSC secretome composition comprising extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-.16. The method of embodiment 15, wherein the therapeutic MSC secretome composition further comprises one or more of the following proteins: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM- C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7 A, NKp80, Cy statin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan- 4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD 109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP -A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD- L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, PlexinDl, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP- 1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl3O, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD- ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL- 19,-n-Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cy statin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA I3, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL- 28 A, FGF-12, METAP2, AS AHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL- 10 Rb, XEDAR, IL-22, PILR-alpha, NRG1- 131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R- Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL- 1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78,Reg3A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13.17. The method of embodiment 15 or 16, wherein the extracellular vesicles comprise one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa- miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa- miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa- miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa- miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa- miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR- 20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa- miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa- miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa- miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir- 30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR- 320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir- 486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa- miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa- miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p.18. The method of any one of embodiments 15 to 17, wherein the subject has received an organ transplant or allograft.19. The method of embodiment 18, wherein the subject has received a modified multivisceral allograft, an isolated intestine allograft, or an isolated liver allograft.20. The method of any one of embodiments 15 to 19, wherein the subject exhibits one or more signs or symptoms of graft-versus-host disease and / or allograft rejection.21. The method of any one of embodiments 15 to 20, wherein the subject exhibits one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.22. The method of any one of embodiments 15 to 21, wherein the subject is receiving corticosteroids.23. The method of embodiment 22, wherein the subject is receiving high dose corticosteroids.24. The method of any one of embodiments 15 to 23, wherein the subject experiences improvement after treatment in one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite, jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.25. The method of any one of embodiments 15 to 24, wherein subject exhibits the improvement within 24 hours of administration of the therapeutic product.26. A method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles (EVs), wherein the therapeutic MSC secretome comprises (i) Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM- C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7 A, NKp80, Cy statin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan- 4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD 109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP -A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD- L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin,-SO-Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP- 1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD- ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF RI, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL- 19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM- A, Calreticulin-2, ErbB4,BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, 01ig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL- 28 A, FGF-12, METAP2, AS AHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL- 10 Rb, XEDAR, IL-22, PILR-alpha, NRG1- 131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R- Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL- 1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p,hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a- 5p, hsa-miR-125b-5p, hsa-miR-13Oa-3p, hsa-mir-13Ob, hsa-miR-13Ob-3p, hsa-miR-132-3p, hsa- miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa- miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa- miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir- 203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir- 221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR- 23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a- 5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR- 30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa- mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa- miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR- 423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa- miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p, or a combination of two or more thereof; or (iii) both (i) and (ii).27. A method of treating graft-versus-host disease, the method comprising administering to the subject a therapeutic MSC secretome composition.28. A method of treating allograft rejection, the method comprising administering to the subject a therapeutic MSC secretome composition.29. A method of reducing symptoms associated with graft-versus host disease in a subject, the method comprising administering to the subject a therapeutic MSC secretome composition.30. A method of improving one or more signs or symptoms of graft-versus-host disease and / or allograft rejection selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.31. The method of any one of embodiments 27-30, wherein extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-.32. The method of any one of embodiments 27-31, wherein the therapeutic MSC secretome comprises (i) Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B,Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM- A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP- A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL- 18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, P0N1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP- 1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM- 1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP- 3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80,Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, GranzymeH, PRX2, p27, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL- 17B, IL- 17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, LTAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alphaI, AMIG02, HCC-1, TFPI-2, ULBP-2, Desm oglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin- 2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R,Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, R0B03, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt- 3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4- 1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa- let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b- 5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa- miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa- mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR- 203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR- 221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa- mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR- 27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa- miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR- 345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423- 3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR- 486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-l, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa- miR-99a-5p, or hsa-miR-99b-5p, or a combination of two or more thereof; or (iii) both (i) and (ii).33. The method of any one of embodiments 27-32, wherein the therapeutic MSC secretome composition is made by a method comprising: (a) culturing bone marrow-derived MSCs under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).34. The method of any one of embodiments 27-33, wherein the subject has received an organ transplant or allograft.35. The method of embodiment 34, wherein the subject has received a modified multivisceral allograft, an isolated intestine allograft, or an isolated liver allograft.36. The method of any one of embodiments 27-35, wherein the subject has exhibits one or more signs or symptoms of graft-versus-host disease and / or allograft rejection.37. The method of any one of embodiments 27-36, wherein the subject exhibits one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.38. The method of any one of embodiments 1-37, wherein the composition comprises 15 mL of the therapeutic MSC secretome composition.39. The method of embodiment 38, wherein the composition is administered intravenously.40. A method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles (EVs), wherein the composition comprises 15 mL of the therapeutic MSC secretome composition.41. A method of treating graft-versus-host disease in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition extracellular vesicles (EVs), wherein the administering improves one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness,burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.42. The method of any one of embodiments 1- 1, wherein the administering improves inflammation.43. Use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles in treating graft-versus-host disease in a subject, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+ CD9- CD81-.44. Use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles (EVs) in treating graft-versus-host disease in a subject in need thereof, wherein the therapeutic mesenchymal stem cell (MSC) secretome composition comprises (i) Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF RI, htPAPP- A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM- A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP- A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL- 18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO,PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP- 1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM- 1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP- 3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A,NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL- 17B, IL- 17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, LTAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f,uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desm oglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt- 3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4- 1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa- let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-lOb, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b- 5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa- miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-l'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR- 203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR- 221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa- mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR- 27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa- miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR- 345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423- 3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR- 486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-l, hsa- mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa- miR-99a-5p, or hsa-miR-99b-5p, or a combination of two or more thereof; or (iii) both (i) and (ii).45. Use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition comprising extracellular vesicles (EVs) in treating graft-versus-host disease in a subject, wherein the composition comprises 15 mL of the therapeutic MSC secretome composition.EXAMPLESExample 1: Production of Therapeutic Composition

[0090] An MSC secretome therapeutic composition was made by the following method: human bone marrow-derived MSCs were cultured in culture vessels with growth media to expand the MSC population. Growth media was then removed, and the cells were washed with PBS. The MSCs were then cultured in reduced glucose media with a pH below 7.0 under hypoxic conditions. The conditioned media was then collected and subjected to diafiltration followed by filter sterilization. The production process for the therapeutic product was done under current Good Manufacturing Practices and Current Good Tissue Practices.

[0091] The tetraspanin profile of extracellular vesicles present in the therapeutic composition was determined, and it was found that greater than 95% of the extracellular vesicles present in the therapeutic composition were CD63+CD9 CD81 .

[0092] Protein content of the therapeutic product was determined, and the following proteins were found to be present: Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), blG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein- coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein- 2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf- related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, and TIMP-2 (Tissue Inhibitor of MMPs 2).

[0093] The nucleic acid content of the therapeutic product was determined, and the following nucleic acids were found to be present: hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR- 23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, and hsa- miR-940.Example 2: Treatment in HumansRegulatory Approval

[0094] Following FDA allowance to proceed with single patient emergency access investigational new drug (IND) applications, patients were consented and offered treatment. Institutional review board (IRB) approval was obtained. Each had a unique treatment plan submitted to the FDA, but all included an initial three doses of 15 mL of investigational therapeutic product every other day over the course of 7 days.Therapeutic product

[0095] The investigational therapeutic product administered was a bone marrow MSC derived EV product derived from a single donor and manufactured according to strict quality criteria with US FDA Master Files and in compliance with United States FDA GMP manufacturing regulations to ensure lot quality and consistency. The MSC derived EV product was produced by bone marrow MSCs cultured under hypoxic, low glucose, and low pH conditions. As example, the product of Example 1.Dosing and Safety

[0096] Previous studies demonstrate the safety of using IV doses of 1 million cell / Kg, 5 million cell / Kg, in addition to a ceiling dose of 10 million cell / Kg; (3) observation of approximately 2,000 extracellular vesicles secreted per stromal cell; and (4) lab analysis of the IP, which showed that each mL contained approximately 60-80 billion extracellular vesicles. For an adult of 70 Kg, extrapolation from the START trial MSC ceiling dose would yield an IV therapeutic product ceiling dose of 17.5 mL. Given a range of body mass indexes (BMIs), 15 mL of IV therapeutic product was determined as a starting dosage per infusion. There are no serious adverse events attributable to the therapeutic product used in this dose range based on FDA- approved clinical trials. Nor is there any known potential for malignant transformation based on prior preclinical studies of human bone marrow derived extracellular vesicles.Patient Presentation

[0097] The patient demographics and transplantation history are shown in Table 2. Three patients had a modified multivisceral, two isolated intestine, and two isolated liver allografts; six were adult and one was pediatric.Table 2Treatment Objectives

[0098] The objective of this emergency use treatment was to administer the therapeutic product, in life-threatening situation(s) due to the concomitant pulmonary involvement with GVHD and / or signs of allograft rejection despite high dose corticosteroids. The primary objective was safety assessed by monitoring for any adverse events, and evidence of infusion toxicity.Secondary objectives were clinical, serologic, and histopathologic evidence for improvement in signs of allograft rejection and GVHD.Treatment Plan and Mode of Administration

[0099] All patients continued their immunosuppressive medications (unless had lost response or contraindicated) during the treatment protocol (see Table 2). The treatment plan proposing the total number of doses for each patient, and dose volume for the pediatric patient, that was submitted to the FDA was based on adult versus pediatric status, ongoing disease severity, acute or chronic disease stage, and allografts present. The general treatment plan included the administration of the therapeutic product intravenously at a dose of 15 mL suspended in a total of 100 mL of normal saline at Day 0. The 100 mL is infused over one hour, without a need for a filter. This was repeated on Day 2, and again on Day 4, after an assessment was made determining no signs of infusion toxicity of adverse events. Patients’ clinical status, serologies and histopathology were assessed per standard of care following the infusions (Table 3).Table 3ResultsAcute monitoring after Therapeutic product delivery

[0100] Patients were observed following administration of the therapeutic product in the post infusion unit to assess for acute adverse events, reaction to product, or significant change in vital signs.Clinical Assessment

[0101] During the course of treatment plans for all seven patients, there were no adverse or serious adverse events related to therapeutic product. All patients had improvement in clinical symptoms within 24 hours of the initial 15 mL of the therapeutic product. Similarly, in those patients with graft versus host disease (n=2), pulmonary symptoms and dermatologic manifestations of graft versus host disease improved within 24 hours of the initial 15 mL of the therapeutic product. All had improved serologic laboratory evaluation with regard to graft function within 7 days of their initial therapeutic product dose, and complete histologic resolution of graft inflammation / rej ection within 7 days of treatment. (Tables 2 and 3).

[0102] FIG. 1 shows histologic improvement in allograft inflammation and resolution of acute cellular rejection following therapeutic product administration. (A) Severe acute cellular rejection of intestinal allograft in patient 1 associated with confluent crypt apoptosis, crypt loss, and ulceration. (B) Resolution of acute cellular rejection of intestinal allograft in patient 1 following therapeutic product administration. (C) Severe acute cellular rejection of liver allograft in patient 2 characterized by widespread bile duct injury, portal venous endotheliitis, and centrizonal hepatocellular injury, (D) Marked histologic improvement in liver allograft in patient 2 with only focal residual ductitis following therapeutic product administration. (E) Mildacute cellular rejection of intestinal allograft in patient 3 characterized by increased apoptotic crypt epithelial cells. (F) Complete histologic resolution of acute cellular rejection in patient 3. (G) Severe acute cellular rejection of intestinal allograft in patient 4 with crypt loss and ulceration. (H) Complete mucosal healing of intestinal allograft in patient 4 following administration of Therapeutic product with no residual increase in apoptotic activity or crypt loss. (I) Mild acute cellular rejection of intestinal allograft in patient 5 with only occasional increased apoptotic crypt epithelial cells. (J) Resolution of acute cellular rejection in patient 5 following therapeutic product administration. (K,L) Patient 6 with normal small bowel allograft before and after treatment of GVHD with therapeutic product.

[0103] In summary, the safety and efficacy of an extracellular vesicle (EV) product derived from mesenchymal stem cells in the transplant patient population was tested. Seven separate Emergency Investigational New Drug (eIND) Applications were filed with the FDA for the emergency treatment of rejection of an isolated intestinal graft (n=2), liver allograft graft (n=2), modified multivisceral graft (n=3), and graft versus host disease (GVHD) in isolated intestinal transplant patients (n=2). 15 mL of the therapeutic product was administered intravenously on Day 0, 2, 4 and this treatment cycle was repeated up to four times in each patient depending on the treatment protocol allowed by the FDA. Safety (adverse event reporting) and efficacy (clinical status, serologies, and histopathology) were evaluated. There were no adverse events related to therapeutic product. All patients had improvement in clinical symptoms within 24 hours, improved serologic laboratory evaluation, improved pulmonary symptoms and dermatologic manifestations of GVHD, and complete histologic resolution of graft inflammation / rej ection within 7 days of therapeutic product administration. Systemic use of the MSC derived EV product was successful in achieving histological clearance of intestinal, liver and multivisceral graft inflammation, and skin and pulmonary manifestations of GVHD.Example 3: Characterizing Improvement in Serum Inflammatory Markers

[0104] Patients are treated with the therapeutic product of the present disclosure as described in Example 2. In some embodiments, patients treated with the therapeutic product have severe or life-threatening abdominal solid organ transplant rejection or are evaluated and determined to be at high risk of progression to severe or life-threatening condition related to rejection of an abdominal solid organ transplant, at risk of worsening allograft function, or at risk of complications from current immunosuppressive therapeutic regimens. Patients are assessed before, during, and after treatment in order to characterize the improvement seen in serum inflammatory markers and inflammation of solid abdominal organ. This could include improvements seen in the following transplant types:• Liver transplant: overall improved liver function, as seen by reduction in liver function test and improved albumin.• Small bowel transplant: decreased inflammation on biopsy• Pancreas: decreased amylase and lipase• Multi visceral: any of the above criteria

[0105] 15 mL of therapeutic product is given intravenously in a total volume of 100 mL(mixed with 85 mL of normal saline) up to nine times over the course of 1 year. Each patient is followed after treatment for 6 months. As an example, the therapeutic product of Example 1.

[0106] Inclusion Criteria:• Provision of signed and dated informed consent form• Stated willingness to comply with all study procedures and availability for the duration of the study• Male or female, ages 18 to 75• Previous abdominal solid organ transplant• Diagnosis of acute or chronic rejection based on clinical observations, laboratory analysis, histological evaluation.• Diagnosis of worsening allograft function based on clinical observations, laboratory analysis, histological evaluation.• Failed primary and alternate standard of care therapies• Serious or life-threatening condition or progressing to serious or life-threatening condition if not treated as evaluated by the treating physician.• In otherwise good general health as evidenced by medical history• Male or female of reproductive potential must utilize birth control method during from time of enrollment to 6 months after study completion

[0107] Exclusion Criteria:• Pregnancy or lactation• Treatment with another investigational drug or other intervention within 30 days of enrollment• Subj ects with a history of laboratory evidence of hypercoagulability• Subjects with a history of deep venous thrombosis or pulmonary embolus.

[0108] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understoodthat various alternatives to the embodiments of the present disclosure may be employed in practicing the present disclosure. It is intended that the following claims define the scope of the present disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating graft-versus-host disease in a subject in need thereof, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa- miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR- 29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

2. A method of treating graft-versus-host disease in a subject in need thereof, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-.

3. A method of treating graft-versus-host disease in a subject in need thereof, the method comprising administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factorbeta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulinlike growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-0- sulfotransf erase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf- related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM- CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

4. The method of claim 2, wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR- 145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222- 3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p,hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa- miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

5. The method of claim 1 or 2, wherein the composition comprises Ferritin, IGFBP-4 (Insulinlike growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factorbeta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulinlike growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-0- sulfotransf erase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf- related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM- CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

6. The method of any one of claims 1-5, wherein the subject has received an organ transplant or allograft.

7. The method of claim 6, wherein the subject has received a modified multivisceral allograft, an isolated intestine allograft, or an isolated liver allograft.

8. The method of any one of claims 1-7, wherein the subject exhibits one or more signs or symptoms of graft-versus-host disease and / or allograft rejection.

9. The method of any one of claims 1-8, wherein the subject exhibits one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.

10. The method of any one of claims 1-9, wherein the subject is receiving corticosteroids.

11. The method of claim 10, wherein the subject is receiving high dose corticosteroids.

12. The method of any one of claims 1-11, wherein the subject experiences improvement after treatment in one or more signs or symptoms selected from the group consisting of: crypt apoptosis, crypt loss, ulceration, cellular rejection of an allograft, bile duct injury, portal venous endotheliitis, centrizonal hepatocellular injury, ductitis, inflammation, pain, bleeding, fever, chills, redness, burning, itching, cramping, nausea, vomiting, loss of appetite, jaundice, enlarged liver, rashes, blisters, peeling, tenderness, liver failure, ulcers, and combinations thereof.

13. The method of any one of claims 1-12, wherein the dosage of the therapeutic MSC secretome composition administered to the subject is a cell-equivalent dosage of 0.7 to 7 million cells / kg.

14. The method of any one of claims 1-13, wherein administering comprises intravenous administration.

15. The method of any one of claims 1-14, wherein the composition is prepared by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

16. The method of any one of claims 1-15, the method comprising preparing the composition prior to the administering, wherein preparing the composition occurs by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

17. The method of claim 15 or 16, wherein the culture media is serum-free.

18. The method of any one of claims 15-17, wherein the culture media has a glucose concentration below 4.5 g / L.

19. The method of any one of claims 15-18, wherein formulating the MSC conditioned media comprises exchanging the conditioned media for a pharmaceutically acceptable formulation.

20. The method of claim 19, wherein the pharmaceutically acceptable formulation comprises saline.

21. The method of any one of claims 1, 2, or 4, wherein the composition comprises at least 6xlO10to 8xlO10extracellular vesicles per ml and is administered at a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml.

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