Mesenchymal stromal cell based therapies for the treatment of immune disorders: recent milestones and future challenges

References

• Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol. 2012;12:383–396.
   PubMed Web of Science ®Google Scholar
• Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. the international society for cellular therapy position statement. Cytotherapy. 2006;8:315–317. https://doi.org/10.1080/14653240600855905.
   PubMed Web of Science ®Google Scholar
• Bianco P, Barker R, Brustle O, et al. Regulation of stem cell therapies under attack in europe: for whom the bell tolls. Embo J. 2013;32:1489–1495.
   PubMed Web of Science ®Google Scholar
• Bianco P. “Mesenchymal” stem cells. Annu Rev Cell Dev Biol. 2014;30:677–704.
   PubMed Web of Science ®Google Scholar
• Bianco P, Cao X, Frenette PS, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19:35–42.
   PubMed Web of Science ®Google Scholar
• Galipeau J, Krampera M, Barrett J, et al. International society for cellular therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy. 2016;18:151–159.
   PubMed Web of Science ®Google Scholar
• Naji A, Eitoku M, Favier B, et al. Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci. 2019;76:3323–3348.
   PubMed Web of Science ®Google Scholar
• Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32:252–260.
   PubMed Web of Science ®Google Scholar
• Horwitz EM, Le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: the international society for cellular therapy position statement. Cytotherapy. 2005;7:393–395.
   PubMed Web of Science ®Google Scholar
• Caplan AI. Mesenchymal stem cells: time to change the name! Stem Cells Transl Med. 2017;6:1445–1451.
   PubMed Web of Science ®Google Scholar
• Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9:641–650.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Chen M, Tian J, et al. In situ bone regeneration enabled by a biodegradable hybrid double-network hydrogel. Biomater Sci. 2019;7:3266–3276.
   PubMed Web of Science ®Google Scholar
• Jiang L, Su D, Ding S, et al. Salt-assisted toughening of protein hydrogel with controlled degradation for bone regeneration. Adv Funct Mater. 2019;29:1901314.
   Web of Science ®Google Scholar
• Ribeiro VP, da Silva Morais A, Maia FR, et al. Combinatory approach for developing silk fibroin scaffolds for cartilage regeneration. Acta Biomater. 2018;72:167–181.
   PubMed Web of Science ®Google Scholar
• Ferreira JR, Teixeira GQ, Santos SG, et al. Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning. Front Immunol. 2018;9:2837.
   PubMed Web of Science ®Google Scholar
• Gao F, Chiu SM, Motan DA, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7:e2062.
   PubMed Web of Science ®Google Scholar
• Spaggiari GM, Capobianco A, Abdelrazik H, et al. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008;111:1327–1333.
   PubMed Web of Science ®Google Scholar
• Terness P, Bauer TM, Rose L, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med. 2002;196:447–457.
   PubMed Web of Science ®Google Scholar
• Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367–372.
   PubMed Web of Science ®Google Scholar
• Benkhoucha M, Santiago-Raber ML, Schneiter G, et al. Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. Proc Natl Acad Sci USA. 2010;107:6424–6429.
   PubMed Web of Science ®Google Scholar
• Francois M, Romieu-Mourez R, Li M, et al. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther. 2012;20:187–195.
   PubMed Web of Science ®Google Scholar
• Ylostalo JH, Bartosh TJ, Coble K, et al. Human mesenchymal stem/stromal cells cultured as spheroids are self-activated to produce prostaglandin E2 that directs stimulated macrophages into an anti-inflammatory phenotype. Stem Cells. 2012;30:2283–2296.
   PubMed Web of Science ®Google Scholar
• Waterman RS, Tomchuck SL, Henkle SL, et al. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS One. 2010;5:e10088.
   PubMed Web of Science ®Google Scholar
• Gazdic M, Volarevic V, Arsenijevic N, et al. Mesenchymal stem cells: a friend or foe in immune-mediated diseases. Stem Cell Rev. 2015;11:280–287.
   PubMed Web of Science ®Google Scholar
• Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13:392–402.
   PubMed Web of Science ®Google Scholar
• Chen X, Wang S, Cao W. Mesenchymal stem cell-mediated immunomodulation in cell therapy of neurodegenerative diseases. Cell Immunol. 2018;326:8–14.
   PubMed Web of Science ®Google Scholar
• Mao F, Tu Q, Wang L, et al. Mesenchymal stem cells and their therapeutic applications in inflammatory bowel disease. Oncotarget. 2017;8:38008–38021.
   PubMedGoogle Scholar
• Kim Y, Jin HJ, Heo J, et al. Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease. Leukemia. 2018;32:2672–2684.
   PubMed Web of Science ®Google Scholar
• de Mare-bredemeijer EL, Mancham S, Verstegen MM, et al. Human graft-derived mesenchymal stromal cells potently suppress alloreactive T-cell responses. Stem Cells Dev. 2015;24:1436–1447.
   PubMed Web of Science ®Google Scholar
• Yu Y, Liao L, Shao B, et al. Knockdown of microRNA let-7a improves the functionality of bone marrow-derived mesenchymal stem cells in immunotherapy. Mol Ther. 2017;25:480–493.
   PubMed Web of Science ®Google Scholar
• Akiyama K, Chen C, Wang D, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-Ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell. 2012;10:544–555.
   PubMed Web of Science ®Google Scholar
• Elliott MR, Koster KM, Murphy PS. Efferocytosis signaling in the regulation of macrophage inflammatory responses. J Immunol. 2017;198:1387–1394.
   PubMed Web of Science ®Google Scholar
• Galleu A, Riffo-Vasquez Y, Trento C, et al. Apoptosis in mesenchymal stromal cells induced in vivo recipient-mediated immunomodulation. Sci Transl Med. 2017;9. DOI:10.1126/scitranslmed.aam7828.
   PubMed Web of Science ®Google Scholar
• Ghahremani Piraghaj M, Soudi S, Ghanbarian H, et al. Effect of efferocytosis of apoptotic mesenchymal stem cells (MSCs) on C57BL/6 peritoneal macrophages function. Life Sci. 2018;212:203–212. https://doi.org/10.1016/j.lfs.2018.09.052
   PubMed Web of Science ®Google Scholar
• Li C, Cheung MKH, Han S, et al. Mesenchymal stem cells and their mitochondrial transfer: a double-edged sword. Biosci Rep. 2019;39. https://doi.org/BSR20182417 10.1042/BSR20182417
   Web of Science ®Google Scholar
• Yao Y, Fan XL, Jiang D, et al. Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation. Stem Cell Reports. 2018;11:1120–1135. https://doi.org/10.1016/j.stemcr.2018.09.012
   PubMed Web of Science ®Google Scholar
• Jackson MV, Morrison TJ, Doherty DF, et al. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells. 2016;34:2210–2223.
   PubMed Web of Science ®Google Scholar
• Vizoso FJ, Eiro N, Cid S, et al. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017;18. DOI:10.3390/ijms18091852.
   PubMed Web of Science ®Google Scholar
• Wiklander OPB, Brennan MA, Lotvall J, et al. Advances in therapeutic applications of extracellular vesicles. Sci Transl Med. 2019;11. https://doi.org/10.1126/scitranslmed.aav8521.
   PubMed Web of Science ®Google Scholar
• Eirin A, Zhu XY, Puranik AS, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int. 2017;92:114–124.
   PubMed Web of Science ®Google Scholar
• Cosenza S, Toupet K, Maumus M, et al. Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics. 2018;8:1399–1410.
   PubMed Web of Science ®Google Scholar
• Ruppert KA, Nguyen TT, Prabhakara KS, et al. Human mesenchymal stromal cell-derived extracellular vesicles modify microglial response and improve clinical outcomes in experimental spinal cord injury. Sci Rep. 2018;8: 480-017-18867-w.
   Web of Science ®Google Scholar
• Krampera M, Cosmi L, Angeli R, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24:386–398.
   PubMed Web of Science ®Google Scholar
• Sugimoto H, Oda S, Otsuki T, et al. Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc Natl Acad Sci USA. 2006;103:2611–2616.
   PubMed Web of Science ®Google Scholar
• Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176:6752–6761.
   PubMed Web of Science ®Google Scholar
• Li F, Zhang R, Li S, et al. IDO1: an important immunotherapy target in cancer treatment. Int Immunopharmacol. 2017;47:70–77.
   PubMed Web of Science ®Google Scholar
• Duffin R, O’Connor RA, Crittenden S, et al. Prostaglandin E(2) constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science. 2016;351:1333–1338.
   PubMed Web of Science ®Google Scholar
• Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol. 2012;188:21–28.
   PubMed Web of Science ®Google Scholar
• English K, Barry FP, Field-Corbett CP, et al. IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett. 2007;110:91–100.
   PubMed Web of Science ®Google Scholar
• Jarvinen L, Badri L, Wettlaufer S, et al. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol. 2008;181:4389–4396.
   PubMed Web of Science ®Google Scholar
• Tatara R, Ozaki K, Kikuchi Y, et al. Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation. Cytotherapy. 2011;13:686–694.
   PubMed Web of Science ®Google Scholar
• Galland S, Vuille J, Martin P, et al. Tumor-derived mesenchymal stem cells use distinct mechanisms to block the activity of natural killer cell subsets. Cell Rep. 2017;20:2891–2905.
   PubMed Web of Science ®Google Scholar
• Vasandan AB, Jahnavi S, Shashank C, et al. Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism. Sci Rep. 2016;6:38308.
   PubMed Web of Science ®Google Scholar
• Choi JS, Ryu HA, Cheon SH, et al. Human adipose derived stem cells exhibit enhanced liver regeneration in acute liver injury by controlled releasing hepatocyte growth factor. Cell Physiol Biochem. 2019;52:935–950.
   PubMedGoogle Scholar
• Lee EJ, Hwang I, Lee JY, et al. Hepatocyte growth factor improves the therapeutic efficacy of human bone marrow mesenchymal stem cells via RAD51. Mol Ther. 2018;26:845–859.
   PubMed Web of Science ®Google Scholar
• Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–3843.
   PubMed Web of Science ®Google Scholar
• Nasef A, Chapel A, Mazurier C, et al. Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells. Gene Expr. 2007;13:217–226.
   PubMed Web of Science ®Google Scholar
• Ilarregui JM, Bianco GA, Toscano MA, et al. The coming of age of galectins as immunomodulatory agents: impact of these carbohydrate binding proteins in T cell physiology and chronic inflammatory disorders. Ann Rheum Dis. 2005;64(Suppl 4):iv96–103.
   PubMedGoogle Scholar
• Johannes L, Jacob R, Leffler H. Galectins at a Glance. J Cell Sci. 2018;131. DOI:10.1242/jcs.208884.
   PubMed Web of Science ®Google Scholar
• Gieseke F, Bohringer J, Bussolari R, et al. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood. 2010;116:3770–3779.
   PubMed Web of Science ®Google Scholar
• Ilarregui JM, Croci DO, Bianco GA, et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol. 2009;10:981–991.
   PubMed Web of Science ®Google Scholar
• Gieseke F, Kruchen A, Tzaribachev N, et al. Proinflammatory stimuli induce galectin-9 in human mesenchymal stromal cells to suppress T-cell proliferation. Eur J Immunol. 2013;43:2741–2749.
   PubMed Web of Science ®Google Scholar
• Ungerer C, Quade-Lyssy P, Radeke HH, et al. Galectin-9 is a suppressor of T and B cells and predicts the immune modulatory potential of mesenchymal stromal cell preparations. Stem Cells Dev. 2014;23:755–766.
   PubMed Web of Science ®Google Scholar
• Kim SN, Lee HJ, Jeon MS, et al. Galectin-9 is involved in immunosuppression mediated by human bone marrow-derived clonal mesenchymal stem cells. Immune Netw. 2015;15:241–251.
   PubMed Web of Science ®Google Scholar
• Chen PM, Liu KJ, Hsu PJ, et al. Induction of Immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2. J Leukoc Biol. 2014;96:295–303.
   PubMed Web of Science ®Google Scholar
• Murai M, Turovskaya O, Kim G, et al. Interleukin 10 Acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10:1178–1184.
   PubMed Web of Science ®Google Scholar
• de Vries JE. Immunosuppressive and anti-inflammatory properties of interleukin 10. Ann Med. 1995;27:537–541.
   PubMed Web of Science ®Google Scholar
• Shi Y, Su J, Roberts AI, et al. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 2012;33:136–143.
   PubMed Web of Science ®Google Scholar
• Ivanova-Todorova E, Bochev I, Dimitrov R, et al. Conditioned medium from adipose tissue-derived mesenchymal stem cells induces CD4+FOXP3+ cells and increases IL-10 secretion. J Biomed Biotechnol. 2012;2012:295167.
   PubMedGoogle Scholar
• Putra A, Ridwan FB, Putridewi AI, et al. The role of TNF-alpha induced MSCs on suppressive inflammation by increasing TGF-beta and IL-10. Open Access Maced J Med Sci. 2018;6:1779–1783. https://doi.org/10.3889/oamjms.2018.404
   PubMedGoogle Scholar
• Kyurkchiev D, Bochev I, Ivanova-Todorova E, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 2014;6:552–570. https://doi.org/10.4252/wjsc.v6.i5.552
   PubMedGoogle Scholar
• Lu D, Ma T, Zhou X, et al. B lymphocytes are the target of mesenchymal stem cells immunoregulatory effect in a murine graft-versus-host disease model. Cell Transplant. 2019;963689719860127. DOI:10.1177/0963689719860127.
   Web of Science ®Google Scholar
• Najar M, Raicevic G, Fayyad-Kazan H, et al. Bone marrow mesenchymal stromal cells induce proliferative, cytokinic and molecular changes during the T cell response: the importance of the IL-10/CD210 axis. Stem Cell Rev. 2015;11:442–452.
   PubMed Web of Science ®Google Scholar
• Arend WP, Malyak M, Guthridge CJ, et al. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol. 1998;16:27–55.
   PubMed Web of Science ®Google Scholar
• Volarevic V, Al-Qahtani A, Arsenijevic N, et al. Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis. Autoimmunity. 2010;43:255–263.
   PubMed Web of Science ®Google Scholar
• Luz-Crawford P, Djouad F, Toupet K, et al. Mesenchymal stem cell-derived interleukin 1 receptor antagonist promotes macrophage polarization and inhibits B cell differentiation. Stem Cells. 2016;34:483–492.
   PubMed Web of Science ®Google Scholar
• Lee K, Park N, Jung H, et al. Mesenchymal stem cells ameliorate experimental arthritis via expression of interleukin-1 receptor antagonist. PLoS One. 2018;13:e0193086.
   PubMed Web of Science ®Google Scholar
• Ortiz LA, Dutreil M, Fattman C, et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA. 2007;104:11002–11007.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Yamamoto Y, Xiao Z, et al. The Immunomodulatory Functions of Mesenchymal Stromal/Stem Cells Mediated Via Paracrine Activity. J Clin Med. 2019;8. https://doi.org/E1025 [pii].
   Web of Science ®Google Scholar
• Li H, Tian Y, Xie L, et al. Mesenchymal stem cells in allergic diseases: current status. Allergol Int. 2020;69:35-45. https://doi.org/10.1016/j.alit.2019.08.001.
   PubMed Web of Science ®Google Scholar
• Ferrara JL, Levine JE, Reddy P, et al. Graft-versus-host disease. Lancet. 2009;373:1550–1561.
   PubMed Web of Science ®Google Scholar
• Zhang L, Chu J, Yu J, et al. Cellular and molecular mechanisms in graft-versus-host disease. J Leukoc Biol. 2016;99:279–287.
   PubMed Web of Science ®Google Scholar
• Mehler VJ, Burns C, Moore ML. Concise review: exploring immunomodulatory features of mesenchymal stromal cells in humanized mouse models. Stem Cells. 2019;37:298–305.
   PubMed Web of Science ®Google Scholar
• Tisato V, Naresh K, Girdlestone J, et al. Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. Leukemia. 2007;21:1992–1999.
   PubMed Web of Science ®Google Scholar
• Tobin LM, Healy ME, English K, et al. Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin Exp Immunol. 2013;172:333–348.
   PubMed Web of Science ®Google Scholar
• Bruck F, Belle L, Lechanteur C, et al. Impact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic graft-versus-host disease. Cytotherapy. 2013;15:267–279.
   PubMed Web of Science ®Google Scholar
• Laing AG, Riffo-Vasquez Y, Sharif-Paghaleh E, et al. Immune modulation by apoptotic dental pulp stem cells in vivo. Immunotherapy. 2018;10:201–211.
   PubMed Web of Science ®Google Scholar
• Gregoire C, Ritacco C, Hannon M, et al. Comparison of mesenchymal stromal cells from different origins for the treatment of graft-vs.-host-disease in a humanized mouse model. Front Immunol. 2019;10:619. https://doi.org/10.3389/fimmu.2019.00619
   PubMed Web of Science ®Google Scholar
• Zanotti L, Sarukhan A, Dander E, et al. Encapsulated mesenchymal stem cells for in vivo immunomodulation. Leukemia. 2013;27:500–503.
   PubMed Web of Science ®Google Scholar
• Wang L, Gu Z, Zhao X, et al. Extracellular vesicles released from human umbilical cord-derived mesenchymal stromal cells prevent life-threatening acute graft-versus-host disease in a mouse model of allogeneic hematopoietic stem cell transplantation. Stem Cells Dev. 2016;25:1874–1883.
   PubMed Web of Science ®Google Scholar
• Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015;12:205–217.
   PubMed Web of Science ®Google Scholar
• Chao K, Zhang S, Yao J, et al. Imbalances of CD4(+) T-cell subgroups in Crohn’s disease and their relationship with disease activity and prognosis. J Gastroenterol Hepatol. 2014;29:1808–1814.
   PubMed Web of Science ®Google Scholar
• Chen QQ, Yan L, Wang CZ, et al. Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses. World J Gastroenterol. 2013;19:4702–4717. https://doi.org/10.3748/wjg.v19.i29.4702
   PubMed Web of Science ®Google Scholar
• Kawata Y, Tsuchiya A, Seino S, et al. Early injection of human adipose tissue-derived mesenchymal stem cell after inflammation ameliorates dextran sulfate sodium-induced colitis in mice through the induction of M2 macrophages and regulatory T cells. Cell Tissue Res. 2019;376:257–271.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Jin Y, Lin Y, et al. Adipose-derived mesenchymal stem cells ameliorate ulcerative colitis through miR-1236 negatively regulating the expression of retinoid-related orphan receptor gamma. DNA Cell Biol. 2015;34:618–625.
   PubMed Web of Science ®Google Scholar
• Kagia A, Tzetis M, Kanavakis E, et al. Therapeutic effects of mesenchymal stem cells derived from bone marrow, umbilical cord blood, and pluripotent stem cells in a mouse model of chemically induced inflammatory bowel disease. Inflammation. 2019. DOI:10.1007/s10753-019-01033-x.
   PubMed Web of Science ®Google Scholar
• Yang FY, Chen R, Zhang X, et al. Preconditioning enhances the therapeutic effects of mesenchymal stem cells on colitis through PGE2-mediated T-cell modulation. Cell Transplant. 2018;27:1352–1367.
   PubMed Web of Science ®Google Scholar
• Anderson P, Souza-Moreira L, Morell M, et al. Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis. Gut. 2013;62:1131–1141.
   PubMed Web of Science ®Google Scholar
• Yang J, Liu XX, Fan H, et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells protect against experimental colitis via attenuating colon inflammation, oxidative stress and apoptosis. PLoS One. 2015;10:e0140551.
   PubMed Web of Science ®Google Scholar
• Correale J, Gaitan MI, Ysrraelit MC, et al. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain. 2017;140:527–546.
   PubMed Web of Science ®Google Scholar
• Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal Stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol. 2007;61:219–227.
   PubMed Web of Science ®Google Scholar
• Kim MJ, Ryu CH, Kim SM, et al. Combined treatment with methylprednisolone and human bone marrow-derived mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis. Tissue Eng Regen Med. 2018;15:183–194. https://doi.org/10.1007/s13770-017-0101-y
   PubMed Web of Science ®Google Scholar
• Togha M, Jahanshahi M, Alizadeh L, et al. Rapamycin augments immunomodulatory properties of bone marrow-derived mesenchymal stem cells in experimental autoimmune encephalomyelitis. Mol Neurobiol. 2017;54:2445–2457.
   PubMed Web of Science ®Google Scholar
• Kassis I, Petrou P, Halimi M, et al. Mesenchymal stem cells (MSC) derived from mice with experimental autoimmune encephalomyelitis (EAE) suppress EAE and have similar biological properties with MSC from healthy donors. Immunol Lett. 2013;154:70–76.
   PubMed Web of Science ®Google Scholar
• Sargent A, Bai L, Shano G, et al. CNS disease diminishes the therapeutic functionality of bone marrow mesenchymal stem cells. Exp Neurol. 2017;295:222–232.
   PubMed Web of Science ®Google Scholar
• Sarkar P, Redondo J, Kemp K, et al. Reduced neuroprotective potential of the mesenchymal stromal cell secretome with ex vivo expansion, age and progressive multiple sclerosis. Cytotherapy. 2018;20:21–28.
   PubMed Web of Science ®Google Scholar
• Redondo J, Sarkar P, Kemp K, et al. Dysregulation of mesenchymal stromal cell antioxidant responses in progressive multiple sclerosis. Stem Cells Transl Med. 2018;7:748–758.
   PubMed Web of Science ®Google Scholar
• Torkaman M, Ghollasi M, Mohammadnia-Afrouzi M, et al. The effect of transplanted human wharton’s jelly mesenchymal stem cells treated with IFN-gamma on experimental autoimmune encephalomyelitis mice. Cell Immunol. 2017;311:1–12.
   PubMed Web of Science ®Google Scholar
• Bai L, Lennon DP, Caplan AI, et al. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat Neurosci. 2012;15:862–870.
   PubMed Web of Science ®Google Scholar
• Galipeau J, Sensebe L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell. 2018;22:824–833. .
   PubMed Web of Science ®Google Scholar
• Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant. 2016;25:829–848.
   PubMed Web of Science ®Google Scholar
• Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17:11–22.
   PubMed Web of Science ®Google Scholar
• Martin PJ, Uberti PJ, Soiffer RJ, et al. Prochymal improves response rates in patients with steroid-refractory acute graft versus host disease (SR-GVHD) involving the liver and gut: results of a randomized, placebo-controlled, multicenter phase III trial in GVHD. Biol Blood Marrow Transplant. 2010;16. DOI:10.1016/j.bbmt.2009.12.057.
   Google Scholar
• Muroi K, Miyamura K, Okada M, et al. Bone marrow-derived mesenchymal stem cells (JR-031) for steroid-refractory grade III or IV acute graft-versus-host disease: A phase II/III study. Int J Hematol. 2016;103:243–250.
   PubMed Web of Science ®Google Scholar
• Herreros MD, Garcia-Arranz M, Guadalajara H, et al. Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase iii randomized clinical trial (FATT 1: fistula advanced therapy trial 1) and long-term evaluation. Dis Colon Rectum. 2012;55:762–772.
   PubMed Web of Science ®Google Scholar
• Panes J, Garcia-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388:1281–1290. .
   PubMed Web of Science ®Google Scholar
• Panes J, Garcia-Olmo D, Van Assche G, et al. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018;154:1334–1342.e4.
   PubMed Web of Science ®Google Scholar
• Scott LJ. Darvadstrocel: A review in treatment-refractory complex perianal fistulas in Crohn’s disease. BioDrugs. 2018;32:627–634.
   PubMed Web of Science ®Google Scholar
• Sensebe L, Gadelorge M, Fleury-Cappellesso S. Production of mesenchymal stromal/stem cells according to good manufacturing practices: a review. Stem Cell Res Ther. 2013;4:66.
   PubMed Web of Science ®Google Scholar
• Grau-Vorster M, Rodriguez L, Del Mazo-Barbara A, et al. Compliance with good manufacturing practice in the assessment of immunomodulation potential of clinical grade multipotent mesenchymal stromal cells derived from Wharton’s Jelly. Cells. 2019;8. https://doi.org/10.3390/cells8050484.
   PubMed Web of Science ®Google Scholar
• Zimmermann JA, Hettiaratchi MH, McDevitt TC. Enhanced Immunosuppression of T cells by sustained presentation of bioactive interferon-gamma within three-dimensional mesenchymal stem cell constructs. Stem Cells Transl Med. 2017;6:223–237.
   PubMed Web of Science ®Google Scholar
• Ejtehadifar M, Shamsasenjan K, Movassaghpour A, et al. The effect of hypoxia on mesenchymal stem cell biology. Adv Pharm Bull. 2015;5:141–149.
   PubMed Web of Science ®Google Scholar
• Bartosh TJ, Ylostalo JH, Mohammadipoor A, et al. Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci USA. 2010;107:13724–13729.
   PubMed Web of Science ®Google Scholar
• Mao AS, Özkale B, Shah NJ, et al. Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation. Proc Natl Acad Sci USA. 2019;201819415: Available from: https://doi.org/10.1073/pnas.1819415116
   Web of Science ®Google Scholar
• Attia N, Santos E, Abdelmouty H, et al. Behaviour and ultrastructure of human bone marrow-derived mesenchymal stem cells immobilised in alginate-poly-L-lysine-alginate microcapsules. J Microencapsul. 2014;31:579–589.
   PubMed Web of Science ®Google Scholar
• Shadmanfar S, Labibzadeh N, Emadedin M, et al. Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy. 2018;20:499–506.
   PubMed Web of Science ®Google Scholar