Review Article | Published:

Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases

Nature Reviews Nephrology (2018) | Download Citation


Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn’s disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.

Key points

  • Mesenchymal stem cells (MSCs; also known as mesenchymal stromal cells) actively contribute to the microenvironment of injured tissues, where they promote tissue regeneration by cell replacement, by empowering the regenerative capacity of in situ cells and through immunomodulatory mechanisms.

  • The plasticity of immunoregulation by MSCs is controlled by the intensity and complexity of inflammatory stimuli.

  • Multiple factors, including immunosuppressive factors, growth factors, exosomes, chemokines and apoptotic cells, contribute to the immunosuppressive mechanisms of MSCs.

  • Given the plasticity of the immunoregulatory phenotype of MSCs, inflammatory status and concurrent use of immunosuppressants should be considered when administering MSCs for the treatment of inflammatory diseases.

  • Greater understanding of the mechanisms that control the plasticity of MSC immunoregulation will lead to the development of novel therapeutic strategies.

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  1. 1.

    Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

  2. 2.

    Kfoury, Y. & Scadden, D. T. Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell 16, 239–253 (2015).

  3. 3.

    Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

  4. 4.

    Wang, Y., Chen, X., Cao, W. & Shi, Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat. Immunol. 15, 1009–1016 (2014).

  5. 5.

    Friedenstein, A. J., Chailakhjan, R. K. & Lalykina, K. S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3, 393–403 (1970).

  6. 6.

    Tavassoli, M. & Crosby, W. H. Transplantation of marrow to extramedullary sites. Science 161, 54–56 (1968).

  7. 7.

    Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).

  8. 8.

    Kuznetsov, S. A. et al. Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J. Bone Miner. Res. 12, 1335–1347 (1997).

  9. 9.

    Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

  10. 10.

    Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

  11. 11.

    Le Blanc, K. et. al. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia 21, 1733–1738 (2007).

  12. 12.

    Bartholomew, A. et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol. 30, 42–48 (2002).

  13. 13.

    Espagnolle, N. et al. CD146 expression on mesenchymal stem cells is associated with their vascular smooth muscle commitment. J. Cell. Mol. Med. 18, 104–114 (2014).

  14. 14.

    da Silva Meirelles, L., Chagastelles, P. C. & Nardi, N. B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci. 119, 2204–2213 (2006).

  15. 15.

    Melief, S. M., Zwaginga, J. J., Fibbe, W. E. & Roelofs, H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2, 455–463 (2013).

  16. 16.

    Song, M., Lee, J. H., Bae, J., Bu, Y. & Kim, E. C. Human dental pulp stem cells are more effective than human bone marrow-derived mesenchymal stem cells in cerebral ischemic injury. Cell Transplant 26, 1001–1016 (2017).

  17. 17.

    Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154–168 (2014).

  18. 18.

    Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2013).

  19. 19.

    Yue, R., Zhou, B. O., Shimada, I. S., Zhao, Z. & Morrison, S. J. Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell 18, 782–796 (2016).

  20. 20.

    Kramann, R. et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16, 51–66 (2015).

  21. 21.

    Schraufstatter, I. U., Discipio, R. G., Zhao, M. & Khaldoyanidi, S. K. C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation. J. Immunol. 182, 3827–3836 (2009).

  22. 22.

    Gao, P. et al. Functional effects of TGF-beta1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma. J. Immunol. 192, 4560–4570 (2014).

  23. 23.

    Park, D. et al. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 10, 259–272 (2012).

  24. 24.

    Li, J. et al. Effect of SDF-1/CXCR4 axis on the migration of transplanted bone mesenchymal stem cells mobilized by erythropoietin toward lesion sites following spinal cord injury. Int. J. Mol. Med. 36, 1205–1214 (2015).

  25. 25.

    Acosta, S. A., Tajiri, N., Hoover, J., Kaneko, Y. & Borlongan, C. V. Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke 46, 2616–2627 (2015).

  26. 26.

    Ren, G. et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2, 141–150 (2008).

  27. 27.

    Sun, L. et al. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 27, 1421–1432 (2009).

  28. 28.

    Zappia, E. et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T cell anergy. Blood 106, 1755–1761 (2005).

  29. 29.

    Togel, F. et al. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am. J. Physiol. Renal Physiol. 292, F1626–F1635 (2007).

  30. 30.

    Ortiz, L. A. et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc. Natl Acad. Sci. USA 104, 11002–11007 (2007).

  31. 31.

    Augello, A., Tasso, R., Negrini, S. M., Cancedda, R. & Pennesi, G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 56, 1175–1186 (2007).

  32. 32.

    Vasandan, A. B. et al. Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism. Sci. Rep. 6, 38308 (2016).

  33. 33.

    Mittal, M. et al. TNFalpha-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proc. Natl Acad. Sci. USA 113, E8151–E8158 (2016).

  34. 34.

    Wang, G. et al. Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells. Cell Death Differ. (2017).

  35. 35.

    Selleri, S. et al. Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming. Oncotarget 7, 30193–30210 (2016).

  36. 36.

    Yang, Q. et al. Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages. Cell Death Differ. 23, 1850–1861 (2016).

  37. 37.

    Song, H. B. et al. Mesenchymal stromal cells inhibit inflammatory lymphangiogenesis in the cornea by suppressing macrophage in a TSG-6-dependent manner. Mol. Ther. 26, 162–172 (2018).

  38. 38.

    Sala, E. et al. Mesenchymal stem cells reduce colitis in mice via release of TSG6, independently of their localization to the intestine. Gastroenterology 149, 163–176 e120 (2015).

  39. 39.

    Shi, Y., Du, L., Lin, L. & Wang, Y. Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat. Rev. Drug Discov. 16, 35–52 (2017).

  40. 40.

    Ma, S. et al. Immunobiology of mesenchymal stem cells. Cell Death Differ. 21, 216–225 (2014).

  41. 41.

    Su, J. et al. Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species. Cell Death Differ. 21, 388–396 (2014).

  42. 42.

    Aggarwal, S. & Pittenger, M. F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105, 1815–1822 (2005).

  43. 43.

    Chabannes, D. et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood 110, 3691–3694 (2007).

  44. 44.

    Cao, W. et al. Leukemia inhibitory factor inhibits T helper 17 cell differentiation and confers treatment effects of neural progenitor cell therapy in autoimmune disease. Immunity 35, 273–284 (2011).

  45. 45.

    Augello, A. et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur. J. Immunol. 35, 1482–1490 (2005).

  46. 46.

    Sioud, M., Mobergslien, A., Boudabous, A. & Floisand, Y. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T cell proliferation. Scand. J. Immunol. 71, 267–274 (2010).

  47. 47.

    Hsu, W. T. et al. Prostaglandin E2 potentiates mesenchymal stem cell-induced IL-10+IFN-gamma+CD4+ regulatory T cells to control transplant arteriosclerosis. J. Immunol. 190, 2372–2380 (2013).

  48. 48.

    Groh, M. E., Maitra, B., Szekely, E. & Koc, O. N. Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp. Hematol. 33, 928–934 (2005).

  49. 49.

    Hu, J. et al. Mesenchymal stem cells attenuate ischemic acute kidney injury by inducing regulatory T cells through splenocyte interactions. Kidney Int. 84, 521–531 (2013).

  50. 50.

    Ge, W. et al. Regulatory T cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation 90, 1312–1320 (2010).

  51. 51.

    He, Y. et al. Indoleamine 2, 3-Dioxgenase transfected mesenchymal stem cells induce kidney allograft tolerance by increasing the production and function of regulatory T cells. Transplantation 99, 1829–1838 (2015).

  52. 52.

    Corcione, A. et al. Human mesenchymal stem cells modulate B cell functions. Blood 107, 367–372 (2006).

  53. 53.

    Fan, L. et al. Interaction between mesenchymal stem cells and B-Cells. Int. J. Mol. Sci. 17, 650 (2016).

  54. 54.

    Peng, Y. et al. Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+ regulatory B cells producing interleukin 10. Leukemia 29, 636–646 (2015).

  55. 55.

    Di Nicola, M. et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99, 3838–3843 (2002).

  56. 56.

    Benvenuto, F. et al. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells 25, 1753–1760 (2007).

  57. 57.

    Han, X. et al. Interleukin-17 enhances immunosuppression by mesenchymal stem cells. Cell Death Differ. 21, 1758–1768 (2014).

  58. 58.

    Waterman, R. S., Tomchuck, S. L., Henkle, S. L. & Betancourt, A. M. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS ONE 5, e10088 (2010).

  59. 59.

    Xu, C. et al. TGF-beta promotes immune responses in the presence of mesenchymal stem cells. J. Immunol. 192, 103–109 (2014).

  60. 60.

    Chen, X. et al. The interaction between mesenchymal stem cells and steroids during inflammation. Cell Death Dis. 5, e1009 (2014).

  61. 61.

    Shou, P. et al. Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells. Oncogene 35, 5953–5962 (2016).

  62. 62.

    Inoue, S. et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation 81, 1589–1595 (2006).

  63. 63.

    Sudres, M. et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J. Immunol. 176, 7761–7767 (2006).

  64. 64.

    Taylor, C. T. & Colgan, S. P. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat. Rev. Immunol. 17, 774–785 (2017).

  65. 65.

    Hung, S. C., Pochampally, R. R., Chen, S. C., Hsu, S. C. & Prockop, D. J. Angiogenic effects of human multipotent stromal cell conditioned medium activate the PI3K-Akt pathway in hypoxic endothelial cells to inhibit apoptosis, increase survival, and stimulate angiogenesis. Stem Cells 25, 2363–2370 (2007).

  66. 66.

    Hu, X. et al. A large-scale investigation of hypoxia-preconditioned allogeneic mesenchymal stem cells for myocardial repair in nonhuman primates: paracrine activity without remuscularization. Circ. Res. 118, 970–983 (2016).

  67. 67.

    Sorokin, L. The impact of the extracellular matrix on inflammation. Nat. Rev. Immunol. 10, 712–723 (2010).

  68. 68.

    Li, C. X. et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16, 379–389 (2017).

  69. 69.

    Yang, J. et al. Regulation of the secretion of immunoregulatory factors of mesenchymal stem cells (MSCs) by collagen-based scaffolds during chondrogenesis. Mater. Sci. Eng. C Mater. Biol. Appl. 70, 983–991 (2017).

  70. 70.

    Sato, K. et al. Nitric oxide plays a critical role in suppression of T cell proliferation by mesenchymal stem cells. Blood 109, 228–234 (2007).

  71. 71.

    Pan, M. H. et al. Se-methylselenocysteine inhibits lipopolysaccharide-induced NF-kappaB activation and iNOS induction in RAW 264.7 murine macrophages. Mol. Nutr. Food Res. 55, 723–732 (2011).

  72. 72.

    Cervenka, I. & Agudelo, L. Z. Kynurenines: tryptophan’s metabolites in exercise. inflammation, and mental health. (2017).

  73. 73.

    Ling, W. et al. Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment. Cancer Res. 74, 1576–1587 (2014).

  74. 74.

    Qian, F. et al. Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T cell proliferation in human epithelial ovarian cancer. Cancer Res. 69, 5498–5504 (2009).

  75. 75.

    Francois, M., Romieu-Mourez, R., Li, M. & Galipeau, J. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol. Ther. 20, 187–195 (2012).

  76. 76.

    Maffioli, E. et al. Proteomic analysis of the secretome of human bone marrow-derived mesenchymal stem cells primed by pro-inflammatory cytokines. J. Proteomics 166, 115–126 (2017).

  77. 77.

    Nemoto, Y. et al. Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells. Gut 62, 1142–1152 (2013).

  78. 78.

    English, K. et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells. Clin. Exp. Immunol. 156, 149–160 (2009).

  79. 79.

    Rafei, M. et al. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J. Immunol. 182, 5994–6002 (2009).

  80. 80.

    Tan, J. T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98, 8732–8737 (2001).

  81. 81.

    Rincon, M., Anguita, J., Nakamura, T., Fikrig, E. & Flavell, R. A. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J. Exp. Med. 185, 461–469 (1997).

  82. 82.

    Xu, G., Zhang, Y., Zhang, L., Ren, G. & Shi, Y. The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells. Biochem. Biophys. Res. Commun. 361, 745–750 (2007).

  83. 83.

    Benkhoucha, M. et al. Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells. J. Immunol. 193, 2743–2752 (2014).

  84. 84.

    Bai, L. et al. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat. Neurosci. 15, 862–870 (2012).

  85. 85.

    Galland, S. et al. Tumor-derived mesenchymal stem cells use distinct mechanisms to block the activity of natural killer cell subsets. Cell Rep. 20, 2891–2905 (2017).

  86. 86.

    Tatara, R. et al. Mesenchymal stromal cells inhibit Th17 but not regulatory T cell differentiation. Cytotherapy 13, 686–694 (2011).

  87. 87.

    Nemeth, K. et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15, 42–49 (2009).

  88. 88.

    Mindrescu, C. et al. Reduced susceptibility to collagen-induced arthritis in DBA/1J mice expressing the TSG-6 transgene. Arthritis Rheum. 46, 2453–2464 (2002).

  89. 89.

    Lee, R. H. et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5, 54–63 (2009).

  90. 90.

    Oh, J. Y. et al. Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury. Proc. Natl Acad. Sci. USA 107, 16875–16880 (2010).

  91. 91.

    Choi, H., Lee, R. H., Bazhanov, N., Oh, J. Y. & Prockop, D. J. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Blood 118, 330–338 (2011).

  92. 92.

    Dyer, D. P. et al. The anti-inflammatory protein TSG-6 regulates chemokine function by inhibiting chemokine/glycosaminoglycan interactions. J. Biol. Chem. 291, 12627–12640 (2016).

  93. 93.

    Zou, X. et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res. Ther. 5, 40 (2014).

  94. 94.

    Nargesi, A. A., Lerman, L. O. & Eirin, A. Mesenchymal stem cell-derived extracellular vesicles for renal repair. Curr. Gene Ther. 17, 29–42 (2017).

  95. 95.

    Yu, B. et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int. J. Cardiol. 182, 349–360 (2015).

  96. 96.

    Li, T. et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 22, 845–854 (2013).

  97. 97.

    Morrison, T. J. et al. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am. J. Respir. Crit. Care Med. 196, 1275–1286 (2017).

  98. 98.

    Phinney, D. G. et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat. Commun. 6, 8472 (2015).

  99. 99.

    Sheng, H. et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 18, 846–857 (2008).

  100. 100.

    Akiyama, K. et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 10, 544–555 (2012).

  101. 101.

    Sutton, E. J. et al. An optical imaging method to monitor stem cell migration in a model of immune-mediated arthritis. Opt. Express 17, 24403–24413 (2009).

  102. 102.

    von Bahr, L. et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 30, 1575–1578 (2012).

  103. 103.

    Li, Y., Qiu, W., Zhang, L., Fung, J. & Lin, F. Painting factor H onto mesenchymal stem cells protects the cells from complement- and neutrophil-mediated damage. Biomaterials 102, 209–219 (2016).

  104. 104.

    Galleu, A. & Riffo-Vasquez, Y. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci. Transl. Med. (2017).

  105. 105.

    Chen, H. H. et al. Additional benefit of combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cell against sepsis-induced kidney injury. J. Pineal Res. 57, 16–32 (2014).

  106. 106.

    Sun, E. et al. Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient. Cell Death Differ. 11, 1258–1264 (2004).

  107. 107.

    Ren, G. et al. Apoptotic cells induce immunosuppression through dendritic cells: critical roles of IFN-gamma and nitric oxide. J. Immunol. 181, 3277–3284 (2008).

  108. 108.

    Williams, C. A., Harry, R. A. & McLeod, J. D. Apoptotic cells induce dendritic cell-mediated suppression via interferon-gamma-induced IDO. Immunology 124, 89–101 (2008).

  109. 109.

    Spaggiari, G. M. et al. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111, 1327–1333 (2008).

  110. 110.

    Maitra, B. et al. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T cell activation. Bone Marrow Transplant. 33, 597–604 (2004).

  111. 111.

    Le Blanc, K. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439–1441 (2004).

  112. 112.

    Le Blanc, K. et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371, 1579–1586 (2008).

  113. 113.

    English, K., French, A. & Wood, K. J. Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell 7, 431–442 (2010).

  114. 114.

    Tisato, V., Naresh, K., Girdlestone, J., Navarrete, C. & Dazzi, F. Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. Leukemia 21, 1992–1999 (2007).

  115. 115.

    Casiraghi, F., Perico, N., Cortinovis, M. & Remuzzi, G. Mesenchymal stromal cells in renal transplantation: opportunities and challenges. Nat. Rev. Nephrol. 12, 241–253 (2016).

  116. 116.

    Baker, M. Stem-cell drug fails crucial trials. Nature (2009).

  117. 117.

    Perico, L. et al. Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function. Nat. Commun. 8, 983 (2017).

  118. 118.

    Nagaishi, K. et al. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci. Rep. 6, 34842 (2016).

  119. 119.

    Deng, D., Zhang, P., Guo, Y. & Lim, T. O. A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis. Ann. Rheum. Dis. 76, 1436–1439 (2017).

  120. 120.

    Nephrstrom. The project. Nephstrom (2015).

  121. 121.

    US National Library of Medicine. (2018).

  122. 122.

    Duijvestein, M. et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 59, 1662–1669 (2010).

  123. 123.

    Forbes, G. M. et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy. Clin. Gastroenterol. Hepatol. 12, 64–71 (2014).

  124. 124.

    Tan, J. et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 307, 1169–1177 (2012).

  125. 125.

    Reinders, M. E. et al. Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study. J. Transl Med. 13, 344 (2015).

  126. 126.

    Szabo, E. et al. Licensing by inflammatory cytokines abolishes heterogeneity of immunosuppressive function of mesenchymal stem cell population. Stem Cells Dev. 24, 2171–2180 (2015).

  127. 127.

    Zhuang, Y. et al. Comparison of biological properties of umbilical cord-derived mesenchymal stem cells from early and late passages: immunomodulatory ability is enhanced in aged cells. Mol. Med. Rep. 11, 166–174 (2015).

  128. 128.

    Liu, S. et al. MSC transplantation improves osteopenia via epigenetic regulation of notch signaling in Lupus. Cell Metab. 22, 606–618 (2015).

  129. 129.

    Duijvestein, M. et al. Pretreatment with interferon-gamma enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells 29, 1549–1558 (2011).

  130. 130.

    Luo, Y. et al. Pretreating mesenchymal stem cells with interleukin-1beta and transforming growth factor-beta synergistically increases vascular endothelial growth factor production and improves mesenchymal stem cell-mediated myocardial protection after acute ischemia. Surgery 151, 353–363 (2012).

  131. 131.

    Polchert, D. et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur. J. Immunol. 38, 1745–1755 (2008).

  132. 132.

    Yamamoto, K. et al. Direct conversion of human fibroblasts into functional osteoblasts by defined factors. Proc. Natl Acad. Sci. USA 112, 6152–6157 (2015).

  133. 133.

    French, M. M., Rose, S., Canseco, J. & Athanasiou, K. A. Chondrogenic differentiation of adult dermal fibroblasts. Ann. Biomed. Eng. 32, 50–56 (2004).

  134. 134.

    Nie, T. et al. Conversion of non-adipogenic fibroblasts into adipocytes by a defined hormone mixture. Biochem. J. 467, 487–494 (2015).

  135. 135.

    Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).

  136. 136.

    Morigi, M. et al. Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J. Am. Soc. Nephrol. 15, 1794–1804 (2004).

  137. 137.

    Morigi, M. et al. Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival in mice. Stem Cells 26, 2075–2082 (2008).

  138. 138.

    Duffield, J. S. et al. Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J. Clin. Invest. 115, 1743–1755 (2005).

  139. 139.

    Bai, M. et al. IL-17A improves the efficacy of mesenchymal stem cells in ischemic-reperfusion renal injury by increasing Treg percentages by the COX-2/PGE2 pathway. Kidney Int. 93, 814–825 (2017).

  140. 140.

    Jiang, M. H. et al. Nestin(+) kidney resident mesenchymal stem cells for the treatment of acute kidney ischemia injury. Biomaterials 50, 56–66 (2015).

  141. 141.

    Togel, F. et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am. J. Physiol.Renal Physiol. 289, F31–F42 (2005).

  142. 142.

    Semedo, P. et al. Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model. Stem Cells 27, 3063–3073 (2009).

  143. 143.

    Eirin, A. et al. Adipose tissue-derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cells 30, 1030–1041 (2012).

  144. 144.

    Zhu, X. Y. et al. Mesenchymal stem cells and endothelial progenitor cells decrease renal injury in experimental swine renal artery stenosis through different mechanisms. Stem Cells 31, 117–125 (2013).

  145. 145.

    Eirin, A. et al. Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int. 92, 114–124 (2017).

  146. 146.

    Franquesa, M. et al. Mesenchymal stem cell therapy prevents interstitial fibrosis and tubular atrophy in a rat kidney allograft model. Stem Cells Dev. 21, 3125–3135 (2012).

  147. 147.

    Molendijk, I. et al. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn’s disease. Gastroenterology 149, 918–927 e916 (2015).

  148. 148.

    Panes, J. 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 388, 1281–1290 (2016).

  149. 149.

    Liang, J. et al. Mesenchymal stem cell transplantation for diffuse alveolar hemorrhage in SLE. Nat. Rev. Rheumatol. 6, 486–489 (2010).

  150. 150.

    Liang, J. et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann. Rheum. Dis. 69, 1423–1429 (2010).

  151. 151.

    Alvaro-Gracia, J. M. et al. Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann. Rheum. Dis. 76, 196–202 (2017).

  152. 152.

    Ball, L. M. et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 110, 2764–2767 (2007).

  153. 153.

    Hare, J. M. et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J. Am. Coll. Cardiol. 54, 2277–2286 (2009).

  154. 154.

    Heldman, A. W. et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 311, 62–73 (2014).

  155. 155.

    Florea, V. et al. Dose comparison study of allogeneic mesenchymal stem cells in patients with ischemic cardiomyopathy (The TRIDENT Study). Circ. Res. 121, 1279–1290 (2017).

  156. 156.

    Butler, J. et al. Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy: safety and efficacy results of a phase II-A randomized trial. Circ. Res. 120, 332–340 (2017).

  157. 157.

    Lin, B. L. et al. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: a randomized controlled trial. Hepatology 66, 209–219 (2017).

  158. 158.

    Suk, K. T. et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: phase 2 trial. Hepatology 64, 2185–2197 (2016).

  159. 159.

    El-Kheir, W. A. et al. Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients. Cell Transplant 23, 729–745 (2014).

  160. 160.

    Mendonca, M. V. et al. Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury. Stem Cell Res. Ther. 5, 126 (2014).

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The authors apologize to those whose work is not discussed here owing to space limitations. The authors’ work described in this Review is supported by grants from the National Key R&D Program of China (2018YFA0107500), the Scientific Innovation Project of the Chinese Academy of Sciences (XDA16020403), the Ministry of Science and Technology of China (2015CB964400), the National Natural Science Foundation of China (81530043, 81330046, 81861138015, 31771641 and 81571612), the Youth Innovation Promotion Association research fund from the Chinese Academy of Sciences, a start-up fund from Soochow University and the Department of Science and Technology of Jiangsu Province research fund (BE2016671).

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  1. The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, China

    • Yufang Shi
    • , Jianquan Hou
    •  & Changshun Shao
  2. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    • Yufang Shi
    • , Yu Wang
    • , Qing Li
    • , Keli Liu
    •  & Ying Wang


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All authors contributed to discussion of the outline and the content of the article, wrote the article and reviewed and edited the manuscript before submission. Y.S., Yu.W., Q.L., K.L., C.S. and Yi.W. created the figure drafts, and Yu.W., Q.L. and K.L. prepared the tables.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Yufang Shi or Ying Wang.



Cell communities in which all of the daughter cells are derived from one ancestor cell.

Mechanical memory

A phenomenon whereby cells can be permanently imprinted by exposure to certain mechanical conditions.


A pore-forming cytolytic protein expressed in cytotoxic T cells and NK cells. It aids the delivery of granzymes to target cells to induce cell death.


The process by which phagocytic cells remove dead cells.

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