Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications


Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in many tissues and are capable of differentiating into several different cell types. Exogenously administered MSCs migrate to damaged tissue sites, where they participate in tissue repair. Their communication with the inflammatory microenvironment is an essential part of this process. In recent years, much has been learned about the cellular and molecular mechanisms of the interaction between MSCs and various participants in inflammation. Depending on their type and intensity, inflammatory stimuli confer on MSCs the ability to suppress the immune response in some cases or to enhance it in others. Here we review the current findings on the immunoregulatory plasticity of MSCs in disease pathogenesis and therapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Modes of MSC-based therapy: cell replacement versus cell 'empowerment'.
Figure 2: Plasticity of MSCs in immunomodulation.
Figure 3: Timeline for major events in studies of the immunosuppressive effects of MSCs.
Figure 4: Correlation between inflammatory status and efficacy of MSC therapy.


  1. 1

    Le Blanc, K. & Mougiakakos, D. Multipotent mesenchymal stromal cells and the innate immune system. Nat. Rev. Immunol. 12, 383–396 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Prockop, D.J. & Oh, J.Y. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol. Ther. 20, 14–20 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nat. Rev. Immunol. 8, 726–736 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    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). Demonstrated that the immunosuppressive function of MSCs is not constitutive but is instead 'licensed' by inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Agata, K. Regeneration and gene regulation in planarians. Curr. Opin. Genet. Dev. 13, 492–496 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Wagers, A.J. & Weissman, I.L. Plasticity of adult stem cells. Cell 116, 639–648 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Bianco, P. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35–42 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Caplan, A.I. Mesenchymal stem cells. J. Orthop. Res. 9, 641–650 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

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

    CAS  PubMed  Google Scholar 

  11. 11

    Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002).

    CAS  Google Scholar 

  12. 12

    Bianco, P., Robey, P.G. & Simmons, P.J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2, 313–319 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Keating, A. Mesenchymal stromal cells: new directions. Cell Stem Cell 10, 709–716 (2012).

    CAS  Google Scholar 

  14. 14

    Horwitz, E.M. et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7, 393–395 (2005).

    CAS  Google Scholar 

  15. 15

    Roberts, E.W. et al. Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia. J. Exp. Med. 210, 1137–1151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Zhao, H. et al. Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 14, 160–173 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).Demonstrated that nestin-positive cells in bone marrow act functionally like MSCs and constitute the HSC niche.

    PubMed  PubMed Central  Google Scholar 

  18. 18

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Sugiyama, T., Kohara, H., Noda, M. & Nagasawa, T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988 (2006).

    CAS  Google Scholar 

  20. 20

    Ren, G. et al. Concise review: mesenchymal stem cells and translational medicine: emerging issues. Stem Cells Transl Med 1, 51–58 (2012).

    CAS  Google Scholar 

  21. 21

    Gao, P. et al. Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma. J. Immunol. 192, 4560–4570 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Qian, H. et al. Bone marrow mesenchymal stem cells ameliorate rat acute renal failure by differentiation into renal tubular epithelial-like cells. Int. J. Mol. Med. 22, 325–332 (2008).

    Google Scholar 

  23. 23

    Cho, K.A. et al. Mesenchymal stem cells showed the highest potential for the regeneration of injured liver tissue compared with other subpopulations of the bone marrow. Cell Biol. Int. 33, 772–777 (2009).

    CAS  Google Scholar 

  24. 24

    Han, F. et al. Contribution of murine bone marrow mesenchymal stem cells to pancreas regeneration after partial pancreatectomy in mice. Cell Biol. Int. 36, 823–831 (2012).

    Google Scholar 

  25. 25

    Rose, R.A. et al. Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functional cardiomyocytes in vitro. Stem Cells 26, 2884–2892 (2008).

    CAS  Google Scholar 

  26. 26

    Prockop, D.J., Kota, D.J., Bazhanov, N. & Reger, R.L. Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs). J. Cell. Mol. Med. 14, 2190–2199 (2010).

    PubMed  PubMed Central  Google Scholar 

  27. 27

    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).

    CAS  Google Scholar 

  28. 28

    Tögel, 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).

    Google Scholar 

  29. 29

    Sakaida, I. et al. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology 40, 1304–1311 (2004).

    Google Scholar 

  30. 30

    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)Showed that intravenous infusion of human MSCs improves myocardial infarction in mice via TSG6 and that TSG6 alone is sufficient to provide the therapeutic effect.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

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

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Wolf, D. et al. Regenerative capacity of intravenous autologous, allogeneic and human mesenchymal stem cells in the infarcted pig myocardium-complicated by myocardial tumor formation. Scand. Cardiovasc. J. 43, 39–45 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Ranganath, S.H., Levy, O., Inamdar, M.S. & Karp, J.M. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10, 244–258 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    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).

    PubMed  PubMed Central  Google Scholar 

  37. 37

    McIntosh, K.R., Mosca, J.D. & Klyushnenkova, E.N. Mesenchymal stem cells for prevention and treatment of immune responses in transplantation. WO Patent 1999047163 A2, (1998).

  38. 38

    Shi, Y. et al. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 33, 136–143 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Bernardo, M.E. & Fibbe, W.E. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13, 392–402 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Luz-Crawford, P. et al. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res. Ther. 4, 65 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Deng, Y. et al. Umbilical cord-derived mesenchymal stem cells instruct dendritic cells to acquire tolerogenic phenotypes through the IL-6-mediated upregulation of SOCS1. Stem Cells Dev. 23, 2080–2092 (2014).

    CAS  Google Scholar 

  42. 42

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

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Németh, K. et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15, 42–49 (2009).

    Google Scholar 

  44. 44

    Abumaree, M.H. et al. Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages. Stem Cell Rev. 9, 620–641 (2013).

    CAS  Google Scholar 

  45. 45

    Spaggiari, G.M., Capobianco, A., Becchetti, S., Mingari, M.C. & Moretta, L. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 107, 1484–1490 (2006).

    CAS  Google Scholar 

  46. 46

    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).

    CAS  Google Scholar 

  47. 47

    Nemeth, K. et al. Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc. Natl. Acad. Sci. USA 107, 5652–5657 (2010).

    CAS  Google Scholar 

  48. 48

    DelaRosa, O. et al. Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng. Part A 15, 2795–2806 (2009).

    CAS  Google Scholar 

  49. 49

    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).

    CAS  Google Scholar 

  50. 50

    Spaggiari, G.M., Abdelrazik, H., Becchetti, F. & Moretta, L. MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113, 6576–6583 (2009).

    CAS  Google Scholar 

  51. 51

    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).

    CAS  Google Scholar 

  52. 52

    Krampera, M. et al. Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24, 386–398 (2006).

    CAS  Google Scholar 

  53. 53

    Gieseke, F. et al. Human multipotent mesenchymal stromal cells inhibit proliferation of PBMCs independently of IFNγR1 signaling and IDO expression. Blood 110, 2197–2200 (2007).

    CAS  Google Scholar 

  54. 54

    Ren, G. et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27, 1954–1962 (2009).

    CAS  Google Scholar 

  55. 55

    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).

    CAS  Google Scholar 

  56. 56

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

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    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)Proposed the concept of proinflammatory (MSC1) and anti-inflammatory (MSC2) phenotypes of MSCs and demonstrated differences in their induction by TLR ligands.

    PubMed  PubMed Central  Google Scholar 

  58. 58

    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).

    CAS  Google Scholar 

  59. 59

    Constantin, G. et al. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells 27, 2624–2635 (2009).

    CAS  Google Scholar 

  60. 60

    Li, W. et al. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death Differ. 19, 1505–1513 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Renner, P. et al. Mesenchymal stem cells require a sufficient, ongoing immune response to exert their immunosuppressive function. Transplant. Proc. 41, 2607–2611 (2009).

    CAS  Google Scholar 

  62. 62

    Chan, J.L. et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-γ. Blood 107, 4817–4824 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    François, M. et al. Mesenchymal stromal cells cross-present soluble exogenous antigens as part of their antigen-presenting cell properties. Blood 114, 2632–2638 (2009).

    Google Scholar 

  64. 64

    Mills, K.H. TLR-dependent T cell activation in autoimmunity. Nat. Rev. Immunol. 11, 807–822 (2011).

    CAS  Google Scholar 

  65. 65

    Han, X. et al. Interleukin-17 enhances immunosuppression by mesenchymal stem cells. Cell Death Differ. 10.1038/cdd.2014.85 (2014).

  66. 66

    Li, M.O. & Flavell, R.A. Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10. Immunity 28, 468–476 (2008).

    Google Scholar 

  67. 67

    Li, Z., Kupcsik, L., Yao, S.J., Alini, M. & Stoddart, M.J. Mechanical load modulates chondrogenesis of human mesenchymal stem cells through the TGF-β pathway. J. Cell. Mol. Med. 14, 1338–1346 (2010).

    CAS  Google Scholar 

  68. 68

    Crane, J.L. & Cao, X. Bone marrow mesenchymal stem cells and TGF-beta signaling in bone remodeling. J. Clin. Invest. 124, 466–472 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Xu, C. et al. TGF-β promotes immune responses in the presence of mesenchymal stem cells. J. Immunol. 192, 103–109 (2014).Demonstrated that MSC-mediated immunosuppression of T cells can be reversed by TGF-β, a well-known immunosuppressive cytokine.

    CAS  Google Scholar 

  70. 70

    Raicevic, G. et al. Inflammation modifies the pattern and the function of Toll-like receptors expressed by human mesenchymal stromal cells. Hum. Immunol. 71, 235–244 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Inoue, S. et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation 81, 1589–1595 (2006).Showed that concurrent administration of MSCs with a low dose of cyclosporin A accelerates allograft rejection.

    PubMed  PubMed Central  Google Scholar 

  72. 72

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

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Burr, S.P., Dazzi, F. & Garden, O.A. Mesenchymal stromal cells and regulatory T cells: the Yin and Yang of peripheral tolerance? Immunol. Cell Biol. 91, 12–18 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    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). First report of a clinical application of MSCs in treating acute steroid-resistant GvHD.

    PubMed  PubMed Central  Google Scholar 

  75. 75

    Hare, J.M. et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. J. Am. Med. Assoc. 308, 2369–2379 (2012).

    CAS  Google Scholar 

  76. 76

    Zhang, Z. et al. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J. Gastroenterol. Hepatol. 27 (suppl. 2), 112–120 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Sun, L. et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum. 62, 2467–2475 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Tyndall, A. & van Laar, J.M. Stem cells in the treatment of inflammatory arthritis. Best Pract. Res. Clin. Rheumatol. 24, 565–574 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Krampera, M., Galipeau, J., Shi, Y., Tarte, K. & Sensebe, L. Immunological characterization of multipotent mesenchymal stromal cells–The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy 15, 1054–1061 (2013).

    Google Scholar 

  81. 81

    Krampera, M. Mesenchymal stromal cell 'licensing': a multistep process. Leukemia 25, 1408–1414 (2011).

    CAS  Google Scholar 

  82. 82

    Dalal, J., Gandy, K. & Domen, J. Role of mesenchymal stem cell therapy in Crohn's disease. Pediatr. Res. 71, 445–451 (2012).

    CAS  Google Scholar 

  83. 83

    Baker, M. Stem-cell drug fails crucial trials. in Nature (2009). Revealed that Prochymal (an MSC-based product) performed no more effectively than a placebo in a phase III clinical trial targeting GvHD; here, Prochymal was used together with steroid and that treatment was compared with steroid alone.

  84. 84

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

    CAS  Google Scholar 

  85. 85

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

    Google Scholar 

  86. 86

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

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


We thank A. Roberts, A. Rabson and G. Brewer for critically reviewing and discussing the manuscript. Supported by the Scientific Innovation Project of the Chinese Academy of Science (XDA01040107 and XDA01040110) and the Ministry of Science and Technology of China (2010CB945600).

Author information



Corresponding author

Correspondence to Yufang Shi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing