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Review article: Biomedical intelligence

Vol. 145 No. 5152 (2015)

Mesenchymal stem cells: myths and reality

  • Adelaida Sarukhan
  • Lucia Zanotti
  • Antonella Viola
DOI
https://doi.org/10.4414/smw.2015.14229
Cite this as:
Swiss Med Wkly. 2015;145:w14229
Published
13.12.2015

Summary

Mesenchymal stem cells (MSCs; also called mesenchymal stromal cells) have received much attention during the last two decades, at first because of their regeneration capacity and poor immunogenicity and, more recently, because of their proved immunomodulatory function. Consequently, the number of studies addressing MSC biology and their capacity to treat a broad range of human diseases at the preclinical and clinical level has grown exponentially, with often confusing and conflicting results. The use of poorly defined cell preparations and experimental models, many of them in vitro, has added to such confusion. In this review, we identify what in our opinion remain the main open questions on MSC biology and we attempt to distinguish the facts from the myths concerning endogenous and therapeutic MSC.

References

  1. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–47.
  2. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3(4):393–403.
  3. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641–50.
  4. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.
  5. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41–9.
  6. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279–95.
  7. Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109(1):235–42.
  8. Wang H-S, Hung S-C, Peng S-T, Huang C-C, Wei H-M, Guo Y-J, et al. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells. 2004;22(7):1330–7.
  9. De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001;44(8):1928–42.
  10. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA. 2000;97(25):13625–30.
  11. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.
  12. Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell. 2012;10(3):244–58.
  13. Nombela-Arrieta C, Ritz J, Silberstein LE. The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol. 2011;12(2):126–31.
  14. Crisan M, Corselli M, Chen WCW, Péault B. Perivascular cells for regenerative medicine. J Cell Mol Med. 2012;16(12):2851–60.
  15. Crisan M, Yap S, Casteilla L, Chen C-W, Corselli M, Park TS, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301–13.
  16. James AW, Zara JN, Corselli M, Askarinam A, Zhou AM, Hourfar A, et al. An abundant perivascular source of stem cells for bone tissue engineering. Stem Cells Transl Med. 2012;1(9):673–84.
  17. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252–60.
  18. Feng J, Mantesso A, De Bari C, Nishiyama A, Sharpe PT. Dual origin of mesenchymal stem cells contributing to organ growth and repair. Proceedings of the National Academy of Sciences. 2011;108(16):6503–8.
  19. Kaukua N, Shahidi MK, Konstantinidou C, Dyachuk V, Kaucka M, Furlan A, et al. Glial origin of mesenchymal stem cells in a tooth model system. Nature. Nature Publishing Group; 2014;513(7519):551–4.
  20. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007;131(2):324–36.
  21. Méndez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–34.
  22. Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol. 2006;36(10):2566–73.
  23. O’Donoghue K, Chan J, la Fuente de J, Kennea N, Sandison A, Anderson JR, et al. Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet. 2004;364(9429):179–82.
  24. Seppanen E, Roy E, Ellis R, Bou-Gharios G, Fisk NM, Khosrotehrani K. Distant mesenchymal progenitors contribute to skin wound healing and produce collagen: evidence from a murine fetal microchimerism model. PLoS ONE. 2013;8(5):e62662.
  25. Hoogduijn MJ, Crop MJ, Peeters AMA, Korevaar SS, Eijken M, Drabbels JJ, et al. Donor-derived mesenchymal stem cells remain present and functional in the transplanted human heart. Am J Transplant. 2009;9(1):222–30.
  26. Lama VN, Smith L, Badri L, Flint A, Andrei A-C, Murray S, et al. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest. 2007;117(4):989–96.
  27. Sarugaser R, Hanoun L, Keating A, Stanford WL, Davies JE. Human mesenchymal stem cells self-renew and differentiate according to a deterministic hierarchy. PLoS ONE. 2009;4(8):e6498.
  28. Caplan AI, Hariri R. Body Management: Mesenchymal Stem Cells Control the Internal Regenerator. Stem Cells Transl Med. 2015;4(7):695–701.
  29. Muraglia A, Cancedda R, Quarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci. 2000;113 (Pt 7):1161–6.
  30. Kouris NA, Schaefer JA, Hatta M, Freeman BT, Kamp TJ, Kawaoka Y, et al. Directed Fusion of Mesenchymal Stem Cells with Cardiomyocytes via VSV-G Facilitates Stem Cell Programming. Stem Cells International. 2012;2012:414038.
  31. Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, et al. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther. 2006;14(6):840–50.
  32. Bronckaers A, Hilkens P, Martens W, Gervois P, Ratajczak J, Struys T, et al. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol Ther. 2014;143(2):181–96.
  33. Lee J-K, Park S-R, Jung B-K, Jeon Y-K, Lee Y-S, Kim M-K, et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE. 2013;8(12):e84256.
  34. Burlacu A, Grigorescu G, Rosca A-M, Preda MB, Simionescu M. Factors secreted by mesenchymal stem cells and endothelial progenitor cells have complementary effects on angiogenesis in vitro. Stem Cells Dev. 2013;22(4):643–53.
  35. Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. 2014;15(11):1009–16.
  36. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–43.
  37. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75(3):389–97.
  38. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30(1):42–8.
  39. Bernardo ME, Fibbe WE. Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation. Stem Cell. Elsevier Inc; 2013;13(4):392–402.
  40. Prockop DJ. Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation. Stem Cells. 2013;31(10):2042–6.
  41. Keating A. Perspective. Stem Cell. Elsevier Inc; 2012;10(6):709–16.
  42. Wang J, Lu Z-H, Gabius H-J, Rohowsky-Kochan C, Ledeen RW, Wu G. Cross-linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis. J Immunol. 2009;182(7):4036–45.
  43. Uccelli A, Mancardi G, Chiesa S. Is there a role for mesenchymal stem cells in autoimmune diseases? Autoimmunity. 2008;41(8):592–5.
  44. Yagi H. The role of mesenchymal stem cells in cancer development. 2013:1–6.
  45. Stagg J, Galipeau J. Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. Curr Mol Med. 2013;13(5):856–67.
  46. Herrera MB, Bussolati B, Bruno S, Morando L, Mauriello-Romanazzi G, Sanavio F, et al. Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int. 2007;72(4):430–41.
  47. Assis ACM, Carvalho JL, Jacoby BA, Ferreira RLB, Castanheira P, Diniz SOF, et al. Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart. Cell Transplant. 2010;19(2):219–30.
  48. Hoogduijn MJ. The life and fate of mesenchymal stem cells. 2014:1–6.
  49. Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E, et al. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells. 2009;27(10):2624–35.
  50. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18(5):683–92.
  51. Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297.
  52. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, 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. 2009;5(1):54–63.
  53. Lu W, Fu C, Song L, Yao Y, Zhang X, Chen Z, et al. Exposure to supernatants of macrophages that phagocytized dead mesenchymal stem cells improves hypoxic cardiomyocytes survival. Int J Cardiol. 2013;165(2):333–40.
  54. Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007;56(4):1175–86.
  55. Sala E, Genua M, Petti L, Anselmo A, Arena V, Cibella J, et al. Mesenchymal Stem Cells Reduce Colitis in Mice via Release of TSG6, Independently of Their Localization to the Intestine. Gastroenterology. 2015;149(1):163–176.e20.
  56. Zanotti L, Sarukhan A, Dander E, Castor M, Cibella J, Soldani C, et al. Encapsulated mesenchymal stem cells for in vivo immunomodulation. Leukemia. Nature Publishing Group; 2012;27(2):500–3.
  57. Chiesa S, Morbelli S, Morando S, Massollo M, Marini C, Bertoni A, et al. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proceedings of the National Academy of Sciences. 2011;108(42):17384–9.
  58. Singer NG, Caplan AI. Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol. 2011;6:457–78.
  59. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94(5):678–85.
  60. Chen L, Tredget EE, Wu PYG, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS ONE. 2008;3(4):e1886.
  61. Bruno S, Collino F, Iavello A, Camussi G. Effects of mesenchymal stromal cell-derived extracellular vesicles on tumor growth. Front Immunol. 2014;5:382.
  62. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid A-A, Mardani K. Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett. 2012;147(1-2):47–54.
  63. Zhang B, Yin Y, Lai RC, Tan SS, Choo ABH, Lim SK. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014;23(11):1233–44.
  64. Conforti A, Scarsella M, Starc N, Giorda E, Biagini S, Proia A, et al. Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro. Stem Cells Dev. 2014;23(21):2591–9.
  65. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.
  66. Engela AU, Hoogduijn MJ, Boer K, Litjens NHR, Betjes MGH, Weimar W, et al. Human adipose-tissue derived mesenchymal stem cells induce functional de-novo regulatory T cells with methylated FOXP3 gene DNA. Clin Exp Immunol. 2013;173(2):343–54.
  67. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol. 2005;35(5):1482–90.
  68. Gu Y-Z, Xue Q, Chen Y-J, Yu G-H, Qing M-D, Shen Y, et al. Different roles of PD-L1 and FasL in immunomodulation mediated by human placenta-derived mesenchymal stem cells. Hum Immunol. 2013;74(3):267–76.
  69. Maggini J, Mirkin G, Bognanni I, Holmberg J, Piazzón IM, Nepomnaschy I, et al. Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS ONE. 2010;5(2):e9252.
  70. Liu X, Ren S, Ge C, Cheng K, Zenke M, Keating A, et al. Sca-1+Lin-CD117- Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch-RBP-J Signaling. J Immunol. 2015;194(9):4298–308.
  71. Krampera M. Mesenchymal stromal cell ‘licensing’: a multistep process. Leukemia. 2011;25(9):1408–14.
  72. Polchert D, Sobinsky J, Douglas G, Kidd M, Moadsiri A, Reina E, et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol. 2008;38(6):1745–55.
  73. Delarosa O, Dalemans W, Lombardo E. Toll-like receptors as modulators of mesenchymal stem cells. Front Immunol. 2012;3:182.
  74. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS ONE. 2010;5(4):e10088.
  75. Opitz CA, Litzenburger UM, Lutz C, Lanz TV, Tritschler I, Köppel A, et al. Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R. Stem Cells. 2009;27(4):909–19.
  76. Romieu-Mourez R, François M, Abate A, Boivin M-N, Birman E, Bailey D, et al. Mesenchymal stromal cells expressing ErbB-2/neu elicit protective antibreast tumor immunity in vivo, which is paradoxically suppressed by IFN-gamma and tumor necrosis factor-alpha priming. Cancer Res. 2010;70(20):7742–7.
  77. Sioud M, Mobergslien A, Boudabous A, Fløisand Y. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Scand J Immunol. 2010;71(4):267–74.
  78. English K, Wood KJ. Mesenchymal stromal cells in transplantation rejection and tolerance. Cold Spring Harb Perspect Med. 2013;3(5):a015560.
  79. Nemeth K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi 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. 2009;15(1):42–9.
  80. Li W, Ren G, Huang Y, Su J, Han Y, Li J, et al. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death Differ. 2012;19(9):1505–13.
  81. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2(2):141–50.
  82. Bartosh TJ, Ylöstalo JH, Bazhanov N, Kuhlman J, Prockop DJ. Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1). Stem Cells. 2013;31(11):2443–56.
  83. Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell. 2012;10(5):544–55.
  84. Prockop DJ. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol Ther. 2009;17(6):939–46.
  85. Block GJ, Ohkouchi S, Fung F, Frenkel J, Gregory C, Pochampally R, et al. Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1. Stem Cells. 2009;27(3):670–81.
  86. Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363(9419):1439–41.
  87. Knaän-Shanzer S. Concise review: the immune status of mesenchymal stem cells and its relevance for therapeutic application. Stem Cells. 2014;32(3):603–8.
  88. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45:e54.
  89. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371(9624):1579–86.
  90. Cyranoski D. Canada approves stem cell product. Nat Biotechnol. 2012;30(7):571–1.
  91. Ankrum J, Karp JM. Mesenchymal stem cell therapy: Two steps forward, one step back. Trends in Molecular Medicine. 2010;16(5):203–9.
  92. Kishk NA, Abokrysha NT, Gabr H. Possible induction of acute disseminated encephalomyelitis (ADEM)-like demyelinating illness by intrathecal mesenchymal stem cell injection. J Clin Neurosci. 2013;20(2):310–2.
  93. Kurtz A. Mesenchymal stem cell delivery routes and fate. Int J Stem Cells. 2008;1(1):1–7.
  94. Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. Gut. 2011;60(6):788–98.
  95. 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. 2007;21(9):1992–9.
  96. Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant. 2005;11(5):389–98.
  97. Ball LM, Bernardo ME, Roelofs H, van Tol MJD, Contoli B, Zwaginga JJ, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br J Haematol. 2013;163(4):501–9.
  98. Badillo AT, Beggs KJ, Javazon EH, Tebbets JC, Flake AW. Murine bone marrow stromal progenitor cells elicit an in vivo cellular and humoral alloimmune response. Biol Blood Marrow Transplant. 2007;13(4):412–22.
  99. Campeau PM, Rafei M, François M, Birman E, Forner K-A, Galipeau J. Mesenchymal stromal cells engineered to express erythropoietin induce anti-erythropoietin antibodies and anemia in allorecipients. Mol Ther. 2009;17(2):369–72.
  100. Zangi L, Margalit R, Reich-Zeliger S, Bachar-Lustig E, Beilhack A, Negrin R, et al. Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells. Stem Cells. 2009;27(11):2865–74.
  101. Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S, et al. Sarcoma derived from cultured mesenchymal stem cells. Stem Cells. 2007;25(2):371–9.
  102. Rafei M, Campeau PM, Aguilar-Mahecha A, Buchanan M, Williams P, Birman E, 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. 2009;182(10):5994–6002.
  103. Sioud M, Mobergslien A, Boudabous A, Fløisand Y. Mesenchymal stem cell-mediated T cell suppression occurs through secreted galectins. Int J Oncol. 2011;38(2):385–90.
  104. Chabannes D, Hill M, Merieau E, Rossignol J, Brion R, Soulillou JP, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood. 2007;110(10):3691–4.
  105. Mougiakakos D, Jitschin R, Johansson CC, Okita R, Kiessling R, Le Blanc K. The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. Blood. 2011;117(18):4826–35.
  106. Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells. 2008;26(1):212–22.
  107. Rizzo R, Campioni D, Stignani M, Melchiorri L, Bagnara GP, Bonsi L, et al. A functional role for soluble HLA-G antigens in immune modulation mediated by mesenchymal stromal cells. Cytotherapy. 2008;10(4):364–75.
  108. Ren G, Su J, Zhang L, Zhao X, Ling W, L'huillie A, et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells. 2009;27(8):1954–62.
  109. Najar M, Rouas R, Raicevic G, Boufker HI, Lewalle P, Meuleman N, et al. Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6. Cytotherapy. 2009;11(5):570–83.
  110. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105(5):2214–9.
  111. Qu X, Liu X, Cheng K, Yang R, Zhao RCH. Mesenchymal stem cells inhibit Th17 cell differentiation by IL-10 secretion. Exp Hematol. 2012;40(9):761–70.
  112. Nasef A, Mazurier C, Bouchet S, François S, Chapel A, Thierry D, et al. Leukemia inhibitory factor: Role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol. 2008;253(1-2):16–22.
  113. Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, et al. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol. 2008;181(6):4389–96.
  114. Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Gorham JD, et al. Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proceedings of the National Academy of Sciences. 2010;107(12):5652–7.
  115. Rafei M, Hsieh J, Fortier S, Li M, Yuan S, Birman E, et al. Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction. Blood. 2008;112(13):4991–8.
  116. Peng Y, Chen X, Liu Q, Zhang X, Huang K, Liu L, 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. 2015;29(3):636–46.
  117. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008;111(3):1327–33.
  118. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells. 2006;24(1):74–85.
  119. Djouad F, Charbonnier L-M, Bouffi C, Louis-Plence P, Bony C, Apparailly F, et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells. 2007;25(8):2025–32.
  120. Spaggiari GM, 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. 2009;113(26):6576–83.
  121. Chen L, Zhang W, Yue H, Han Q, Chen B, Shi M, et al. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev. 2007;16(5):719–31.
  122. François 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. 2012;20(1):187–95.
  123. Ylöstalo JH, Bartosh TJ, Coble K, Prockop DJ. 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(10):2283–96.
  124. Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. Blood. 2011;118(2):330–8.