Immunomodulatory properties of bone marrow mesenchymal stem cells

Abstract

Bone marrow mesenchymal stem cells (BM-MSCs) are multipotent progenitor cells of mesodermal origin possessing multilineage differentiation potential and ease of expansion in vitro. Over the years, these cells have gained attention owing to their potential in cell-based therapies in treating various diseases. In particular, the wide spectrum of immunoregulatory/immunomodulatory role of MSCs in various clinical conditions has gained immense attention. The immunomodulatory properties of BM-MSCs are mediated by either cell–cell contact (interactions with various immune cells in a context-dependent manner), paracrine mode of action or extracellular vesicles, making them a potential option as immunosuppressants/immunomodulators in treating various clinical conditions. A plethora of studies have demonstrated that MSCs do so by exhibiting a profound effect on various immune cells for example they can inhibit the proliferation of T cells, B cells, and natural killer cells; modulate the activities of dendritic cells and induce regulatory T cells both in vitro and in vivo. In this review we aim at briefly elucidating the characteristics of BM-MSCs, specifically addressing the current understanding on the hypoimmunogeneticity and immunomodulatory properties of the same with specific reference to their interactions with B cells, T cells, Dendritic cells and natural killer cells. We also aim at reviewing the secretory profile and their role in some clinical conditions that have shown promising outcomes.

This is a preview of subscription content, access via your institution.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Figure 1

References

  1. Ab Kadir R, Zainal Ariffin SH, Megat Abdul Wahab R, Kermani S and Senafi S 2012 Characterization of mononucleated human peripheral blood cells. ScientificWorldJournal 2012 843843

    PubMed  PubMed Central  Google Scholar 

  2. Aggarwal S and Pittenger MF 2005 Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105 1815–1822

    CAS  PubMed  Google Scholar 

  3. Amsel S and Dell ES 1971 Bone marrow repopulation of subcutaneously grafted mouse femurs. Proc. Soc. Exp. Biol. Med. 138 550–552

    CAS  PubMed  Google Scholar 

  4. An SY, Han J, Lim HJ, Park SY, Kim JH, et al. 2014 Valproic acid promotes differentiation of hepatocyte-like cells from whole human umbilical cord-derived mesenchymal stem cells. Tissue Cell 46 127–135

    CAS  PubMed  Google Scholar 

  5. Anghileri E, Marconi S, Pignatelli A, Cifelli P, Galié M, et al. 2008 Neuronal differentiation potential of human adipose-derived mesenchymal stem cells. Stem Cells Dev. 17 909–916

    CAS  PubMed  Google Scholar 

  6. Asari S, Itakura S, Ferreri K, Liu CP, Kuroda Y, et al. 2009 Mesenchymal stem cells suppress B-cell terminal differentiation. Exp. Hematol. 37 604–615

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, et al. 2005 Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur. J. Immunol. 35 1482–1490

    CAS  PubMed  Google Scholar 

  8. Bai L, Lennon DP, Eaton V, Maier K, Caplan AI, et al. 2009 Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 57 1192–1203

    PubMed  PubMed Central  Google Scholar 

  9. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, et al. 2002 Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol. 30 42–48

    PubMed  Google Scholar 

  10. Beresford JN 1989 Osteogenic stem cells and the stromal system of bone and marrow. Clin. Orthop. Relat. Res. 240 270–280

    Google Scholar 

  11. Biancone L, Bruno S, Deregibus MC, Tetta C and Camussi G 2012 Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol. Dial. Trans. 27 3037–3042

    CAS  Google Scholar 

  12. Bonab MM, Sahraian MA, Aghsaie A, Karvigh SA, Hosseinian SM, et al. 2012 Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr. Stem Cell Res. Ther. 7 407–414

    CAS  PubMed  Google Scholar 

  13. Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, et al. 2001 Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98 2396–2402

    CAS  PubMed  Google Scholar 

  14. Carmeliet P and Jain RK 2011 Molecular mechanisms and clinical applications of angiogenesis. Nature 473 298–307

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Chamberlain G, Fox J, Ashton B and Middleton J 2007 Mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25 2739–2749

    CAS  PubMed  Google Scholar 

  16. Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, et al. 2006 Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood 107 4817–4824

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Chan WK, Lau AS, Li JC, Law HK, Lau YL, et al. 2008 MHC expression kinetics and immunogenicity of mesenchymal stromal cells after short-term IFN-gamma challenge. Exp. Hematol. 36 1545–1555

    CAS  PubMed  Google Scholar 

  18. Chen HW, Chen HY, Wang LT, Wang FH, Fang LW, et al. 2013 Mesenchymal stem cells tune the development of monocyte-derived dendritic cells toward a myeloid-derived suppressive phenotype through growth-regulated oncogene chemokines. J. Immunol. 190 5065–5077

    CAS  PubMed  Google Scholar 

  19. Chen J, Li C and Chen L 2015 The role of microvesicles derived from mesenchymal stem cells in lung diseases. Biomed. Res. Int. 2015 985814

    PubMed  PubMed Central  Google Scholar 

  20. Cho KA, Lee JK, Kim YH, Park M, Woo SY, et al. 2017 Mesenchymal stem cells ameliorate B-cell-mediated immune responses and increase IL-10-expressing regulatory B cells in an EBI3-dependent manner. Cell. Mol. Immunol. 14 895–908

    CAS  PubMed Central  Google Scholar 

  21. Cohen JA 2013 Mesenchymal stem cell transplantation in multiple sclerosis. J. Neurol. Sci. 333 43–49

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, et al. 2006 Human mesenchymal stem cells modulate B-cell functions. Blood 107 367–372

    CAS  PubMed  Google Scholar 

  23. Cosenza S, Ruiz M, Maumus M, Jorgensen C and Noël D 2017 Pathogenic or therapeutic extracellular vesicles in rheumatic diseases: role of mesenchymal stem cell-derived vesicles. Int. J. Mol. Sci. 18 889

    PubMed Central  Google Scholar 

  24. Cui R, Rekasi H, Hepner-Schefczyk M, Fessmann K, Petri RM, et al. 2016 Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients. Stem Cell Res. Ther. 7 88

    PubMed  PubMed Central  Google Scholar 

  25. Daneshmandi S, Karimi MH and Pourfathollah AA 2017 TGF-β1 transduced mesenchymal stem cells have profound modulatory effects on DCs and T cells. Iran J. Immunol. 14 13–23

    PubMed  Google Scholar 

  26. Datta I, Mishra S, Mohanty L, Pulikkot S and Joshi PG 2011 Neuronal plasticity of human Wharton’s jelly mesenchymal stromal cells to the dopaminergic cell type compared with human bone marrow mesenchymal stromal cells. Cytotherapy 13 918–932

    CAS  PubMed  Google Scholar 

  27. Dazzi F, Ramasamy R, Glennie S, Jones SP and Roberts I 2006 The role of mesenchymal stem cells in haemopoiesis. Blood Rev. 20 161–171

    CAS  PubMed  Google Scholar 

  28. Dean RM and Bishop MR 2003 Graft-versus-host disease: emerging concepts in prevention and therapy. Curr. Hematol. Rep. 2 287–294

    PubMed  Google Scholar 

  29. Deans RJ and Moseley AB 2000 Mesenchymal stem cells: biology and potential clinical uses. Exp. Hematol. 28 875–884

    CAS  PubMed  Google Scholar 

  30. Dexter TM, Allen TD and Lajtha LG 1977 Conditions controlling the proliferation of haemopoietic stem cells in vitro. J. Cell. Physiol. 91 335–344

    CAS  PubMed  Google Scholar 

  31. Di Ianni M, Del Papa B, De Ioanni M, Moretti L, Bonifacio E, et al. 2008 Mesenchymal cells recruit and regulate T regulatory cells. Exp. Hematol. 36 309–318

    PubMed  Google Scholar 

  32. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, et al. 2002 Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99 3838–3843

    PubMed  Google Scholar 

  33. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, et al. 2006 Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 8 315–317

    CAS  PubMed  Google Scholar 

  34. Du YM, Zhuansun YX, Chen R, Lin L, Lin Y, et al. 2018 Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. Exp Cell Res 363 114–120

    CAS  PubMed  Google Scholar 

  35. Duffy MM, Pindjakova J, Hanley SA, McCarthy C, Weidhofer GA, et al. 2011a Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor. Eur. J. Immunol. 41 2840–2851

    CAS  PubMed  Google Scholar 

  36. Duffy MM, Ritter T, Ceredig R and Griffin MD 2011b Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res. Ther. 2 34

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, et al. 2010 Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 59 1662–1669

    PubMed  Google Scholar 

  38. Erbey F, Atay D, Akcay A, Ovali E and Ozturk G 2016 Mesenchymal stem cell treatment for steroid refractory graft-versus-host disease in children: a pilot and first study from Turkey. Stem Cells Int. 2016 1641402

    PubMed  Google Scholar 

  39. Erices A, Conget P and Minguell JJ 2000 Mesenchymal progenitor cells in human umbilical cord blood. 109 235–242

    CAS  Google Scholar 

  40. Ezquer F, Ezquer M, Contador D, Ricca M, Simon V, et al. 2012 The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells 30 1664–1674

    CAS  PubMed  Google Scholar 

  41. Favaro E, Carpanetto A, Caorsi C, Giovarelli M, Angelini C, et al. 2016 Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients. Diabetologia 59 325–333

    CAS  PubMed  Google Scholar 

  42. Figueroa FE, Cuenca Moreno J and La Cava A 2014 Novel approaches to lupus drug discovery using stem cell therapy. Role of mesenchymal-stem-cell-secreted factors. Exp. Opin. Drug Discov. 9 555–566

    CAS  Google Scholar 

  43. Fiorina P, Jurewicz M, Augello A, Vergani A, Dada S, et al. 2009 Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J. Immunol. 183 993–1004

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Freedman MS, Bar-Or A, Atkins HL, Karussis D, Frassoni F, et al. 2010 The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT study group. Mult. Scler. 16 503–510

    PubMed  Google Scholar 

  45. Friedenstein AJ, Chailakhjan RK and Lalykina KS 1970 The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3 393–403

    CAS  PubMed  Google Scholar 

  46. Friedenstein AJ, Piatetzky S, II and Petrakova KV 1966 Osteogenesis in transplants of bone marrow cells. J. Embryol. Exp. Morphol. 16 381–390

    CAS  PubMed  Google Scholar 

  47. Fu X, Chen Y, Xie FN, Dong P, Liu WB, et al. 2015 Comparison of immunological characteristics of mesenchymal stem cells derived from human embryonic stem cells and bone marrow. Tissue Eng. Part A 21 616–626

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gabr MM, Zakaria MM, Refaie AF, Ismail AM, Abou-El-Mahasen MA, et al. 2013 Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice. Cell Trans. 22 133–145

    Google Scholar 

  49. Gazdic M, Simovic Markovic B, Vucicevic L, Nikolic T, Djonov V, et al. 2018 Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner. J. Tissue Eng. Regen. Med. 12 e1173–e1185

    CAS  PubMed  Google Scholar 

  50. Glennie S, Soeiro I, Dyson PJ, Lam EW and Dazzi F 2005 Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105 2821–2827

    CAS  PubMed  Google Scholar 

  51. Gonçalves FDC, Luk F, Korevaar SS, Bouzid R, Paz AH, et al. 2017 Membrane particles generated from mesenchymal stromal cells modulate immune responses by selective targeting of pro-inflammatory monocytes. Sci. Rep. 7 12100

    PubMed  PubMed Central  Google Scholar 

  52. Goodwin M, Sueblinvong V, Eisenhauer P, Ziats NP, LeClair L, et al. 2011 Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice. Stem Cells 29 1137–1148

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Götherström C, Ringdén O, Westgren M, Tammik C and Le Blanc K 2003 Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells. Bone Marrow Transpl. 32 265–272

    Google Scholar 

  54. Govindasamy V, Ronald VS, Abdullah AN, Nathan KR, Ab Aziz ZA, et al. 2011 Differentiation of dental pulp stem cells into islet-like aggregates. J. Dent. Res. 90 646–652

    CAS  PubMed  Google Scholar 

  55. Gronthos S, Mankani M, Brahim J, Robey PG and Shi S 2000 Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc. Natl. Acad. Sci U. S. A. 97 13625–13630

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hang H, Yu Y, Wu N, Huang Q, Xia Q, et al. 2014 Induction of highly functional hepatocytes from human umbilical cord mesenchymal stem cells by HNF4α transduction. PLoS One 9 e104133

    PubMed  PubMed Central  Google Scholar 

  57. Hass R, Kasper C, Böhm S and Jacobs R 2011 Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun. Signal 9 12

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, et al. 2002 Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc. Natl. Acad. Sci U. S. A. 99 8932–8937

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hwu P, Du MX, Lapointe R, Do M, Taylor MW, et al. 2000 Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J. Immunol. 164 3596–3599

    CAS  PubMed  Google Scholar 

  60. Ianus A, Holz GG, Theise ND and Hussain MA 2003 In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J. Clin. Invest. 111 843–850

    CAS  PubMed  PubMed Central  Google Scholar 

  61. In’t Anker PS, Scherjon SA, Kleijburg-van der Keur C, Noort WA, Claas FH, et al. 2003 Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 102 1548–1549

    Google Scholar 

  62. Jang E, Jeong M, Kim S, Jang K, Kang BK, et al. 2016 Infusion of human bone marrow-derived mesenchymal stem cells alleviates autoimmune nephritis in a lupus model by suppressing follicular helper T-cell development. Cell Trans. 25 1–15

    Google Scholar 

  63. Jiang W and Xu J 2020 Immune modulation by mesenchymal stem cells. Cell Prolif. 53 e12712

    PubMed  Google Scholar 

  64. Johnson A and Dorshkind K 1986 Stromal cells in myeloid and lymphoid long-term bone marrow cultures can support multiple hemopoietic lineages and modulate their production of hemopoietic growth factors. Blood 68 1348–1354

    CAS  PubMed  Google Scholar 

  65. Joo SY, Cho KA, Jung YJ, Kim HS, Park SY, et al. 2010 Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner. Cytotherapy 12 361–370

    CAS  PubMed  Google Scholar 

  66. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, et al. 2010 Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch. Neurol. 67 1187–1194

    PubMed  PubMed Central  Google Scholar 

  67. Kicic A, Shen W-Y, Wilson AS, Constable IJ, Robertson T, et al. 2003 Differentiation of marrow stromal cells into photoreceptors in the rat eye. J. Neurosci. 23 7742–7749

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, et al. 2005 T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J. Biomed. Sci. 12 47–57

    CAS  PubMed  Google Scholar 

  69. Knospe WH, Gregory SA, Husseini SG, Fried W and Trobaugh FE, Jr 1972 Origin and recovery of colony-forming units in locally curetted bone marrow of mice. Blood 39 331–340

    CAS  PubMed  Google Scholar 

  70. Koç ON, Day J, Nieder M, Gerson SL, Lazarus HM, et al. 2002 Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Trans. 30 215–222

    Google Scholar 

  71. Koppula PR, Chelluri LK, Polisetti N and Vemuganti GK 2009 Histocompatibility testing of cultivated human bone marrow stromal cells—a promising step towards pre-clinical screening for allogeneic stem cell therapy. Cell. Immunol. 259 61–65

    CAS  PubMed  Google Scholar 

  72. Koppula PR, Polisetti N and Vemuganti GK 2010 Unstimulated diagnostic marrow tap–a minimally invasive and reliable source for mesenchymal stem cells. Cell Biol. Int. 34 275–281

    PubMed  Google Scholar 

  73. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, et al. 2003 Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101 3722–3729

    CAS  PubMed  Google Scholar 

  74. Kyurkchiev D 2014 Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J. Stem Cells 6 552

    PubMed  PubMed Central  Google Scholar 

  75. Lai P, Chen X, Guo L, Wang Y, Liu X, et al. 2018 A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD. J. Hematol. Oncol. 11 135

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Lai RC, Yeo RW and Lim SK 2015 Mesenchymal stem cell exosomes. Semin. Cell Dev. Biol. 40 82–88

    CAS  PubMed  Google Scholar 

  77. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, et al. 2008 Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371 1579–1586

    PubMed  Google Scholar 

  78. Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, et al. 2004 Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363 1439–1441

    PubMed  Google Scholar 

  79. Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, et al. 2004 In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 40 1275–1284

    CAS  PubMed  Google Scholar 

  80. Li M and Ikehara S 2014 Stem cell treatment for type 1 diabetes. 2

  81. Liang C, Jiang E, Yao J, Wang M, Chen S, et al. 2018 Interferon-γ mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro. Hematology 23 44–49

    CAS  PubMed  Google Scholar 

  82. Lim JY, Min BH, Kim BG, Shin JS, Park CS, et al. 2009 Combinations of growth factors enhance the potency of islets in vitro. Pancreas 38 447–453

    CAS  PubMed  Google Scholar 

  83. Lim JY, Park MJ, Im KI, Kim N, Jeon EJ, et al. 2014 Combination cell therapy using mesenchymal stem cells and regulatory T-cells provides a synergistic immunomodulatory effect associated with reciprocal regulation of TH1/TH2 and th17/treg cells in a murine acute graft-versus-host disease model. Cell Trans. 23 703–714

    Google Scholar 

  84. Liotta F, Angeli R, Cosmi L, Filì L, Manuelli C, et al. 2008 Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells 26 279–289

    CAS  PubMed  Google Scholar 

  85. Liu M, Zeng X, Wang J, Fu Z, Wang J, et al. 2016 Immunomodulation by mesenchymal stem cells in treating human autoimmune disease-associated lung fibrosis. Stem Cell Res. Ther. 7 63

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Liu X, Ren S, Qu X, Ge C, Cheng K, et al. 2015 Mesenchymal stem cells inhibit Th17 cells differentiation via IFN-γ-mediated SOCS3 activation. Immunol. Res. 61 219–229

    CAS  PubMed  Google Scholar 

  87. Llufriu S, Sepúlveda M, Blanco Y, Marín P, Moreno B, et al. 2014 Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One 9 e113936

    PubMed  PubMed Central  Google Scholar 

  88. Lu Y, Wang Z and Zhu M 2006 Human bone marrow mesenchymal stem cells transfected with human insulin genes can secrete insulin stably. Ann. Clin. Lab. Sci. 36 127–136

    CAS  PubMed  Google Scholar 

  89. Luk F, de Witte SF, Korevaar SS, Roemeling-van Rhijn M, Franquesa M, et al. 2016 Inactivated mesenchymal stem cells maintain immunomodulatory capacity. Stem Cells Dev. 25 1342–1354

    CAS  PubMed  Google Scholar 

  90. Majumdar MK, Thiede MA, Haynesworth SE, Bruder SP and Gerson SL 2000 Human marrow-derived mesenchymal stem cells (MSCs) express hematopoietic cytokines and support long-term hematopoiesis when differentiated toward stromal and osteogenic lineages. J Hematother. Stem Cell Res. 9 841–848

    CAS  PubMed  Google Scholar 

  91. Méndez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, et al. 2010 Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466 829–834

    PubMed  PubMed Central  Google Scholar 

  92. Monsel A, Zhu YG, Gennai S, Hao Q, Liu J, et al. 2014 Cell-based therapy for acute organ injury: preclinical evidence and ongoing clinical trials using mesenchymal stem cells. Anesthesiology 121 1099–1121

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Moriscot C, de Fraipont F, Richard MJ, Marchand M, Savatier P, et al. 2005 Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro. Stem Cells 23 594–603

    CAS  PubMed  Google Scholar 

  94. Muguruma Y, Yahata T, Miyatake H, Sato T, Uno T, et al. 2006 Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment. Blood 107 1878–1887

    CAS  PubMed  Google Scholar 

  95. Naghdi M, Tiraihi T, Namin SA and Arabkheradmand J 2009 Transdifferentiation of bone marrow stromal cells into cholinergic neuronal phenotype: a potential source for cell therapy in spinal cord injury. Cytotherapy 11 137–152

    CAS  PubMed  Google Scholar 

  96. Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, et al. 2018 Mesenchymal stromal cells of the bone marrow and natural killer cells: cell interactions and cross modulation. J. Cell Commun. Signal 12 673–688

    PubMed  PubMed Central  Google Scholar 

  97. Newman RE, Yoo D, LeRoux MA and Danilkovitch-Miagkova A 2009 Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm. Allergy Drug Targets 8 110–123

    CAS  PubMed  Google Scholar 

  98. Owen ME, Cavé J and Joyner CJ 1987 Clonal analysis in vitro of osteogenic differentiation of marrow CFU-F. J. Cell Sci. 87 731–738

    PubMed  Google Scholar 

  99. Park CW, Kim KS, Bae S, Son HK, Myung PK, et al. 2009 Cytokine secretion profiling of human mesenchymal stem cells by antibody array. Int. J. Stem Cells 2 59–68

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Pavlova G, Lopatina T, Kalinina N, Rybalkina E, Parfyonova Y, et al. 2012 In vitro neuronal induction of adipose-derived stem cells and their fate after transplantation into injured mouse brain. Curr. Med. Chem. 19 5170–5177

    CAS  PubMed  Google Scholar 

  101. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, et al. 2004 Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 103 1662–1668

    CAS  PubMed  Google Scholar 

  102. Pevsner-Fischer M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, et al. 2007 Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood 109 1422–1432

    CAS  PubMed  Google Scholar 

  103. Phinney DG and Pittenger MF 2017 Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells 35 851–858

    CAS  PubMed  Google Scholar 

  104. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, et al. 1999 Multilineage potential of adult human mesenchymal stem cells. Science 284 143–147

    CAS  PubMed  Google Scholar 

  105. Polisetti N, Chaitanya VG, Babu PP and Vemuganti GK 2010 Isolation, characterization and differentiation potential of rat bone marrow stromal cells. Neurol. India 58 201–208

    PubMed  Google Scholar 

  106. Polisetty N, Fatima A, Madhira SL, Sangwan VS and Vemuganti GK 2008 Mesenchymal cells from limbal stroma of human eye. Mol. Vis. 14 431–442

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Qin Y, Zhou Z, Zhang F, Wang Y, Shen B, et al. 2015 Induction of regulatory B-cells by mesenchymal stem cells is affected by SDF-1α-CXCR7. Cell. Physiol. Biochem. 37 117–130

    CAS  PubMed  Google Scholar 

  108. Rasmusson I 2006 Immune modulation by mesenchymal stem cells. Exp. Cell Res. 312 2169–2179

    CAS  PubMed  Google Scholar 

  109. Raynaud CM, Maleki M, Lis R, Ahmed B, Al-Azwani I, et al. 2012 Comprehensive characterization of mesenchymal stem cells from human placenta and fetal membrane and their response to osteoactivin stimulation. Stem Cells Int. 2012 658356

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, et al. 2008 Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2 141–150

    CAS  PubMed  Google Scholar 

  111. Ren G, Zhao X, Zhang L, Zhang J, L’Huillier A, et al. 2010 Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J. Immunol. 184 2321–2328

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, et al. 2002 Origin of endothelial progenitors in human postnatal bone marrow. J. Clin. Invest. 109 337–346

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Rice CM, Mallam EA, Whone AL, Walsh P, Brooks DJ, et al. 2010 Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis. Clin. Pharmacol. Ther. 87 679–685

    CAS  PubMed  Google Scholar 

  114. Ringdén O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, et al. 2006 Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81 1390–1397

    PubMed  Google Scholar 

  115. Rivera FJ, de la Fuente AG, Zhao C, Silva ME, Gonzalez GA, et al. 2019 Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination. Glia 67 1510–1525

    PubMed  PubMed Central  Google Scholar 

  116. Rosado MM, Bernardo ME, Scarsella M, Conforti A, Giorda E, et al. 2015 Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev. 24 93–103

    CAS  PubMed  Google Scholar 

  117. Rubtsov YP, Suzdaltseva YG, Goryunov KV, Kalinina NI, Sysoeva VY, et al. 2012 Regulation of Immunity via multipotent mesenchymal stromal cells. Acta Naturae 4 23–31

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Safford KM, Hicok KC, Safford SD, Halvorsen YD, Wilkison WO, et al. 2002 Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem. Biophys. Res. Commun. 294 371–379

    CAS  PubMed  Google Scholar 

  119. Saleh M, Shamsasanjan K, Movassaghpourakbari A, Akbarzadehlaleh P and Molaeipour Z 2015 The impact of mesenchymal stem cells on differentiation of hematopoietic stem cells. Adv. Pharm. Bull. 5 299–304

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, et al. 2007 Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109 228–234

    CAS  PubMed  Google Scholar 

  121. Schofield R 1978 The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4 7–25

    CAS  PubMed  Google Scholar 

  122. Shi Y, Hu G, Su J, Li W, Chen Q, et al. 2010 Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 20 510–518

    CAS  PubMed  Google Scholar 

  123. Singaravelu K and Padanilam BJ 2009 In vitro differentiation of MSC into cells with a renal tubular epithelial-like phenotype. Ren. Fail. 31 492–502

    CAS  PubMed  Google Scholar 

  124. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN and Papamichail M 2006 Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24 74–85

    PubMed  Google Scholar 

  125. Stock P, Brückner S, Winkler S, Dollinger MM and Christ B 2014 Human bone marrow mesenchymal stem cell-derived hepatocytes improve the mouse liver after acute acetaminophen intoxication by preventing progress of injury. Int. J. Mol. Sci. 15 7004–7028

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Suarez-Pinzon WL, Lakey JR, Brand SJ and Rabinovitch A 2005 Combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet {beta}-cells from pancreatic duct cells and an increase in functional {beta}-cell mass. J. Clin. Endocrinol. Metab. 90 3401–3409

    CAS  PubMed  Google Scholar 

  127. Sun LY, Zhang HY, Feng XB, Hou YY, Lu LW, et al. 2007 Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus 16 121–128

    CAS  PubMed  Google Scholar 

  128. Syková E, Rychmach P, Drahorádová I, Konrádová Š, Růžičková K, et al. 2017 Transplantation of mesenchymal stromal cells in patients with amyotrophic lateral sclerosis: results of phase I/IIa clinical trial. Cell Trans. 26 647–658

    Google Scholar 

  129. Tabera S, Pérez-Simón JA, Díez-Campelo M, Sánchez-Abarca LI, Blanco B, et al. 2008 The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica 93 1301–1309

    CAS  PubMed  Google Scholar 

  130. Tang DQ, Wang Q, Burkhardt BR, Litherland SA, Atkinson MA, et al. 2012 In vitro generation of functional insulin-producing cells from human bone marrow-derived stem cells, but long-term culture running risk of malignant transformation. Am. J. Stem Cells 1 114–127

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Tatara R, Ozaki K, Kikuchi Y, Hatanaka K, Oh I, et al. 2011 Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation. Cytotherapy 13 686–694

    CAS  PubMed  Google Scholar 

  132. Tavassoli M and Crosby WH 1968 Transplantation of marrow to extramedullary sites. Science 161 54–56

    CAS  PubMed  Google Scholar 

  133. Tian Y, Deng YB, Huang YJ and Wang Y 2008 Bone marrow-derived mesenchymal stem cells decrease acute graft-versus-host disease after allogeneic hematopoietic stem cells transplantation. Immunol. Invest. 37 29–42

    CAS  PubMed  Google Scholar 

  134. Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES, et al. 2008 Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells 26 99–107

    CAS  PubMed  Google Scholar 

  135. Trinchieri G 1989 Biology of Natural Killer Cells. in Advances in Immunology (Dixon FJ Ed) Academic Press, Cambridge, pp 187–376

    Google Scholar 

  136. Trivedi A, Miyazawa B, Gibb S, Valanoski K, Vivona L, et al. 2019 Bone marrow donor selection and characterization of MSCs is critical for pre-clinical and clinical cell dose production. J. Trans. Med. 17 1–16

    Google Scholar 

  137. Tse WT, Pendleton JD, Beyer WM, Egalka MC and Guinan EC 2003 Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75 389–397

    CAS  PubMed  Google Scholar 

  138. Ulyanova O, Askarov M, Kozina L, Karibekov T, Shaimardanova G, et al. 2019 Autologous mesenchymal stem cell transplant in patients with type 1 diabetes mellitus. Exp. Clin. Trans. 17 236–238

    Google Scholar 

  139. Undale AH, Westendorf JJ, Yaszemski MJ and Khosla S 2009 Mesenchymal stem cells for bone repair and metabolic bone diseases. Mayo Clin. Proc. 84 893–902

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Varin A, Pontikoglou C, Labat E, Deschaseaux F and Sensebé L 2013 CD200R/CD200 inhibits osteoclastogenesis: new mechanism of osteoclast control by mesenchymal stem cells in human. PLoS One 8 e72831

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Wagner W, Roderburg C, Wein F, Diehlmann A, Frankhauser M, et al. 2007 Molecular and secretory profiles of human mesenchymal stromal cells and their abilities to maintain primitive hematopoietic progenitors. Stem Cells 25 2638–2647

    CAS  PubMed  Google Scholar 

  142. Wang D, Zhang H, Liang J, Wang H, Hua B, et al. 2018 A long-term follow-up study of allogeneic mesenchymal stem/stromal cell transplantation in patients with drug-resistant systemic lupus erythematosus. Stem Cell Rep. 10 933–941

    CAS  Google Scholar 

  143. Wang H-S, Hung S-C, Peng S-T, Huang C-C, Wei H-M, et al. 2004 Mesenchymal stem cells in the Wharton’s Jelly of the human umbilical cord. Stem Cells 22 1330–1337

    PubMed  Google Scholar 

  144. Wang H, Zhang H, Huang B, Miao G, Yan X, et al. 2018 Mesenchymal stem cells reverse high-fat diet induced non-alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice. Mol. Med. Rep. 17 3769–3774

    CAS  PubMed  Google Scholar 

  145. Wang Q, Qian S, Li J, Che N, Gu L, et al. 2015 Combined transplantation of autologous hematopoietic stem cells and allogenic mesenchymal stem cells increases T regulatory cells in systemic lupus erythematosus with refractory lupus nephritis and leukopenia. Lupus 24 1221–1226

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  147. Xue Q, Luan XY, Gu YZ, Wu HY, Zhang GB, et al. 2010 The negative co-signaling molecule b7-h4 is expressed by human bone marrow-derived mesenchymal stem cells and mediates its T-cell modulatory activity. Stem Cells Dev. 19 27–38

    CAS  PubMed  Google Scholar 

  148. Zhang B, Yin Y, Lai RC, Tan SS, Choo AB, et al. 2014 Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 23 1233–1244

    CAS  PubMed  Google Scholar 

  149. Zhang W, Ge W, Li C, You S, Liao L, et al. 2004 Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev. 13 263–271

    CAS  PubMed  Google Scholar 

  150. Zhang Y, Ge XH, Guo XJ, Guan SB, Li XM, et al. 2017 Bone marrow mesenchymal stem cells inhibit the function of dendritic cells by secreting galectin-1. Biomed. Res. Int. 2017 3248605

    PubMed  PubMed Central  Google Scholar 

  151. Zhou H, Guo M, Bian C, Sun Z, Yang Z, et al. 2010 Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report. Biol. Blood Marrow Trans. 16 403–412

    CAS  Google Scholar 

  152. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, et al. 2001 Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7 211–228

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the funding agency Indian council of Medical Research (ICMR) for supporting this work. We appreciate DST-Purse II and UPE-II for financial support. We also thank Dr. Rohini Nair for comments in earlier versions of the manuscript. Last but not the least, we would like to thank our colleagues for their inputs and support.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Geeta K Vemuganti.

Additional information

Corresponding editor: Sorab Dalal

Communicated by Sorab Dalal.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mohanty, A., Polisetti, N. & Vemuganti, G.K. Immunomodulatory properties of bone marrow mesenchymal stem cells. J Biosci 45, 98 (2020). https://doi.org/10.1007/s12038-020-00068-9

Download citation

Keywords

  • Bone marrow mesenchymal stem cells
  • cytokine
  • immune disorders
  • immunomodulation
  • immunosuppression