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Immune Plasticity of Bone Marrow-Derived Mesenchymal Stromal Cells

  • J. Stagg
  • J. GalipeauEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 180)

Abstract

Isolated from simple bone marrow aspirates, mesenchymal stromal cells (MSCs) can be easily expanded ex vivo and differentiated into various cell lineages. Because they are present in humans of all ages, are harvested in the absence of prior mobilization and preserve their plasticity following gene modification, MSCs are particularly attractive for cell-based medicine. One of the most fascinating properties of ex vivo expanded MSCs is their ability to suppress ongoing immune responses, both in vitro and in vivo. Although not fully understood, the immunosuppressive properties of MSCs have been reported to affect the function of a broad range of immune cells, including T cells, antigen-presenting cells, natural killer cells and B cells. Whereas successful harnessing of these immunosuppressive properties might one day open the door to the development of new cell-based strategies for the control of graft-versus-host and other autoimmune diseases, recent studies suggest that the immune-modulating properties of MSCs are far more complex than first thought. Reminiscent of the dichotomy of function of dendritic cells (DCs), which can act as potent activators or potent suppressors of immune responses, new studies including our own work has shown that MSCs in fact possess the dual ability to suppress or activate immune responses. In this review, we summarize the different biological properties of MSCs and discuss the current literature on the complex mechanism of immune modulation mediated by ex vivo expanded MSCs.

Keywords

Mesenchymal stem cells Adult stem cells Antigen presentation Immune suppression Graft-vs-host disease 

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References

  1. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822PubMedCrossRefGoogle Scholar
  2. Al-Khaldi A, Eliopoulos N, Martineau D, et al (2003) Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neo-angiogenic response in vivo. Gene Ther 10:621–629PubMedCrossRefGoogle Scholar
  3. Anversa P, Nadal-Ginard B (2002) Myocyte renewal and ventricular remodeling. Nature 415:240–243PubMedCrossRefGoogle Scholar
  4. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G (2005) Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 35:1482–1490PubMedCrossRefGoogle Scholar
  5. Barda-Saad M, Rozenszajn LA, Globerson A, Zhang AS, Zipori D (1996) Selective adhesion of immature thymocytes to bone marrows tromal cells: relevance to T cell lymphopoiesis. Exp Hematol 24:386–391PubMedGoogle Scholar
  6. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, Galun E, Rachmilewitz J (2005) Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 105:2214–2219PubMedCrossRefGoogle Scholar
  7. Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, Rameshwar P (2006) Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood 107:4817–4824PubMedCrossRefGoogle Scholar
  8. Clark BR, Keating A (1995) Biology of bone marrow stroma. Ann N Y Acad Sci 770:70–78PubMedCrossRefGoogle Scholar
  9. Colter DC, Class R, DiGirolamo CM, Prockop DJ (2000) Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci U S A 97:3213–3218PubMedCrossRefGoogle Scholar
  10. Colter DC, Sekiya I, Prockop DJ (2001) Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci U S A 98:7841–7845PubMedCrossRefGoogle Scholar
  11. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107:367–372PubMedCrossRefGoogle Scholar
  12. Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28:875–884PubMedCrossRefGoogle Scholar
  13. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843PubMedCrossRefGoogle Scholar
  14. Digirolamo CM, Stokes D, Colter D, Phinney DG, Class R, Prockop DJ (1999) Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate. Br J Haematol 107:275–281PubMedCrossRefGoogle Scholar
  15. Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noel D, Jorgensen C (2003) Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 102:3837–3844PubMedCrossRefGoogle Scholar
  16. Djouad F, Fritz V, Apparailly F, Louis-Plence P, Bony C, Sany J, Jorgensen C, Noel D (2005) Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. Arthritis Rheum 52:1595–1603PubMedCrossRefGoogle Scholar
  17. Eglitis MA, Dawson D, Park KW, Mouradian MM (1999) Targeting of marrow-derived astrocytes to the ischemic brain. Neuroreport 10:1289–1292PubMedCrossRefGoogle Scholar
  18. Eliopoulos N, Stagg J, Lejeune L, Pommey S, Galipeau J (2005) Allogeneic marrow stromal cells are immune rejected by MHC class I-and class II-mismatched recipient mice. Blood 106:4057–4065PubMedCrossRefGoogle Scholar
  19. Forrester JS, Price MJ, Makkar RR (2003) Stem cell repair of infarcted myocardium: an overview for clinicians. Circulation 108:1139–1145PubMedCrossRefGoogle Scholar
  20. Friedenstein AJ, Gorskaja JF, Kulagina NN (1976) Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 4:267–274PubMedGoogle Scholar
  21. Geijtenbeek TB, van Vliet SJ, Engering A, ’t Hart BA, van Kooyk Y (2004) Self-and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol 22:33–54PubMedCrossRefGoogle Scholar
  22. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105:2821–2827PubMedCrossRefGoogle Scholar
  23. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11:367–368PubMedCrossRefGoogle Scholar
  24. Gotherstrom C, Ringden O, Tammik C, Zetterberg E, Westgren M, Le Blanc K (2004) Immunologic properties of human fetal mesenchymal stem cells. Am J Obstet Gynecol 190:239–245PubMedCrossRefGoogle Scholar
  25. Gregory CA, Perry AS, Reyes E, Conley A, Gunn WG, Prockop DJ (2005) Dkk-1-derived synthetic peptides and lithium chloride for the control and recovery of adult stem cells from bone marrow. J Biol Chem 280:2309–2323PubMedCrossRefGoogle Scholar
  26. Hill JM, Dick AJ, Raman VK, et al (2003) Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 108:1009–1014PubMedCrossRefGoogle Scholar
  27. Hoffmann A, Pelled G, Turgeman G, Eberle P, Zilberman Y, Shinar H, Keinan-Adamsky K, Winkel A, Shahab S, Navon G, Gross G, Gazit D (2006) Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells. J Clin Invest 116:940–952PubMedCrossRefGoogle Scholar
  28. Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE (2006) Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells 24:1030–1041PubMedCrossRefGoogle Scholar
  29. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N, Yaffe MB (2005) TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309:1074–1078PubMedCrossRefGoogle Scholar
  30. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313PubMedCrossRefGoogle Scholar
  31. Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T (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 99:8932–8937PubMedCrossRefGoogle Scholar
  32. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, et al (2005) Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7:393–395PubMedCrossRefGoogle Scholar
  33. Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, Mao N (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105:4120–4126PubMedCrossRefGoogle Scholar
  34. Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II, Nguyen AT, Malide D, Combs CA, Hall G, Zhang J, Raffeld M, Rogers TB, Stetler-Stevenson W, Frank JA, Reitz M, Finkel T (2006) Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J Exp Med 203:1235–1247PubMedCrossRefGoogle Scholar
  35. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F (2003) Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101:3722–3729PubMedCrossRefGoogle Scholar
  36. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F (2006) Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24:386–398PubMedCrossRefGoogle Scholar
  37. Kreisel D, Krupnick AS, Balsara KR, Riha M, Gelman AE, Popma SH, Szeto WY, Turka LA, Rosengard BR (2002) Mouse vascular endothelium activates CD8+ T lymphocytes in a B7-dependent fashion. J Immunol 169:6154–6161PubMedGoogle Scholar
  38. Laouar A, Harias V, Vargas D, Zhinan X, Chaplin D, van Lier RA, Manjunath N (2005) CD70+ antigen-presenting cells control the proliferation and differentiation of T cells in the intestinal mucosa. Nat Immunol 6:698–706PubMedCrossRefGoogle Scholar
  39. Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, Klemm M, Kuchroo VK, Freeman GJ, Sharpe AH (2004) PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci U S A 101:10691–10696PubMedCrossRefGoogle Scholar
  40. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O (2003) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 10:890–896CrossRefGoogle Scholar
  41. Le Blanc K, Rasmusson I, Gotherstrom C, Seidel C, Sundberg B, Sundin M, Rosendahl K, Tammik C, Ringden O (2004a) Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol 60:307–315PubMedCrossRefGoogle Scholar
  42. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O (2004b) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441PubMedCrossRefGoogle Scholar
  43. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N, Chopp M (2002) Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:514–523PubMedGoogle Scholar
  44. Massague J, Blain SW, Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309PubMedCrossRefGoogle Scholar
  45. Mazo IB, Honczarenko M, Leung H, Cavanagh LL, Bonasio R, Weninger W, Engelke K, Xia L, McEver RP, Koni PA, Silberstein LE, von Andrian UH (2005) Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity 22:259–270PubMedCrossRefGoogle Scholar
  46. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D (2004) Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103:4619–4621PubMedCrossRefGoogle Scholar
  47. Milne CD, Fleming HE, Zhang Y, Paige CJ (2004) Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokinin-1 during B-cell development. Immunol Rev 197:75–88PubMedCrossRefGoogle Scholar
  48. Mishra L, Derynck R, Mishra B (2005) Transforming growth factor-beta signaling in stem cells and cancer. Science 310:68–71PubMedCrossRefGoogle Scholar
  49. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, Andreeff M, Lang FF (2005) Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65:3307–3318. Erratum in: Cancer Res 2006 Jun 1 66:5975PubMedGoogle Scholar
  50. Nakashima K, de Crombrugghe B (2003) Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet 19:458–466PubMedCrossRefGoogle Scholar
  51. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE (2006) Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a non-myeloablative setting. Blood 108:2114–2120PubMedCrossRefGoogle Scholar
  52. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ (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 103:1662–1668PubMedCrossRefGoogle Scholar
  53. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedCrossRefGoogle Scholar
  54. Pober JS, Kluger MS, Schechner JS (2001) Human endothelial cell presentation of antigen and the homing of memory/effector T cells to skin. Ann N Y Acad Sci 941:12–25PubMedCrossRefGoogle Scholar
  55. Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P (2003) Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol 171:3426–3434PubMedGoogle Scholar
  56. Prockop DJ, Gregory CA, Spees JL (2003) One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci U S A 100[Suppl 1]:11917–11923PubMedCrossRefGoogle Scholar
  57. Rasmusson I, Ringden O, Sundberg B, Le Blanc K (2005) Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 305:33–41PubMedCrossRefGoogle Scholar
  58. Reddy P, Liu L, Ren C, Lindgren P, Boman K, Shen Y, Lundin E, Ottander U, Rytinki M, Liu K (2005) Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells. Mol Endocrinol 19:2564–2578PubMedCrossRefGoogle Scholar
  59. Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie CM (2001) Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98:2615–2625PubMedCrossRefGoogle Scholar
  60. Rodig N, Ryan T, Allen JA, Pang H, Grabie N, Chernova T, Greenfield EA, Liang SC, Sharpe AH, Lichtman AH, Freeman GJ (2003) Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol 33:3117–3126PubMedCrossRefGoogle Scholar
  61. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM (2000) Transcriptional regulation of adipogenesis. Genes Dev 14:1293–1307PubMedGoogle Scholar
  62. Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, Bernad A (2005) Spontaneous human adult stem cell transformation. Cancer Res 65:3035–3039PubMedGoogle Scholar
  63. Ruscetti FW, Akel S, Bartelmez SH (2005) Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context. Oncogene 24:5751–5763PubMedCrossRefGoogle Scholar
  64. Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC (2002) Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg 74:19–24PubMedCrossRefGoogle Scholar
  65. Sekiya I, Larson BL, Smith JR, Pochampally R, Cui JG, Prockop DJ (2002) Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality. Stem Cells 20:530–541PubMedCrossRefGoogle Scholar
  66. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L (2006) 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 107:1484–1490PubMedCrossRefGoogle Scholar
  67. Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A, Peister A, Wang MY, Prockop DJ (2003) Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci U S A 100:2397–2402PubMedCrossRefGoogle Scholar
  68. Stagg J, Pommey S, Eliopoulos N, Galipeau J (2006) Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood 107:2570–2577PubMedCrossRefGoogle Scholar
  69. Studeny M, Marini FC, Champlin RE, et al (2002) Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. Stem Cells 62:3603–3608Google Scholar
  70. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545PubMedCrossRefGoogle Scholar
  71. Torlakovic E, Tenstad E, Funderud S, Rian E (2005) CD10+ stromal cells form B-lymphocyte maturation niches in the human bone marrow. J Pathol 205:311–317PubMedCrossRefGoogle Scholar
  72. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75:389–397PubMedCrossRefGoogle Scholar
  73. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761PubMedCrossRefGoogle Scholar
  74. Zhang W, Ge W, Li C, You S, Liao L, Han Q, Deng W, Zhao RC (2004) Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev 13:263–271PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  1. 1.Sir Mortimer B. Davis Jewish General Hospital Lady Davis Research InstituteMcGill UniversityMontrealCanada

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