Abstract
Objective
Human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) are well known to modulate T cells. However, the molecular mechanisms that mark hBM-MSCs immunomodulation of T cells are not fully resolved.
Materials and methods
hBM-MSCs harvested from sternum or iliac crest of five healthy donors and characterized in accordance with the International Society of Cellular Therapy (ISCT) guidelines are co-cultured with T cells. Additionally, modulatory effects of MSCs on T-cell viability, proliferation, cytokine profile, co-stimulatory pathway, activation and immunomodulation are also determined.
Results
hBM-MSCs significantly reduced the expression of T-cell activation marker CD38 as well as co-stimulatory markers CD134 and CD154, whilst that of CD27 remained unchanged. BrdU, CFSE and Ki67 proliferation assays showed that hBM-MSCs reduced T-cell proliferation. Moreover, viability of T cells remained unchanged when co-cultured with hBM-MSCs. Finally, T cells when co-cultured with hBM-MSCs showed increased secretion of IL-10 and IL-11.
Conclusion
Collectively, hBM-MSCs are able to modulate the main steps involved in T-cell response toward a tolerogenic state. Thus, establishing immunobiological criteria defining the immunosuppressive effect of hBM-MSCs is of importance to reach efficient immunotherapeutic intervention.
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References
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;8:315–7.
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;418:41–9.
Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest. 1999;103:697–705.
Noth U, Osyczka AM, Tuli R, Hickok NJ, Danielson KG, Tuan RS. Multilineage mesenchymal differentiation potential of human trabecular bone-derived cells. J Orthop Res. 2002;20:1060–9.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.
Song L, Tuan RS. Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow. Faseb J. 2004;18:980–2.
Tuan RS, Boland G, Tuli R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther. 2003;5:32–45.
Wang G, Bunnell BA, Painter RG, Quiniones BC, Tom S, Lanson NA Jr, et al. Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: potential therapy for cystic fibrosis. Proc Natl Acad Sci USA. 2005;102:186–91.
Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. 2000;61:364–70.
Tavassoli M, Friedenstein A. Hemopoietic stromal microenvironment. Am J Hematol. 1983;15:195–203.
Caterson EJ, Nesti LJ, Danielson KG, Tuan RS. Human marrow-derived mesenchymal progenitor cells: isolation, culture expansion, and analysis of differentiation. Mol Biotechnol. 2002;20:245–56.
Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood. 2005;105:2821–7.
Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101:3722–9.
Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105:4120–6.
Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, 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. 2006;107:1484–90.
Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367–72.
Prigione I, Benvenuto F, Bocca P, Battistini L, Uccelli A, Pistoia V. Reciprocal interactions between human mesenchymal stem cells and gammadelta T cells or invariant natural killer T cells. Stem Cells. 2009;27:693–702.
Gao L, Liu F, Tan L, Liu T, Chen Z, Shi C. The immunosuppressive properties of non-cultured dermal-derived mesenchymal stromal cells and the control of graft-versus-host disease. Biomaterials. 2014;35:3582–8.
Hematti P. Role of mesenchymal stromal cells in solid organ transplantation. Transplant Rev (Orlando). 2008;22:262–73.
Yan Z, Zhuansun Y, Liu G, Chen R, Li J, Ran P. Mesenchymal stem cells suppress T cells by inducing apoptosis and through PD-1/B7-H1 interactions. Immunol Lett. 2014;162:248–55.
Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13:392–402.
Le Blanc K, Davies LC. Mesenchymal stromal cells and the innate immune response. Immunol Lett. 2015;168:140–6.
Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation. 2005;80:555–63.
Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M, et al. Bone marrow mesenchymal stromal cells induce proliferative, cytokinic and molecular changes during the T cell response: the importance of the IL-10/CD210 Axis. Stem Cell Rev. 2015;11:442–52.
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;11:570–83.
Bryant RJ, Banks PM, O’Malley DP. Ki67 staining pattern as a diagnostic tool in the evaluation of lymphoproliferative disorders. Histopathology. 2006;48:505–15.
Soares A, Govender L, Hughes J, Mavakla W, de Kock M, Barnard C, et al. Novel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation. J Immunol Methods. 2010;362:43–50.
Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol. 2009;9:271–85.
Bozza M, Bliss JL, Dorner AJ, Trepicchio WL. Interleukin-11 modulates Th1/Th2 cytokine production from activated CD4+ T cells. J Interferon Cytokine Res. 2001;21:21–30.
Chong AS, Perkins DL. Transplantation: molecular phenotyping of T-cell-mediated rejection. Nat Rev Nephrol. 2014;10:678–80.
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–19.
Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361:2066–78.
Bakr MA, Nagib AM, Donia AF. Induction immunosuppressive therapy in kidney transplantation. Exp Clin Transplant. 2014;12(Suppl 1):60–9.
O’Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med. 2004;350:2591–602.
Siegel G, Schafer R, Dazzi F. The immunosuppressive properties of mesenchymal stem cells. Transplantation. 2009;87:S45–9.
Tanavde V, Vaz C, Rao MS, Vemuri MC, Pochampally RR. Research using Mesenchymal Stem/Stromal Cells: quality metric towards developing a reference material. Cytotherapy. 2015;17:1169–77.
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. 2007.
Li M, Sun X, Kuang X, Liao Y, Li H, Luo D. Mesenchymal stem cells suppress CD8+ T cell-mediated activation by suppressing natural killer group 2, member D protein receptor expression and secretion of prostaglandin E2, indoleamine 2, 3-dioxygenase and transforming growth factor-β. Clin Exp Immunol. 2014;178:516–24.
Ling W, Zhang J, Yuan Z, Ren G, Zhang L, Chen X, et al. Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment. Cancer Res. 2014;74:1576–87.
Cuerquis J, Romieu-Mourez R, François M, Routy JP, Young YK, Zhao J, et al. Human mesenchymal stromal cells transiently increase cytokine production by activated T cells before suppressing T-cell proliferation: effect of interferon-γ and tumor necrosis factor-α stimulation. Cytotherapy. 2014;16:191–202.
Quarona V, Zaccarello G, Chillemi A, Brunetti E, Singh VK, Ferrero E, et al. CD38 and CD157: a long journey from activation markers to multifunctional molecules. Cytom B Clin Cytom. 2013;84:207–17.
Sandoval-Montes C, Santos-Argumedo L. CD38 is expressed selectively during the activation of a subset of mature T cells with reduced proliferation but improved potential to produce cytokines. J Leukoc Biol. 2005;77:513–21.
Rothstein DM, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Immunol Rev. 2003;196:85–108.
Ni G, Wang T, Walton S, Zhu B, Chen S, Wu X, et al. Manipulating IL-10 signalling blockade for better immunotherapy. Cell Immunol. 2015;293:126–9.
Busser H, Najar M, Raicevic G, Pieters K, Velez Pombo R, Philippart P, et al. Isolation and characterization of human mesenchymal stromal cell subpopulations: comparison of bone marrow and adipose tissue. Stem Cells Dev. 2015;24:2142–57.
Benvenuto F, Ferrari S, Gerdoni E, Gualandi F, Frassoni F, Pistoia V, et al. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells. 2007;25:1753–60.
Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M, et al. Impact of different mesenchymal stromal cell types on T-cell activation, proliferation and migration. Int Immunopharmacol. 2013;15:693–702.
Najar M, Raicevic G, Fayyad-Kazan H, Bron B, Toungouz M, Lagneaux L. Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells. Cytotherapy. 2016;18:160–71.
Acknowledgments
M. Najar is a Télévie research fellow of “Le Fonds National de la Recherche Scientifique”.
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Responsible Editor: John Di Battista.
H. Fayyad-Kazan, W. H. Faour contributed equally to this work.
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Fayyad-Kazan, H., Faour, W.H., Badran, B. et al. The immunomodulatory properties of human bone marrow-derived mesenchymal stromal cells are defined according to multiple immunobiological criteria. Inflamm. Res. 65, 501–510 (2016). https://doi.org/10.1007/s00011-016-0933-2
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DOI: https://doi.org/10.1007/s00011-016-0933-2