Key Points
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The unique immunomodulatory properties of multipotent mesenchymal stromal cells (MSCs) make MSC-based therapy one of the most promising tolerance-promoting cell therapies in solid organ transplantation
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MSCs can down-modulate the effector functions of cells that are involved in the alloimmune response, including those of dendritic cells, T cells, B cells and macrophages, converting them into regulatory cells
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In experimental models of solid organ transplantation, MSCs can induce long-term graft acceptance when given alone or in combination with short-term treatment with immunosuppressive drugs
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In the setting of kidney transplantation MSCs can also acquire proinflammatory function and worsen allograft outcomes
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Initial clinical experience with bone-marrow-derived MSCs in kidney transplantation indicates the safety and feasibility of the procedure and suggests that MSCs can promote donor-specific immunomodulation and possibly a pro-tolerogenic environment
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Future studies should provide evidence for the long-term safety of MSC therapy as well as their efficacy in inducing operational tolerance in kidney transplant recipients
Abstract
Lifelong immunosuppressive therapy is essential to prevent allograft rejection in transplant recipients. Long-term, nonspecific immunosuppression can, however, result in life-threatening complications and fail to prevent chronic graft rejection. Bone marrow (BM)-derived multipotent mesenchymal stromal cells (MSCs) have emerged as a potential candidate for cell-based therapy to modulate the immune response in organ transplantation. These cells can repair tissue after injury and downregulate many of the effector functions of immune cells that participate in the alloimmune response, converting them into regulatory cells. The findings of preclinical and initial clinical studies support the potential tolerance-inducing effects of MSCs and highlight the unanticipated complexity of MSC therapy in kidney transplantation. In animal models of transplantation MSCs promote donor-specific tolerance through the generation of regulatory T cells and antigen-presenting cells. In some settings, however, MSCs can acquire proinflammatory properties and contribute to allograft dysfunction. The available data from small clinical studies suggest that cell infusion is safe and well tolerated by kidney transplant recipients. Ongoing and future trials will provide evidence regarding the long-term safety of MSC therapy and determine the optimum cell source (either autologous or allogeneic) and infusion protocol to achieve operational tolerance in kidney transplant recipients. These studies will also provide additional evidence regarding the risks and benefits of MSC infusion and will hopefully offer definitive answers to the important questions of when, where, how many and which types of MSCs should be infused to fully exploit their immunomodulatory, pro-tolerogenic and tissue-repairing properties.
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References
Kotton, C. N. & Fishman, J. A. Viral infection in the renal transplant recipient. J. Am. Soc. Nephrol. 16, 1758–1774 (2005).
Rama, I. & Grinyo, J. M. Malignancy after renal transplantation: the role of immunosuppression. Nat. Rev. Nephrol. 6, 511–519 (2010).
Stoumpos, S., Jardine, A. G. & Mark, P. B. Cardiovascular morbidity and mortality after kidney transplantation. Transpl. Int. 28, 10–21 (2015).
Tufton, N. et al. New-onset diabetes after renal transplantation. Diabet. Med. 31, 1284–1292 (2014).
Casey, M. J. & Meier-Kriesche, H. U. Calcineurin inhibitors in kidney transplantation: friend or foe? Curr. Opin. Nephrol. Hypertens. 20, 610–615 (2011).
Lodhi, S. A., Lamb, K. E. & Meier-Kriesche, H. U. Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am. J. Transplant. 11, 1226–1235 (2011).
Salama, A. D., Remuzzi, G., Harmon, W. E. & Sayegh, M. H. Challenges to achieving clinical transplantation tolerance. J. Clin. Invest. 108, 943–948 (2001).
Kawai, T. et al. Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression. Am. J. Transplant. 14, 1599–1611 (2014).
Leventhal, J. et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci. Transl. Med. 4, 124ra28 (2012).
Scandling, J. D. et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N. Engl. J. Med. 358, 362–368 (2008).
Wood, K. J., Bushell, A. & Hester, J. Regulatory immune cells in transplantation. Nat. Rev. Immunol. 12, 417–430 (2012).
Friedenstein, A. J., Chailakhjan, R. K. & Lalykina, K. S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3, 393–403 (1970).
Friedenstein, A. J., Chailakhyan, R. K., Latsinik, N. V., Panasyuk, A. F. & Keiliss-Borok, I. V. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17, 331–340 (1974).
Owen, M. & Friedenstein, A. J. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found. Symp. 136, 42–60 (1988).
Bianco, P. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35–42 (2013).
Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).
Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).
Bianco, P., Robey, P. G. & Simmons, P. J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2, 313–319 (2008).
Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).
Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).
Bautch, V. L. Stem cells and the vasculature. Nat. Med. 17, 1437–1443 (2011).
da Silva Meirelles, L., Chagastelles, P. C. & Nardi, N. B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci. 119, 2204–2213 (2006).
Lechler, R. I., Lombardi, G., Batchelor, J. R., Reinsmoen, N. & Bach, F. H. The molecular basis of alloreactivity. Immunol. Today 11, 83–88 (1990).
Zhuang, Q. & Lakkis, F. G. Dendritic cells and innate immunity in kidney transplantation. Kidney Int. 87, 712–718 (2015).
Matzinger, P. & Bevan, M. J. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell. Immunol. 29, 1–5 (1977).
Suchin, E. J. et al. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J. Immunol. 166, 973–981 (2001).
Wood, K. J. & Goto, R. Mechanisms of rejection: current perspectives. Transplantation 93, 1–10 (2012).
Liu, Z., Fan, H. & Jiang, S. CD4+ T-cell subsets in transplantation. Immunol. Rev. 252, 183–191 (2013).
Rosenberg, A. S., Mizuochi, T., Sharrow, S. O. & Singer, A. Phenotype, specificity, and function of T cell subsets and T cell interactions involved in skin allograft rejection. J. Exp. Med. 165, 1296–1315 (1987).
Jiang, S., Herrera, O. & Lechler, R. I. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr. Opin. Immunol. 16, 550–557 (2004).
Lee, C. Y. et al. The involvement of FcR mechanisms in antibody-mediated rejection. Transplantation 84, 1324–1334 (2007).
Williams, M. A. & Bevan, M. J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).
Valujskikh, A. & Lakkis, F. G. In remembrance of things past: memory T cells and transplant rejection. Immunol. Rev. 196, 65–74 (2003).
Noris, M. et al. Regulatory T cells and T cell depletion: role of immunosuppressive drugs. J. Am. Soc. Nephrol. 18, 1007–1018 (2007).
Pearl, J. P. et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am. J. Transplant. 5, 465–474 (2005).
Williams, K. M., Hakim, F. T. & Gress, R. E. T cell immune reconstitution following lymphodepletion. Semin. Immunol. 19, 318–330 (2007).
Page, A. J., Ford, M. L. & Kirk, A. D. Memory T-cell-specific therapeutics in organ transplantation. Curr. Opin. Organ Transplant. 14, 643–649 (2009).
Rudensky, A. Y. Regulatory T cells and Foxp3. Immunol. Rev. 241, 260–268 (2011).
Waldmann, H., Hilbrands, R., Howie, D. & Cobbold, S. Harnessing FOXP3+ regulatory T cells for transplantation tolerance. J. Clin. Invest. 124, 1439–1445 (2014).
English, K., Barry, F. P. & Mahon, B. P. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol. Lett. 115, 50–58 (2008).
Chiesa, S. et al. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc. Natl Acad. Sci. USA 108, 17384–17389 (2011).
Zhang, W. et al. Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev. 13, 263–271 (2004).
Jiang, X. X. et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105, 4120–4126 (2005).
Nauta, A. J., Kruisselbrink, A. B., Lurvink, E., Willemze, R. & Fibbe, W. E. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J. Immunol. 177, 2080–2087 (2006).
Djouad, F. et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells 25, 2025–2032 (2007).
Li, Y. P. et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway. J. Immunol. 180, 1598–1608 (2008).
Spaggiari, G. M., Abdelrazik, H., Becchetti, F. & Moretta, L. MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2 . Blood 113, 6576–6583 (2009).
Beyth, S. et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 105, 2214–2219 (2005).
Bartholomew, A. et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol. 30, 42–48 (2002).
Glennie, S., Soeiro, I., Dyson, P. J., Lam, E. W. & Dazzi, F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105, 2821–2827 (2005).
Krampera, M. et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101, 3722–3729 (2003).
Tse, W. T., Pendleton, J. D., Beyer, W. M., Egalka, M. C. & Guinan, E. C. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75, 389–397 (2003).
Karlsson, H. et al. Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 112, 532–541 (2008).
Reading, J. L. et al. Clinical-grade multipotent adult progenitor cells durably control pathogenic T cell responses in human models of transplantation and autoimmunity. J. Immunol. 190, 4542–4552 (2013).
Rasmusson, I., Ringden, O., Sundberg, B. & Le Blanc, K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 76, 1208–1213 (2003).
Plumas, J. et al. Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia 19, 1597–1604 (2005).
Meisel, R. et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103, 4619–4621 (2004).
Aggarwal, S. & Pittenger, M. F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105, 1815–1822 (2005).
Di Nicola, M. et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99, 3838–3843 (2002).
Gieseke, F. et al. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood 116, 3770–3779 (2010).
Sioud, M., Mobergslien, A., Boudabous, A. & Floisand, Y. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Scand. J. Immunol. 71, 267–274 (2010).
Nasef, A. et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 84, 231–237 (2007).
Sato, K. et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109, 228–234 (2007).
Ren, G. et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2, 141–150 (2008).
Ren, G. et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27, 1954–1962 (2009).
Luz-Crawford, P. et al. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res. Ther. 4, 65 (2013).
English, K. et al. Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25High forkhead box P3+ regulatory T cells. Clin. Exp. Immunol. 156, 149–160 (2009).
Selmani, Z. 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 26, 212–222 (2008).
Melief, S. M. et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells 31, 1980–1991 (2013).
Akiyama, K. et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 10, 544–555 (2012).
Tabera, S. et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica 93, 1301–1309 (2008).
Rosado, M. M. et al. Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev. 24, 93–103 (2015).
Asari, S. et al. Mesenchymal stem cells suppress B-cell terminal differentiation. Exp. Hematol. 37, 604–615 (2009).
Franquesa, M. et al. Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells 33, 880–891 (2015).
Zhou, H. P. et al. Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft. Transplant. Proc. 38, 3046–3051 (2006).
Inoue, S. et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation 81, 1589–1595 (2006).
Chabannes, D. et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood 110, 3691–3694 (2007).
Popp, F. C. et al. Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. Transpl. Immunol. 20, 55–60 (2008).
Roobrouck, V. D. et al. Differentiation potential of human postnatal mesenchymal stem cells, mesoangioblasts, and multipotent adult progenitor cells reflected in their transcriptome and partially influenced by the culture conditions. Stem Cells 29, 871–882 (2011).
Jacobs, S. A., Roobrouck, V. D., Verfaillie, C. M. & Van Gool, S. W. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol. Cell Biol. 91, 32–39 (2013).
Eggenhofer, E. et al. Heart grafts tolerized through third-party multipotent adult progenitor cells can be retransplanted to secondary hosts with no immunosuppression. Stem Cells Transl. Med. 2, 595–606 (2013).
Obermajer, N. et al. Conversion of Th17 into IL-17Aneg regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy. J. Immunol. 193, 4988–4999 (2014).
Ge, W. et al. Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am. J. Transplant. 9, 1760–1772 (2009).
Casiraghi, F. et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J. Immunol. 181, 3933–3946 (2008).
Solari, M. G. et al. Marginal mass islet transplantation with autologous mesenchymal stem cells promotes long-term islet allograft survival and sustained normoglycemia. J. Autoimmun. 32, 116–124 (2009).
Kim, Y. H. et al. Interleukin (IL)-10 induced by CD11b+ cells and IL-10-activated regulatory T cells play a role in immune modulation of mesenchymal stem cells in rat islet allografts. Mol. Med. 17, 697–708 (2011).
Wang, Y., Zhang, A., Ye, Z., Xie, H. & Zheng, S. Bone marrow-derived mesenchymal stem cells inhibit acute rejection of rat liver allografts in association with regulatory T-cell expansion. Transplant. Proc. 41, 4352–4356 (2009).
Jiang, X. et al. CD4+CD25+ regulatory T cells are not required for mesenchymal stem cell function in fully MHC-mismatched mouse cardiac transplantation. Cell Tissue Res. 358, 503–514 (2014).
Ge, W. et al. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation 90, 1312–1320 (2010).
He, Y. et al. Indoleamine 2, 3-dioxgenase transfected mesenchymal stem cells induce kidney allograft tolerance by increasing the production and function of regulatory T cells. Transplantation 99, 1829–1838 (2015).
Franquesa, M. et al. Mesenchymal stem cell therapy prevents interstitial fibrosis and tubular atrophy in a rat kidney allograft model. Stem Cells Dev. 21, 3125–3135 (2012).
Hara, Y. et al. In vivo effect of bone marrow-derived mesenchymal stem cells in a rat kidney transplantation model with prolonged cold ischemia. Transpl. Int. 24, 1112–1123 (2011).
Seifert, M., Stolk, M., Polenz, D. & Volk, H. D. Detrimental effects of rat mesenchymal stromal cell pre-treatment in a model of acute kidney rejection. Front. Immunol. 3, 202 (2012).
Koch, M. et al. Isogeneic MSC application in a rat model of acute renal allograft rejection modulates immune response but does not prolong allograft survival. Transpl. Immunol. 29, 43–50 (2013).
Casiraghi, F. et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am. J. Transplant. 12, 2373–2383 (2012).
Marquez-Curtis, L. A. & Janowska-Wieczorek, A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. Biomed. Res. Int. 2013, 561098 (2013).
Cao, Z. et al. Protective effects of mesenchymal stem cells with CXCR4 up-regulation in a rat renal transplantation model. PLoS ONE 8, e82949 (2013).
Liu, N., Patzak, A. & Zhang, J. CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury. Am. J. Physiol. Renal Physiol. 305, F1064–F1073 (2013).
Perico, N. et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin. J. Am. Soc. Nephrol. 6, 412–422 (2011).
Perico, N. et al. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transpl. Int. 26, 867–878 (2013).
Tan, J. et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 307, 1169–1177 (2012).
Reinders, M. E. et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl. Med. 2, 107–111 (2013).
Mudrabettu, C. et al. Safety and efficacy of autologous mesenchymal stromal cells transplantation in patients undergoing living donor kidney transplantation: a pilot study. Nephrology (Carlton) 20, 25–33 (2015).
Peng, Y. et al. Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation 95, 161–168 (2013).
Ruggenenti, P. et al. Basiliximab combined with low-dose rabbit anti-human thymocyte globulin: a possible further step toward effective and minimally toxic T cell-targeted therapy in kidney transplantation. Clin. J. Am. Soc. Nephrol. 1, 546–554 (2006).
Farris, A. B. et al. Acute renal endothelial injury during marrow recovery in a cohort of combined kidney and bone marrow allografts. Am. J. Transplant. 11, 1464–1477 (2011).
Bluestone, J. A. et al. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am. J. Transplant. 8, 2086–2096 (2008).
US National Library of Science. ClinicalTrials.gov[online], (2015).
Vincenti, F. et al. Costimulation blockade with belatacept in renal transplantation. N. Engl. J. Med. 353, 770–781 (2005).
Riella, L. V. & Chandraker, A. Stem cell therapy in kidney transplantation. JAMA 308, 130; author reply 130–131 (2012).
Griffin, M. D. et al. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: what have we learned so far? Immunol. Cell Biol. 91, 40–51 (2013).
Badillo, A. T., Beggs, K. J., Javazon, E. H., Tebbets, J. C. & Flake, A. W. Murine bone marrow stromal progenitor cells elicit an in vivo cellular and humoral alloimmune response. Biol. Blood Marrow Transplant. 13, 412–422 (2007).
Beggs, K. J. et al. Immunologic consequences of multiple, high-dose administration of allogeneic mesenchymal stem cells to baboons. Cell Transplant. 15, 711–721 (2006).
Isakova, I. A., Dufour, J., Lanclos, C., Bruhn, J. & Phinney, D. G. Cell-dose-dependent increases in circulating levels of immune effector cells in rhesus macaques following intracranial injection of allogeneic MSCs. Exp. Hematol. 38, 957–967.e1 (2010).
Zaim, M., Karaman, S., Cetin, G. & Isik, S. Donor age and long-term culture affect differentiation and proliferation of human bone marrow mesenchymal stem cells. Ann. Hematol. 91, 1175–1186 (2012).
Nemeth, K. Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between. Exp. Dermatol. 23, 625–628 (2014).
Siegel, G. et al. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med. 11, 146 (2013).
Remuzzi, G. & Bromberg, J. S. Mesenchymal stromal cells: what's in the name? (and for what?). Am. J. Transplant. 13, 1625 (2013).
von Bahr, L. et al. Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol. Blood Marrow Transplant. 18, 557–564 (2012).
Forslow, U. et al. Treatment with mesenchymal stromal cells is a risk factor for pneumonia-related death after allogeneic hematopoietic stem cell transplantation. Eur. J. Haematol. 89, 220–227 (2012).
Kawai, T., Sachs, D. H., Sykes, M. & Cosimi, A. B. HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 368, 1850–1852 (2013).
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The authors' experimental studies in organ transplantation are supported by the Fondazione ART (Fondazione per la Ricerca sui Trapianti, Milan, Italy).
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F.C., N.P. and M.C. researched the data and wrote the article. All authors made substantial contributions to discussions of the content and reviewed or edited the manuscript before submission.
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Ongoing clinical studies of MSCs in kidney transplantation registered in clinicaltrials.gov (PDF 135 kb)
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Casiraghi, F., Perico, N., Cortinovis, M. et al. Mesenchymal stromal cells in renal transplantation: opportunities and challenges. Nat Rev Nephrol 12, 241–253 (2016). https://doi.org/10.1038/nrneph.2016.7
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DOI: https://doi.org/10.1038/nrneph.2016.7
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