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  • Review Article
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Mesenchymal stromal cells in renal transplantation: opportunities and challenges

Nature Reviews Nephrology volume 12, pages 241–253 (2016)Cite this article

Subjects

Key Points

  • 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

  • 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

  • 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

  • In the setting of kidney transplantation MSCs can also acquire proinflammatory function and worsen allograft outcomes

  • 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

  • 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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Figure 1: The immunomodulatory effects of mesenchymal stromal cells (MSCs) during the alloimmune response.

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References

  1. Kotton, C. N. & Fishman, J. A. Viral infection in the renal transplant recipient. J. Am. Soc. Nephrol. 16, 1758–1774 (2005).

    PubMed  Google Scholar 

  2. Rama, I. & Grinyo, J. M. Malignancy after renal transplantation: the role of immunosuppression. Nat. Rev. Nephrol. 6, 511–519 (2010).

    CAS  PubMed  Google Scholar 

  3. Stoumpos, S., Jardine, A. G. & Mark, P. B. Cardiovascular morbidity and mortality after kidney transplantation. Transpl. Int. 28, 10–21 (2015).

    PubMed  Google Scholar 

  4. Tufton, N. et al. New-onset diabetes after renal transplantation. Diabet. Med. 31, 1284–1292 (2014).

    CAS  PubMed  Google Scholar 

  5. Casey, M. J. & Meier-Kriesche, H. U. Calcineurin inhibitors in kidney transplantation: friend or foe? Curr. Opin. Nephrol. Hypertens. 20, 610–615 (2011).

    CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  Google Scholar 

  7. Salama, A. D., Remuzzi, G., Harmon, W. E. & Sayegh, M. H. Challenges to achieving clinical transplantation tolerance. J. Clin. Invest. 108, 943–948 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    PubMed  PubMed Central  Google Scholar 

  10. Scandling, J. D. et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N. Engl. J. Med. 358, 362–368 (2008).

    CAS  PubMed  Google Scholar 

  11. Wood, K. J., Bushell, A. & Hester, J. Regulatory immune cells in transplantation. Nat. Rev. Immunol. 12, 417–430 (2012).

    CAS  PubMed  Google Scholar 

  12. 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).

    CAS  PubMed  Google Scholar 

  13. 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).

    CAS  PubMed  Google Scholar 

  14. Owen, M. & Friedenstein, A. J. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found. Symp. 136, 42–60 (1988).

    CAS  PubMed  Google Scholar 

  15. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    CAS  PubMed  Google Scholar 

  17. Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bianco, P., Robey, P. G. & Simmons, P. J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2, 313–319 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    CAS  PubMed  Google Scholar 

  21. Bautch, V. L. Stem cells and the vasculature. Nat. Med. 17, 1437–1443 (2011).

    CAS  PubMed  Google Scholar 

  22. 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).

    PubMed  Google Scholar 

  23. Lechler, R. I., Lombardi, G., Batchelor, J. R., Reinsmoen, N. & Bach, F. H. The molecular basis of alloreactivity. Immunol. Today 11, 83–88 (1990).

    CAS  PubMed  Google Scholar 

  24. Zhuang, Q. & Lakkis, F. G. Dendritic cells and innate immunity in kidney transplantation. Kidney Int. 87, 712–718 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Matzinger, P. & Bevan, M. J. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell. Immunol. 29, 1–5 (1977).

    CAS  PubMed  Google Scholar 

  26. 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).

    CAS  PubMed  Google Scholar 

  27. Wood, K. J. & Goto, R. Mechanisms of rejection: current perspectives. Transplantation 93, 1–10 (2012).

    PubMed  Google Scholar 

  28. Liu, Z., Fan, H. & Jiang, S. CD4+ T-cell subsets in transplantation. Immunol. Rev. 252, 183–191 (2013).

    PubMed  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. Lee, C. Y. et al. The involvement of FcR mechanisms in antibody-mediated rejection. Transplantation 84, 1324–1334 (2007).

    CAS  PubMed  Google Scholar 

  32. Williams, M. A. & Bevan, M. J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).

    CAS  PubMed  Google Scholar 

  33. Valujskikh, A. & Lakkis, F. G. In remembrance of things past: memory T cells and transplant rejection. Immunol. Rev. 196, 65–74 (2003).

    CAS  PubMed  Google Scholar 

  34. Noris, M. et al. Regulatory T cells and T cell depletion: role of immunosuppressive drugs. J. Am. Soc. Nephrol. 18, 1007–1018 (2007).

    CAS  PubMed  Google Scholar 

  35. 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).

    CAS  PubMed  Google Scholar 

  36. Williams, K. M., Hakim, F. T. & Gress, R. E. T cell immune reconstitution following lymphodepletion. Semin. Immunol. 19, 318–330 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    PubMed  PubMed Central  Google Scholar 

  38. Rudensky, A. Y. Regulatory T cells and Foxp3. Immunol. Rev. 241, 260–268 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Waldmann, H., Hilbrands, R., Howie, D. & Cobbold, S. Harnessing FOXP3+ regulatory T cells for transplantation tolerance. J. Clin. Invest. 124, 1439–1445 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 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).

    CAS  PubMed  Google Scholar 

  43. Jiang, X. X. et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105, 4120–4126 (2005).

    CAS  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  Google Scholar 

  45. 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).

    CAS  PubMed  Google Scholar 

  46. 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).

    CAS  PubMed  Google Scholar 

  47. 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).

    CAS  PubMed  Google Scholar 

  48. Beyth, S. et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 105, 2214–2219 (2005).

    CAS  PubMed  Google Scholar 

  49. 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).

    PubMed  Google Scholar 

  50. 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).

    CAS  PubMed  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  Google Scholar 

  53. Karlsson, H. et al. Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 112, 532–541 (2008).

    CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  Google Scholar 

  55. 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).

    PubMed  Google Scholar 

  56. Plumas, J. et al. Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia 19, 1597–1604 (2005).

    CAS  PubMed  Google Scholar 

  57. 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).

    CAS  PubMed  Google Scholar 

  58. Aggarwal, S. & Pittenger, M. F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105, 1815–1822 (2005).

    CAS  PubMed  Google Scholar 

  59. 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).

    CAS  PubMed  Google Scholar 

  60. Gieseke, F. et al. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood 116, 3770–3779 (2010).

    CAS  PubMed  Google Scholar 

  61. 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).

    CAS  PubMed  Google Scholar 

  62. Nasef, A. et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 84, 231–237 (2007).

    CAS  PubMed  Google Scholar 

  63. 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).

    CAS  PubMed  Google Scholar 

  64. 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).

    CAS  PubMed  Google Scholar 

  65. Ren, G. et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27, 1954–1962 (2009).

    CAS  PubMed  Google Scholar 

  66. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 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).

    CAS  PubMed  Google Scholar 

  69. 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).

    CAS  PubMed  Google Scholar 

  70. Akiyama, K. et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 10, 544–555 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Tabera, S. et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica 93, 1301–1309 (2008).

    CAS  PubMed  Google Scholar 

  72. 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).

    CAS  PubMed  Google Scholar 

  73. Asari, S. et al. Mesenchymal stem cells suppress B-cell terminal differentiation. Exp. Hematol. 37, 604–615 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    CAS  PubMed  Google Scholar 

  75. 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).

    CAS  PubMed  Google Scholar 

  76. Inoue, S. et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation 81, 1589–1595 (2006).

    PubMed  Google Scholar 

  77. 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).

    CAS  PubMed  Google Scholar 

  78. 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).

    CAS  PubMed  Google Scholar 

  79. 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).

    CAS  PubMed  Google Scholar 

  80. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 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).

    CAS  PubMed  Google Scholar 

  83. 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).

    CAS  PubMed  Google Scholar 

  84. 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).

    CAS  PubMed  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. 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).

    PubMed  PubMed Central  Google Scholar 

  87. 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).

    CAS  PubMed  Google Scholar 

  88. 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).

    CAS  PubMed  Google Scholar 

  89. 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).

    CAS  PubMed  Google Scholar 

  90. 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).

    CAS  PubMed  Google Scholar 

  91. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    PubMed  Google Scholar 

  93. 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).

    PubMed  PubMed Central  Google Scholar 

  94. 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).

    CAS  PubMed  Google Scholar 

  95. 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).

    CAS  PubMed  Google Scholar 

  96. 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).

    PubMed  PubMed Central  Google Scholar 

  97. 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).

    PubMed  PubMed Central  Google Scholar 

  98. 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).

    CAS  PubMed  Google Scholar 

  99. 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).

    PubMed  PubMed Central  Google Scholar 

  100. 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).

    CAS  PubMed  Google Scholar 

  101. 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).

    CAS  PubMed  Google Scholar 

  102. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 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).

    CAS  Google Scholar 

  104. 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).

    CAS  PubMed  Google Scholar 

  105. 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).

    CAS  PubMed  Google Scholar 

  106. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. US National Library of Science. ClinicalTrials.gov[online], (2015).

  109. Vincenti, F. et al. Costimulation blockade with belatacept in renal transplantation. N. Engl. J. Med. 353, 770–781 (2005).

    CAS  PubMed  Google Scholar 

  110. Riella, L. V. & Chandraker, A. Stem cell therapy in kidney transplantation. JAMA 308, 130; author reply 130–131 (2012).

    CAS  PubMed  Google Scholar 

  111. 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).

    CAS  PubMed  Google Scholar 

  112. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 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).

    PubMed  Google Scholar 

  114. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 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).

    PubMed  Google Scholar 

  116. Nemeth, K. Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between. Exp. Dermatol. 23, 625–628 (2014).

    PubMed  Google Scholar 

  117. Siegel, G. et al. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med. 11, 146 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Remuzzi, G. & Bromberg, J. S. Mesenchymal stromal cells: what's in the name? (and for what?). Am. J. Transplant. 13, 1625 (2013).

    Google Scholar 

  119. 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).

    PubMed  Google Scholar 

  120. 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).

    PubMed  Google Scholar 

  121. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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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Authors and Affiliations

  1. IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Transplant Research Center “Chiara Cucchi de Alessandri e Gilberto Crespi”, Via G.B. Camozzi 3, Ranica, 24020, Bergamo, Italy

    Federica Casiraghi & Monica Cortinovis

  2. IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases “Aldo & Cele Daccò”, Via G.B. Camozzi 3, Ranica, 24020, Bergamo, Italy

    Norberto Perico & Giuseppe Remuzzi

Authors
  1. Federica Casiraghi
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  2. Norberto Perico
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  3. Monica Cortinovis
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  4. Giuseppe Remuzzi
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Contributions

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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Correspondence to Norberto Perico.

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The authors declare no competing financial interests.

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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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