Skip to main content

Advertisement

Log in

Harnessing the Immunomodulatory and Tissue Repair Properties of Mesenchymal Stem Cells to Restore β Cell Function

  • Transplantation (A Pileggi, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Islet cell transplantation has therapeutic potential to cure type 1 diabetes (T1D), which is characterized by autoimmune-mediated destruction of insulin-producing β cells. However, current success rates are limited by long-term decline in islet graft function resulting partially from poor revascularization and immune destruction. Mesenchymal stem cells (MSCs) have the potential to enhance islet transplantation and prevent disease progression by a multifaceted approach. MSCs have been shown to be effective at inhibiting inflammatory-mediated immune responses and at promoting tissue regeneration. The immunomodulatory and tissue repairing properties of MSCs may benefit β cell regeneration in the context of T1D. This review will elucidate how MSCs can minimize β cell damage by providing survival signals and simultaneously modulate the immune response by inhibiting activation, and proliferation of several immune cell types. In addition, MSCs can enhance islet graft revascularization, maintaining long-term β cell viability and function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as:• Of importance •• Of major importance

  1. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:14–37.

    Article  Google Scholar 

  2. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726–36.

    Article  PubMed  CAS  Google Scholar 

  3. Rafei M, Campeau PM, Aguilar-Mahecha A, et al. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J Immunol. 2009;182:5994–6002.

    Article  PubMed  CAS  Google Scholar 

  4. Papadopoulou A, Yiangou M, Athanasiou E, et al. Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis. Ann Rheum Dis. 2012.

  5. Choi EW, Shin IS, Park SY, et al. Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation. Arthritis Rheum. 2012;64:243–53.

    Article  PubMed  CAS  Google Scholar 

  6. Ciccocioppo R, Bernardo ME, Sgarella A, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising crohn's disease. Gut. 2011;60:788–98.

    Article  PubMed  Google Scholar 

  7. Aksu AE, Horibe E, Sacks J, et al. Co-infusion of donor bone marrow with host mesenchymal stem cells treats gvhd and promotes vascularized skin allograft survival in rats. Clin Immunol. 2008;127:348–58.

    Article  PubMed  CAS  Google Scholar 

  8. Fotino C, Ricordi C, Lauriola V, et al. Bone marrow-derived stem cell transplantation for the treatment of insulin-dependent diabetes. Rev Diabet Stud. 2010;7:144–57.

    Article  PubMed  Google Scholar 

  9. Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001;358:221–9.

    Article  PubMed  CAS  Google Scholar 

  10. Schlosser M, Koczwara K, Kenk H, et al. In insulin-autoantibody-positive children from the general population, antibody affinity identifies those at high and low risk. Diabetologia. 2005;48:1830–2.

    Article  PubMed  CAS  Google Scholar 

  11. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204–13.

    Article  PubMed  CAS  Google Scholar 

  12. Friedenstein AJ, Gorskaja UF, Kulagina NN. Fibroblasts precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol. 1976;4:267–74.

    PubMed  CAS  Google Scholar 

  13. Sakaguchi Y, Sekiya I, Yagishita K, et al. Suspended cells from trabecular bone b y collagenase digestion become virtually identical to mesenchymal stem cells o btained from marrow aspirates. Blood. 2004;104:2728–35.

    Article  PubMed  CAS  Google Scholar 

  14. Gronthos S, Zannettino ACW. A method to isolate and purify human bone marrow stromal stem cells. In: Prockop DJ, Phinney DG, Bunnell BA, editors. Methods in molecular biology. Humana Press Inc; 2008. p. 45–57.

  15. Walsh S, Jefferiss C, Stewart K, et al. Expression of the developmental markers Stro-1 and alkaline phosphatase in cultures of human marrow stromal cells: regulation by fibroblast growth factor (FGF)-2 and relationship to the expression of FGF receptors 1-4. Bone. 2000;27:185–95.

    Article  PubMed  CAS  Google Scholar 

  16. Ning H, Lin G, Lue TF, et al. Mesenchymal stem cell marker Stro-1 is a 75kd endothelial antigen. Biochem Biophys Res Commun. 2011;413:353–7.

    Article  PubMed  CAS  Google Scholar 

  17. Horwitz EM, Le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: the international society for cellular therapy position statement. Cytotherapy. 2005;7:393–5.

    Article  PubMed  CAS  Google Scholar 

  18. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy. 2006;8:315–7.

    Article  PubMed  CAS  Google Scholar 

  19. Chamberlain G, Fox J, Ashton B, et al. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25:2739–49.

    Article  PubMed  CAS  Google Scholar 

  20. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal c ells. Blood. 2007;110:3499–506.

    Article  PubMed  CAS  Google Scholar 

  21. Nauta AJ, Westerhuis G, Kruisselbrink AB, et al. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood. 2006;108:2114–20.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Madec AM, Mallone R, Afonso G, et al. Mesenchymal stem cells protect nod mice from diabetes by inducing regulatory T cells. Diabetologia. 2009;52:1391–9.

    Article  PubMed  CAS  Google Scholar 

  24. Jurewicz M, Yang SM, Augello A, et al. Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes. Diabetes. 2010;59:3139–47.

    Article  PubMed  CAS  Google Scholar 

  25. Abdi R, Fiorina P, Adra CN, et al. Immunomodulation by mesenchymal stem cells - a potential therapeutic strategy for type 1 diabetes. Diabetes. 2008;57:1759–67.

    Article  PubMed  CAS  Google Scholar 

  26. Yagi H, Soto-Gutierrez A, Parekkadan B, et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant. 2010;19:667–79.

    Article  PubMed  Google Scholar 

  27. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30:42–8.

    Article  PubMed  Google Scholar 

  28. Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57:11–20.

    Article  PubMed  Google Scholar 

  29. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–43.

    Article  PubMed  Google Scholar 

  30. Ryan JM, Barry F, Murphy JM, et al. Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol. 2007;149:353–63.

    Article  PubMed  CAS  Google Scholar 

  31. Zhao W, Wang Y, Wang DD, et al. TGF-beta expression by allogeneic bone marrow stromal cells ameliorates diabetes in nod mice through modulating the distribution of CD4+ T cell subsets. Cell Immunol. 2008;253:23–30.

    Article  PubMed  CAS  Google Scholar 

  32. Tse WT, Pendleton JD, Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplant. 2003;75:389–97.

    Article  CAS  Google Scholar 

  33. Yanez R, Oviedo A, Aldea M, et al. Prostaglandin E2 plays a key role in the immunosuppressive properties of adipose and bone marrow tissue-derived mesenchymal stromal cells. Exp Cell Res. 2010;316:3109–23.

    Article  PubMed  CAS  Google Scholar 

  34. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–22.

    Article  PubMed  CAS  Google Scholar 

  35. Chen L, Zhang W, Yue H, et al. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev. 2007;16:719–31.

    Article  PubMed  CAS  Google Scholar 

  36. English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4 + CD25(high) Forkhead Box P3+ regulatory T cells. Clin Exp Immunol. 2009;156:149–60.

    Article  PubMed  CAS  Google Scholar 

  37. Duffy MM, Pindjakova J, Hanley SA, et al. 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. 2011;41:2840–51.

    Article  PubMed  CAS  Google Scholar 

  38. Krampera M, Cosmi L, Angeli R, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24:386–98.

    Article  PubMed  CAS  Google Scholar 

  39. Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase mediated tryptophan degradation. Blood. 2004;103:4619–21.

    Article  PubMed  CAS  Google Scholar 

  40. Sato K, Ozaki K, Oh I, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood. 2007;109:228–34.

    Article  PubMed  CAS  Google Scholar 

  41. Bingisser RM, Tilbrook PA, Holt PG, et al. Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the JAK3/STAT5 signaling pathway. J Immunol. 1998;160:5729–34.

    PubMed  CAS  Google Scholar 

  42. Glennie S, Soeiro I, Dyson PJ, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood. 2005;105:2821–7.

    Article  PubMed  CAS  Google Scholar 

  43. Ding YC, Xu DM, Feng G, et al. Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and-9. Diabetes. 2009;58:1797–806.

    Article  PubMed  CAS  Google Scholar 

  44. Sioud M. New insights into mesenchymal stromal cell-mediated T-cell suppression through galectins. Scand J Immunol. 2011;73:79–84.

    Article  PubMed  CAS  Google Scholar 

  45. Perillo NL, Pace KE, Seilhamer JJ, et al. Apoptosis of T cells mediated by galectin-1. Nature. 1995;378:736–9.

    Article  PubMed  CAS  Google Scholar 

  46. Hsu DK, Chen HY, Liu FT. Galectin-3 regulates T-cell functions. Immunol Rev. 2009;230:114–27.

    Article  PubMed  CAS  Google Scholar 

  47. Sioud M, Mobergslien A, Boudabous A, et al. Mesenchymal stem cell-mediated T cell suppression occurs through secreted galectins. Int J Oncol. 2011;38:385–90.

    Article  PubMed  CAS  Google Scholar 

  48. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367–72.

    Article  PubMed  CAS  Google Scholar 

  49. Sotiropoulou PA, Perez SA, Gritzapis AD, et al. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells. 2006;24:74–85.

    Article  PubMed  Google Scholar 

  50. Jiang XX, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105:4120–6.

    Article  PubMed  CAS  Google Scholar 

  51. Nauta AJ, Kruisselbrink AB, Lurvink E, et al. Mesenchymal stem cells inhibit generation and function of both CD34(+)-derived and monocyte-derived dendritic cells. J Immunol. 2006;177:2080–7.

    PubMed  CAS  Google Scholar 

  52. Li FR, Wang XG, Deng CY, et al. Immune modulation of co-transplantation mesenchymal stem cells with islet on T and dendritic cells. Clin Exp Immunol. 2010;161:357–63.

    PubMed  CAS  Google Scholar 

  53. Ryan JM, Barry FP, Murphy JM, et al. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond). 2005;2:8.

    Article  CAS  Google Scholar 

  54. Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105:2214–9.

    Article  PubMed  CAS  Google Scholar 

  55. English K, Barry FP, Mahon BP. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol Lett. 2008;115:50–8.

    Article  PubMed  CAS  Google Scholar 

  56. Augello A, Tasso R, Negrini SM, et al. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007;56:1175–86.

    Article  PubMed  CAS  Google Scholar 

  57. Yamazaki S, Bonito AJ, Spisek R, et al. Dendritic cells are specialized accessory cells along with TGF-beta for the differentiation of Foxp3(+) CD4(+) regulatory t cells from peripheral Foxp3(-) precursors. Blood. 2007;110:4293–302.

    Article  PubMed  CAS  Google Scholar 

  58. Peng YF, Laouar Y, Li MO, et al. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4(+)CD25(+) regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci U S A. 2004;101:4572–7.

    Article  PubMed  CAS  Google Scholar 

  59. Tarbell KV, Petit L, Zuo XP, et al. Dendritic cell-expanded, islet-specific CD4(+) CD25(+) CD62L(+) regulatory T cells restore normoglycemia in diabetic nod mice. J Exp Med. 2007;204:191–201.

    Article  PubMed  CAS  Google Scholar 

  60. Tonkin DR, He J, Barbour G, et al. Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo. J Immunol. 2008;181:4516–22.

    PubMed  CAS  Google Scholar 

  61. Luo X, Yang H, Kim IS, et al. Systemic transforming growth factor-beta I gene therapy induces Foxp3 + regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice. Transplantation. 2005;79:1091–6.

    Article  PubMed  CAS  Google Scholar 

  62. Boumaza I, Srinivasan S, Witt WT, et al. Autologous bone marrow-derived rat mesenchymal stem cells promote Pdx-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia. J Autoimmun. 2009;32:33–42.

    Article  PubMed  CAS  Google Scholar 

  63. Engela AU, Baan CC, Peeters AM, et al. Interaction between adipose-tissue derived mesenchymal stem cells and regulatory T cells. Cell Transplant. 2012.

  64. Crop MJ, Baan CC, Korevaar SS, et al. Human adipose tissue-derived mesenchymal stem cells induce explosive T-cell proliferation. Stem Cells Dev. 2010;19:1843–53.

    Article  PubMed  CAS  Google Scholar 

  65. Casiraghi F, Azzollini N, Cassis P, 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. 2008;181:3933–46.

    PubMed  CAS  Google Scholar 

  66. Berman DM, Willman MA, Han DM, et al. Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes. 2010;59:2558–68.

    Article  PubMed  CAS  Google Scholar 

  67. •• Solari MG, Srinivasan S, Boumaza I, et al. Marginal mass islet transplantation with autologous mesenchymal stem cells promotes long-term islet allograft survival and sustained normoglycemia. J Autoimmun. 2009;32:116–24. This study demonstrates that co-transplantation of MSCs with islets enhances long-term islet graft survival and function with maintenance of normoglycemia.

    Article  PubMed  CAS  Google Scholar 

  68. Ortiz LA, Gambelli F, McBride C, et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003;100:8407–11.

    Article  PubMed  CAS  Google Scholar 

  69. Barbash IM, Chouraqui P, Baron J, et al. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium - feasibility, cell migration, and body distribution. Circulation. 2003;108:863–8.

    Article  PubMed  Google Scholar 

  70. Lin P, Chen L, Li D, et al. Dynamic analysis of bone marrow mesenchymal stem cells migrating to pancreatic islets using coculture microfluidic chips: an accelerated migrating rate and better survival of pancreatic islets were revealed. Neuroendocrinol Lett. 2009;30:204–8.

    PubMed  Google Scholar 

  71. Lee RH, Seo MJ, Reger RL, et al. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/SCID mice. Proc Natl Acad Sci U S A. 2006;103:17438–43.

    Article  PubMed  CAS  Google Scholar 

  72. Sordi V, Malosio ML, Marchesi F, et al. Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood. 2005;106:419–27.

    Article  PubMed  CAS  Google Scholar 

  73. Bell GI, Broughton HC, Levac KD, et al. Transplanted human bone marrow rogenitor subtypes stimulate endogenous islet regeneration and revascularization. Stem Cells Dev. 2012;21:97–109.

    Article  PubMed  CAS  Google Scholar 

  74. Ezquer FE, Ezquer ME, Parrau DB, et al. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type I diabetic mice. Biol Blood Marrow Transplant. 2008;14:631–40.

    Article  PubMed  CAS  Google Scholar 

  75. Si Y, Zhao Y, Hao H, et al. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats. Diabetes. 2012;61:1616–25.

    Article  PubMed  CAS  Google Scholar 

  76. Lu S, Lu C, Han Q, et al. Adipose-derived mesenchymal stem cells protect Pc12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of Xiap through Pi3-k/Akt activation. Toxicology. 2011;279:189–95.

    Article  PubMed  CAS  Google Scholar 

  77. Caja L, Bertran E, Campbell J, et al. The transforming growth factor-beta (TGF-beta) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells. J Cell Physiol. 2011;226:1214–23.

    Article  PubMed  CAS  Google Scholar 

  78. •• Park KS, Kim YS, Kim JH, et al. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation. 2010;89:509–17. This study demonstrates that trophic factors secreted by MSCs enhance islet survival and function in vitro and improve islet graft function and revascularization after transplantation.

    PubMed  CAS  Google Scholar 

  79. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.

    Article  PubMed  CAS  Google Scholar 

  80. Park KS, Kim YS, Kim JH, et al. Influence of human allogenic bone marrow and cord blood-derived mesenchymal stem cell secreting trophic factors on ATP (adenosine-5 '-triphosphate)/ADP (adenosine-5'-diphosphate) ratio and insulin secretory function of isolated human islets from cadaveric donor. Transplant Proc. 2009;41:3813–8.

    Article  PubMed  CAS  Google Scholar 

  81. Lu Y, Jin X, Chen Y, et al. Mesenchymal stem cells protect islets from hypoxia/reoxygenation-induced injury. Cell Biochem Funct. 2010;28:637–43.

    Article  PubMed  CAS  Google Scholar 

  82. Choi SE, Choi KM, Yoon IH, et al. IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo. Transpl Immunol. 2004;13:43–53.

    Article  PubMed  CAS  Google Scholar 

  83. Ogawa M, Nishiura T, Oritani K, et al. Cytokines prevent dexamethasone-induced apoptosis via the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in a new multiple myeloma cell line. Cancer Res. 2000;60:4262–9.

    PubMed  CAS  Google Scholar 

  84. Emamaullee JA, Rajotte RV, Liston P, et al. Xiap overexpression in human islets prevents early posttransplant apoptosis and reduces the islet mass needed to treat diabetes. Diabetes. 2005;54:2541–8.

    Article  PubMed  CAS  Google Scholar 

  85. Plesner A, Liston P, Tan R, et al. The x-linked inhibitor of apoptosis protein enhances survival of murine islet allografts. Diabetes. 2005;54:2533–40.

    Article  PubMed  CAS  Google Scholar 

  86. Vasavada RC, Gonzalez-Pertusa JA, Fujinaka Y, et al. Growth factors and beta cell replication. Int J Biochem Cell Biol. 2006;38:931–50.

    Article  PubMed  CAS  Google Scholar 

  87. Nakano M, Yasunami Y, Maki T, et al. Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts. Transplantation. 2000;69:214–21.

    Article  PubMed  CAS  Google Scholar 

  88. Otonkoski T, Beattie GM, Rubin JS, et al. Hepatocyte growth-factor scatter factor has insulinotropic activity in human fetal pancreatic-cells. Diabetes. 1994;43:947–53.

    Article  PubMed  CAS  Google Scholar 

  89. Kayali AG, Van Gunst K, Campbell IL, et al. The stromal cell-derived factor-1 Alpha/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas. J Cell Biol. 2003;163:859–69.

    Article  PubMed  CAS  Google Scholar 

  90. Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circul Res. 2004;94:678–85.

    Article  CAS  Google Scholar 

  91. Cheng Y, Liu YF, Zhang JL, et al. Elevated vascular endothelial growth factor production and its effect on revascularization and function of graft islets in diabetic rats. World J Gastroenterol. 2007;13:2862–6.

    PubMed  CAS  Google Scholar 

  92. Figliuzzi M, Cornolti R, Perico N, et al. Bone marrow-derived mesenchymal stem cells improve islet graft function in diabetic rats. Transplant Proc. 2009;41:1797–800.

    Article  PubMed  CAS  Google Scholar 

  93. Ito T, Itakura S, Todorov I, et al. Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function. Transplantation. 2010;89:1438–45.

    Article  PubMed  Google Scholar 

  94. Rackham CL, Chagastelles PC, Nardi NB, et al. Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. Diabetologia. 2011;54:1127–35.

    Article  PubMed  CAS  Google Scholar 

  95. Johansson U, Rasmusson I, Niclou SP, et al. Formation of composite endothelial cell-mesenchymal stem cell islets - a novel approach to promote islet revascularization. Diabetes. 2008;57:2393–401.

    Article  PubMed  CAS  Google Scholar 

  96. Neeman Z, Hirshberg B, Harlan D, et al. Radiologic aspects of islet cell transplantation. Curr Diab Rep. 2006;6:310–5.

    Article  PubMed  Google Scholar 

  97. Juang JH, Hsu BRS, Kuo CH. Islet transplantation at subcutaneous and intramuscular sites. Transplant Proc. 2005;37:3479–81.

    Article  PubMed  Google Scholar 

  98. Kemp CB, Knight MJ, Scharp DW, et al. Effect of transplantation site on the results of pancreatic islet isografts in diabetic rats. Diabetologia. 1973;9:486–91.

    Article  PubMed  CAS  Google Scholar 

  99. Juang JH, Bonner-Weir S, Ogawa Y, et al. Outcome of subcutaneous islet transplantation improved by polymer device. Transplantation. 1996;61:1557–61.

    Article  PubMed  CAS  Google Scholar 

  100. Kawakami Y, Iwata H, Gu Y, et al. Modified subcutaneous tissue with neovascularization is useful as the site for pancreatic islet transplantation. Cell Transplant. 2000;9:729–32.

    PubMed  CAS  Google Scholar 

  101. Stendahl JC, Wang LJ, Chow LW, et al. Growth factor delivery from self-assembling nanofibers to facilitate islet transplantation. Transplantation. 2008;86:478–81.

    Article  PubMed  CAS  Google Scholar 

  102. Su J, Hu BH, Lowe WL, et al. Anti-inflammatory peptide-functionalized hydrogels for insulin-secreting cell encapsulation. Biomaterials. 2010;31:308–14.

    Article  PubMed  CAS  Google Scholar 

  103. Pileggi A, Molano RD, Ricordi C, et al. Reversal of diabetes by pancreatic islet transplantation into a subcutaneous, neovascularized device. Transplantation. 2006;81:1318–24.

    Article  PubMed  Google Scholar 

  104. Ashcroft Frances M, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell. 2012;148:1160–71.

    Article  PubMed  CAS  Google Scholar 

  105. Jiang R, Han Z, Zhuo G, et al. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Front Med. 2011;5:94–100.

    Article  PubMed  Google Scholar 

  106. Estrada EJ, Valacchi F, Nicora E, et al. Combined treatment of intrapancreatic autologous bone marrow stem cells and hyperbaric oxygen in type 2 diabetes mellitus. Cell Transplant. 2008;17:1295–304.

    Article  PubMed  Google Scholar 

  107. Zisman A, Peroni OD, Abel ED, et al. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med. 2000;6:924–8.

    Article  PubMed  CAS  Google Scholar 

  108. Bernardo ME, Zaffaroni N, Novara F, et al. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007;67:9142–9.

    Article  PubMed  CAS  Google Scholar 

  109. Rubio D, Garcia S, Paz MF, et al. Molecular characterization of spontaneous esenchymal stem cell transformation. PLoS One. 2008;3:e1398.

    Article  PubMed  CAS  Google Scholar 

  110. Wang M, Yang Y, Yang D, et al. The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro. Immunology. 2009;126:220–32.

    Article  PubMed  CAS  Google Scholar 

  111. Kang JW, Kang KS, Koo HC, et al. Soluble factors-mediated immunomodulatory effects of canine adipose tissue-derived mesenchymal stem cells. Stem Cells Dev. 2008;17:681–93.

    Article  PubMed  CAS  Google Scholar 

  112. • Veriter S, Aouassar N, Adnet PY, et al. The impact of hyperglycemia and the presence of encapsulated islets on oxygenation within a bioartificial pancreas in the presence of mesenchymal stem cells in a diabetic wistar rat model. Biomaterials. 2011;32:5945–56. This study shows how MSCs and biomaterials have been used synergistically to improve islet engraftment and compares the ability of bone marrow-derived versus adipose tissue-derived MSCs to potentiate oxygenation of encapsulated islets in a bioartificial pancreas.

    PubMed  CAS  Google Scholar 

Download references

Disclosure

Conflicts of interest: N.E. Davis: has received a training grant (NIH/NIBIB (R01EB003806); D. Hamilton: none; M.J. Fontaine: has received grant support from Stanford BioX Interdisciplinary Program.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Magali J. Fontaine.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davis, N.E., Hamilton, D. & Fontaine, M.J. Harnessing the Immunomodulatory and Tissue Repair Properties of Mesenchymal Stem Cells to Restore β Cell Function. Curr Diab Rep 12, 612–622 (2012). https://doi.org/10.1007/s11892-012-0305-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-012-0305-4

Keywords

Navigation