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International Journal of Endocrinology
Volume 2012 (2012), Article ID 296485, 9 pages
http://dx.doi.org/10.1155/2012/296485
Review Article

Genetically Engineered Islets and Alternative Sources of Insulin-Producing Cells for Treating Autoimmune Diabetes: Quo Vadis?

1Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Neihu, Taipei 114, Taiwan
2Department of General Surgery, Tri-Service General Hospital, Taipei 114, Taiwan

Received 22 October 2011; Accepted 29 March 2012

Academic Editor: Subbiah Pugazhenthi

Copyright © 2012 Feng-Cheng Chou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. K. M. Gillespie, “Type 1 diabetes: pathogenesis and prevention,” Canadian Medical Association Journal, vol. 175, no. 2, pp. 165–170, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. M. Karvonen, M. Viik-Kajander, E. Moltchanova, I. Libman, R. LaPorte, and J. Tuomilehto, “Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (diamond) project group,” Diabetes Care, vol. 23, no. 10, pp. 1516–1526, 2000. View at Scopus
  3. C. C. Patterson, G. Dahlquist, G. Soltesz, and A. Green, “Variation and trends in incidence of childhood diabetes in Europe. Eurodiab ace study group,” The Lancet, vol. 355, no. 9207, pp. 873–876, 2000. View at Publisher · View at Google Scholar · View at Scopus
  4. V. Harjutsalo, L. Sjöberg, and J. Tuomilehto, “Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study,” The Lancet, vol. 371, no. 9626, pp. 1777–1782, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. H. Shamoon, H. Duffy, N. Fleischer et al., “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus,” The New England Journal of Medicine, vol. 329, no. 14, pp. 977–986, 1993. View at Publisher · View at Google Scholar · View at Scopus
  6. D. M. Nathan, P. A. Cleary, J. Y. C. Backlund et al., “Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes,” The New England Journal of Medicine, vol. 353, no. 25, pp. 2643–2653, 2005. View at Publisher · View at Google Scholar · View at Scopus
  7. S. A. White, J. A. Shaw, and D. E. Sutherland, “Pancreas transplantation,” The Lancet, vol. 373, no. 9677, pp. 1808–1817, 2009. View at Publisher · View at Google Scholar · View at Scopus
  8. T. Berney and P. R. Johnson, “Donor pancreata: evolving approaches to organ allocation for whole pancreas versus islet transplantation,” Transplantation, vol. 90, no. 3, pp. 238–243, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. R. Bottino, A. N. Balamurugan, H. Tse et al., “Response of human islets to isolation stress and the effect of antioxidant treatment,” Diabetes, vol. 53, no. 10, pp. 2559–2568, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Abdelli, J. Ansite, R. Roduit et al., “Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure,” Diabetes, vol. 53, no. 11, pp. 2815–2823, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. R. Abdi, T. K. Means, and A. D. Luster, “Chemokines in islet allograft rejection,” Diabetes/Metabolism Research and Reviews, vol. 19, no. 3, pp. 186–190, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. P. J. O'Connell, A. Pacheco-Silva, P. W. Nickerson et al., “Unmodified pancreatic islet allograft rejection results in the preferential expression of certain T cell activation transcripts,” Journal of Immunology, vol. 150, no. 3, pp. 1093–1104, 1993. View at Scopus
  13. T. B. Strom, P. Roy-Chaudhury, R. Manfro et al., “The Th1/Th2 paradigm and the allograft response,” Current Opinion in Immunology, vol. 8, no. 5, pp. 688–693, 1996. View at Publisher · View at Google Scholar · View at Scopus
  14. P. T. Walsh, T. B. Strom, and L. A. Turka, “Routes to transplant tolerance versus rejection: the role of cytokines,” Immunity, vol. 20, no. 2, pp. 121–131, 2004. View at Publisher · View at Google Scholar · View at Scopus
  15. W. Suarez-Pinzon, R. V. Rajotte, T. R. Mosmann, and A. Rabinovitch, “Both CD4+ and CD8+ T-cells in syngeneic islet grafts in NOD mice produce interferon-γ during β-cell destruction,” Diabetes, vol. 45, no. 10, pp. 1350–1357, 1996. View at Scopus
  16. X. C. Li, P. Roy-Chaudhury, W. W. Hancock et al., “IL-2 and IL-4 double knockout mice reject islet allografts: a role for novel T cell growth factors in allograft rejection,” Journal of Immunology, vol. 161, no. 2, pp. 890–896, 1998. View at Scopus
  17. D. A. Rao, R. E. Eid, L. Qin et al., “Interleukin (IL)-1 promotes allogeneic T cell intimal infiltration and IL-17 production in a model of human artery rejection,” Journal of Experimental Medicine, vol. 205, no. 13, pp. 3145–3158, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. X. Yuan, J. Paez-Cortez, I. Schmitt-Knosalla et al., “A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy,” Journal of Experimental Medicine, vol. 205, no. 13, pp. 3133–3144, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. L. Chen, E. Ahmed, T. Wang et al., “TLR Signals promote IL-6/IL-17-dependent transplant rejection,” Journal of Immunology, vol. 182, no. 10, pp. 6217–6225, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. Y. P. Chuang, C. H. Chu, and H. K. Sytwu, “Genetic manipulation of islet cells in autoimmune diabetes: from bench to bedside,” Frontiers in Bioscience, vol. 13, pp. 6155–6169, 2008. View at Scopus
  21. R. Mueller, T. Krahl, and N. Sarvetnick, “Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice,” Journal of Experimental Medicine, vol. 184, no. 3, pp. 1093–1099, 1996. View at Scopus
  22. I. S. Grewal, K. D. Grewal, F. S. Wong et al., “Expression of transgene encoded TGF-β in islets prevents autoimmune diabetes in NOD mice by a local mechanism,” Journal of Autoimmunity, vol. 19, no. 1-2, pp. 9–22, 2002. View at Publisher · View at Google Scholar · View at Scopus
  23. M. S. Lee, S. Sawyer, M. Arnush et al., “Transforming growth factor-β fails to inhibit allograft rejection or virus-induced autoimmune diabetes in transgenic mice,” Transplantation, vol. 61, no. 7, pp. 1112–1115, 1996. View at Scopus
  24. M. Moritani, K. Yoshimoto, S. F. Wong et al., “Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-β1,” The Journal of Clinical Investigation, vol. 102, no. 3, pp. 499–506, 1998. View at Scopus
  25. I. S. Grewal, K. D. Grewal, F. S. Wong, D. E. Picarella, C. A. Janeway, and R. A. Flavell, “Local expression of transgene encoded TNFα in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells,” Journal of Experimental Medicine, vol. 184, no. 5, pp. 1963–1974, 1996. View at Scopus
  26. M. Solomon, M. Flodström-Tullberg, and N. Sarvetnick, “Differences in suppressor of cytokine signaling-1 (SOCS-1) expressing islet allograft destruction in normal BALB/c and spontaneously-diabetic NOD recipient mice,” Transplantation, vol. 79, no. 9, pp. 1104–1109, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. C. J. Wang, F. C. Chou, C. H. Chu et al., “Protective role of programmed death 1 ligand 1 (PD-L1) in nonobese diabetic mice: the paradox in transgenic models,” Diabetes, vol. 57, no. 7, pp. 1861–1869, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. J. Yantha, H. Tsui, S. Winer et al., “Unexpected acceleration of type 1 diabetes by transgenic expression of B7-H1 in NOD mouse peri-islet glia,” Diabetes, vol. 59, no. 10, pp. 2588–2596, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. S. K. Subudhi, P. Zhou, L. M. Yerian et al., “Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection,” The Journal of Clinical Investigation, vol. 113, no. 5, pp. 694–700, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. S. J. Shieh, F. C. Chou, P. N. Yu et al., “Transgenic expression of single-chain anti-CTLA-4 Fv on β cells protects nonobese diabetic mice from autoimmune diabetes,” Journal of Immunology, vol. 183, no. 4, pp. 2277–2285, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. R. M. Sutherland, J. L. Brady, H. M. Georgiou, H. E. Thomas, and A. M. Lew, “Protective effect of CTLA4Ig secreted by transgenic fetal pancreas allografts,” Transplantation, vol. 69, no. 9, pp. 1806–1812, 2000. View at Scopus
  32. M. Hotta, F. Tashiro, H. Ikegami et al., “Pancreatic β cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes,” Journal of Experimental Medicine, vol. 188, no. 8, pp. 1445–1451, 1998. View at Publisher · View at Google Scholar · View at Scopus
  33. S. H. Huang, C. H. Chu, J. C. Yu et al., “Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation,” Diabetologia, vol. 53, no. 11, pp. 2389–2400, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. H. H. Sung, J. H. Juang, Y. C. Lin et al., “Transgenic expression of decoy receptor 3 protects islets from spontaneous and chemical-induced autoimmune destruction in nonobese diabetic mice,” Journal of Experimental Medicine, vol. 199, no. 8, pp. 1143–1151, 2004. View at Publisher · View at Google Scholar · View at Scopus
  35. G. J. Lin, S. H. Huang, Y. W. Chen et al., “Transgenic expression of murine chemokine decoy receptor D6 by islets reveals the role of inflammatory CC chemokines in the development of autoimmune diabetes in NOD mice,” Diabetologia, vol. 54, no. 7, pp. 1777–1787, 2011. View at Publisher · View at Google Scholar · View at Scopus
  36. B. T. Fife and J. A. Bluestone, “Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways,” Immunological Reviews, vol. 224, no. 1, pp. 166–182, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. A. Amrani, J. Verdaguer, S. Thiessen, B. Sonny, and P. Santamaria, “IL-1α, IL-1β, and IFN-γ mark β cells for Fas-dependent destruction by diabetogenic CD4+ T lymphocytes,” The Journal of Clinical Investigation, vol. 105, no. 4, pp. 459–468, 2000. View at Scopus
  38. S. Lenzen, J. Drinkgern, and M. Tiedge, “Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues,” Free Radical Biology and Medicine, vol. 20, no. 3, pp. 463–466, 1996. View at Publisher · View at Google Scholar · View at Scopus
  39. X. G. Lei and M. Z. Vatamaniuk, “Two tales of antioxidant enzymes on β cells and diabetes,” Antioxidants and Redox Signaling, vol. 14, no. 3, pp. 489–503, 2011. View at Publisher · View at Google Scholar · View at Scopus
  40. T. B. Mysore, T. A. Shinkel, J. Collins et al., “Overexpression of glutathione peroxidase with two isoforms of superoxide dismutase protects mouse islets from oxidative injury and improves islet graft function,” Diabetes, vol. 54, no. 7, pp. 2109–2116, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. H. Chen, X. Li, and P. N. Epstein, “MnSOD and catalase transgenes demonstrate that protection of islets from oxidative stress does not alter cytokine toxicity,” Diabetes, vol. 54, no. 5, pp. 1437–1446, 2005. View at Publisher · View at Google Scholar · View at Scopus
  42. B. Xu, J. T. Moritz, and P. N. Epstein, “Overexpression of catalase provides partial protection to transgenic mouse beta cells,” Free Radical Biology and Medicine, vol. 27, no. 7-8, pp. 830–837, 1999. View at Publisher · View at Google Scholar · View at Scopus
  43. X. Li, H. Chen, and P. N. Epstein, “Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species,” The Journal of Biological Chemistry, vol. 279, no. 1, pp. 765–771, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. R. Bottino, P. Lemarchand, M. Trucco, and N. Giannoukakis, “Gene- and cell-based therapeutics for type I diabetes mellitus,” Gene Therapy, vol. 10, no. 10, pp. 875–889, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. A. L. Gainer, G. S. Korbutt, R. V. Rajotte, G. L. Warnock, and J. F. Elliott, “Expression of CTLA4-Ig by biolistically transfected mouse islets promotes islet allograft survival,” Transplantation, vol. 63, no. 7, pp. 1017–1021, 1997. View at Publisher · View at Google Scholar · View at Scopus
  46. J. R. Fernandes, V. F. Duvivier-Kali, M. Keegan et al., “Transplantation of islets transduced with CTLA4-Ig and TGFβ using adenovirus and lentivirus vectors,” Transplant Immunology, vol. 13, no. 3, pp. 191–200, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. J. L. Contreras, G. Bilbao, C. A. Smyth et al., “Cytoprotection of pancreatic islets before and soon after transplantation by gene transfer of the anti-apoptotic Bcl-2 gene,” Transplantation, vol. 71, no. 8, pp. 1015–1023, 2001. View at Scopus
  48. F. C. Chou and H. K. Sytwu, “Overexpression of thioredoxin in islets transduced by a lentiviral vector prolongs graft survival in autoimmune diabetic NOD mice,” Journal of Biomedical Science, vol. 16, no. 1, article 71, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. S. Bertera, M. L. Crawford, A. M. Alexander et al., “Gene transfer of manganese superoxide dismutase extends islet graft function in a mouse model of autoimmune diabetes,” Diabetes, vol. 52, no. 2, pp. 387–393, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. N. Giannoukakis, W. A. Rudert, S. C. Ghivizzani et al., “Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-lβ-induced β-cell impairment and activation of islet cell apoptosis in vitro,” Diabetes, vol. 48, no. 9, pp. 1730–1736, 1999. View at Publisher · View at Google Scholar · View at Scopus
  51. W. L. Suarez-Pinzon, Y. Marcoux, A. Ghahary, and A. Rabinovitch, “Gene transfection and expression of transforming growth factor-β1 in nonobese diabetic mouse islets protects β-cells in syngeneic islet grafts from autoimmune destruction,” Cell Transplantation, vol. 11, no. 6, pp. 519–528, 2002. View at Scopus
  52. Y. C. Zhang, A. Pileggi, A. Agarwal et al., “Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice,” Diabetes, vol. 52, no. 3, pp. 708–716, 2003. View at Publisher · View at Google Scholar · View at Scopus
  53. W. S. Gallichan, T. Kafri, T. Krahl, I. M. Verma, and N. Sarvetnick, “Lentivirus-mediated transduction of islet grafts with interleukin 4 results in sustained gene expression and protection from insulitis,” Human Gene Therapy, vol. 9, no. 18, pp. 2717–2726, 1998. View at Scopus
  54. P. Wang, M. V. Yigit, Z. Medarova et al., “Combined small interfering RNA therapy and in vivo magnetic resonance imaging in islet transplantation,” Diabetes, vol. 60, no. 2, pp. 565–571, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. A. Plesner, G. Soukhatcheva, R. G. Korneluk, and C. B. Verchere, “XIAP inhibition of β-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model,” Islets, vol. 2, no. 1, pp. 18–23, 2010. View at Scopus
  56. H. Dellê and I. L. Noronha, “Induction of indoleamine 2,3-dioxygenase by gene delivery in allogeneic islets prolongs allograft survival,” American Journal of Transplantation, vol. 10, no. 8, pp. 1918–1924, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. Y. H. Kim, D. G. Lim, Y. M. Wee et al., “Viral IL-10 gene transfer prolongs rat islet allograft survival,” Cell Transplantation, vol. 17, no. 6, pp. 609–618, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. C. Aguayo-Mazzucato and S. Bonner-Weir, “Stem cell therapy for type 1 diabetes mellitus,” Nature Reviews Endocrinology, vol. 6, no. 3, pp. 139–148, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. L. Baeyens, S. De Breuck, J. Lardon, J. K. Mfopou, I. Rooman, and L. Bouwens, “In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells,” Diabetologia, vol. 48, no. 1, pp. 49–57, 2005. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Zalzman, S. Gupta, R. K. Giri et al., “Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 12, pp. 7253–7258, 2003. View at Publisher · View at Google Scholar · View at Scopus
  61. T. Sapir, K. Shternhall, I. Meivar-Levy et al., “Cell-replacement therapy for diabetes: generating functional insulin-producing tissue from adult human liver cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 22, pp. 7964–7969, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. V. K. Ramiya, M. Maraist, K. E. Arfors, D. A. Schatz, A. B. Peck, and J. G. Cornelius, “Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells,” Nature Medicine, vol. 6, no. 3, pp. 278–282, 2000. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Zalzman, L. Anker-Kitai, and S. Efrat, “Differentiation of human liver-derived, insulin-producing cells toward the β-cell phenotype,” Diabetes, vol. 54, no. 9, pp. 2568–2575, 2005. View at Publisher · View at Google Scholar · View at Scopus
  64. N. Lumelsky, O. Blondel, P. Laeng, I. Velasco, R. Ravin, and R. McKay, “Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets,” Science, vol. 292, no. 5520, pp. 1389–1394, 2001. View at Publisher · View at Google Scholar · View at Scopus
  65. Y. Hori, I. C. Rulifson, B. C. Tsai, J. J. Heit, J. D. Cahoy, and S. K. Kim, “Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 25, pp. 16105–16110, 2002. View at Publisher · View at Google Scholar · View at Scopus
  66. J. Rajagopal, W. J. Anderson, S. Kume, O. I. Martinez, and D. A. Melton, “Insulin staining of ES cell progeny from insulin uptake,” Science, vol. 299, no. 5605, article 363, 2003. View at Publisher · View at Google Scholar · View at Scopus
  67. E. Kroon, L. A. Martinson, K. Kadoya et al., “Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo,” Nature Biotechnology, vol. 26, no. 4, pp. 443–452, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. K. C. Chao, K. F. Chao, Y. S. Fu, and S. H. Liu, “Islet-like clusters derived from mesenchymal stem cells in Wharton's jelly of the human umbilical cord for transplantation to control type 1 diabetes,” Public Library of Science ONE, vol. 3, no. 1, Article ID e1451, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. V. Sordi and L. Piemonti, “Mesenchymal stem cells as feeder cells for pancreatic islet transplants,” The Review of Diabetic Studies, vol. 7, no. 2, pp. 132–143, 2010. View at Scopus
  70. T. Ito, S. Itakura, I. Todorov et al., “Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function,” Transplantation, vol. 89, no. 12, pp. 1438–1445, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Figliuzzi, R. Cornolti, N. Perico et al., “Bone marrow-derived mesenchymal stem cells improve islet graft function in diabetic rats,” Transplantation Proceedings, vol. 41, no. 5, pp. 1797–1800, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. Y. Ding, A. Bushell, and K. J. Wood, “Mesenchymal stem-cell immunosuppressive capabilities: therapeutic implications in islet transplantation,” Transplantation, vol. 89, no. 3, pp. 270–273, 2010. View at Publisher · View at Google Scholar · View at Scopus
  73. K. Takahashi and S. Yamanaka, “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors,” Cell, vol. 126, no. 4, pp. 663–676, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. K. Tateishi, J. He, O. Taranova, G. Liang, A. C. D'Alessio, and Y. Zhang, “Generation of insulin-secreting islet-like clusters from human skin fibroblasts,” The Journal of Biological Chemistry, vol. 283, no. 46, pp. 31601–31607, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. R. Maehr, S. Chen, M. Snitow et al., “Generation of pluripotent stem cells from patients with type 1 diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 37, pp. 15768–15773, 2009. View at Publisher · View at Google Scholar · View at Scopus
  76. Z. Alipio, W. Liao, E. J. Roemer et al., “Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic β-like cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 30, pp. 13426–13431, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. T. Zhao, Z. N. Zhang, Z. Rong, and Y. Xu, “Immunogenicity of induced pluripotent stem cells,” Nature, vol. 474, no. 7350, pp. 212–215, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. K. Kim, A. Doi, B. Wen et al., “Epigenetic memory in induced pluripotent stem cells,” Nature, vol. 467, no. 7313, pp. 285–290, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. A. M. Shapiro, J. R. Lakey, E. A. Ryan et al., “Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen,” The New England Journal of Medicine, vol. 343, no. 4, pp. 230–238, 2000. View at Publisher · View at Google Scholar · View at Scopus
  80. A. M. Shapiro, C. Ricordi, B. J. Hering et al., “International trial of the edmonton protocol for islet transplantation,” The New England Journal of Medicine, vol. 355, no. 13, pp. 1318–1330, 2006. View at Publisher · View at Google Scholar · View at Scopus