Stem cell therapy to cure type 1 diabetes: From hype to hope

Stem Cells Translational Medicine

Volumn 2, Issue 5, 2013, Pages 328-336

  Chhabra, Preeti ^a   Brayman, Kenneth L ^a  

^a UNIVERSITY OF VIRGINIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; CORTICOSTEROID; CYCLOPHOSPHAMIDE; FLUDARABINE; HLA ANTIGEN; IMMUNOSUPPRESSIVE AGENT; INSULIN; MESSENGER RNA; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; TACROLIMUS;

APOPTOSIS; ARTICLE; AUTOIMMUNITY; BIOENGINEERING; BONE MARROW TRANSPLANTATION; CELL DESTRUCTION; CELL PROLIFERATION; CELL REGENERATION; EMBRYONIC STEM CELL; GENETIC PREDISPOSITION; GLUCOSE BLOOD LEVEL; GRAFT SURVIVAL; HOMEOSTASIS; HUMAN; HYPERGLYCEMIA; IMMUNOMODULATION; IMMUNOPATHOGENESIS; IMMUNOSUPPRESSIVE TREATMENT; INSULIN DEPENDENT DIABETES MELLITUS; MESENCHYMAL STROMA CELL; NEPHROTOXICITY; NONHUMAN; PANCREAS ISLET TRANSPLANTATION; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RISK FACTOR; STEM CELL TRANSPLANTATION; STREPTOZOCIN DIABETES; TISSUE REPAIR; VIRAL GENE DELIVERY SYSTEM;

EID: 84877673917     PISSN: 21576564     EISSN: 21576580     Source Type: Journal    
DOI: 10.5966/sctm.2012-0116     Document Type: Article

References (120)

1. van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: Etiology, immunology, and therapeutic strategies. Physiol Rev 2011; 91:79-118.
2. Eisenbarth GS. Type I diabetes mellitus: A chronic autoimmune disease. N Engl J Med 1986;314:1360-1368.
3. Sherry NA, Tsai EB, Herold KC. Natural history of beta-cell function in type 1 diabetes. Diabetes 2005;54:S32-S39.
4. Tsai EB, Sherry NA, Palmer JP et al. The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia 2006;49:261-270.
5. Tooley JE, Waldron-Lynch F, Herold KC. New and future immunomodulatory therapy in type 1 diabetes. Trends Mol Med 2012;18: 173-181.
6. Atkinson MA, Bluestone JA, Eisenbarth GS et al. How does type 1 diabetes develop?: The notion of homicide or Β-cell suicide revisited. Diabetes 2011;60:1370-1379.
7. Chhabra P, Brayman KL. Current status of immunomodulatory and cellular therapies in preclinical and clinical islet transplantation. J Transplant 2011;2011:637692.
8. Eisenbarth GS. Prevention of type 1A diabetes. Endocr Pract 2012;18:745-749.
9. Waldron-Lynch F, Herold KC. Immunomodulatory therapy to preserve pancreatic Β-cell function in type 1 diabetes. Nat Rev Drug Discov 2011;10:439-452.
10. Yoon JW, Jun HS, Santamaria P. Cellular and molecular mechanisms for the initiation and progression of beta cell destruction resulting from the collaboration between macrophages and T cells. Autoimmunity 1998;27: 109-122.
11. Eizirik DL, Colli ML, Ortis F. The role of inflammation in insulitis and Β-cell loss in type 1 diabetes. Nat Rev Endocrinol 2009;5:219-226.
12. Honkanen J, Nieminen JK, Gao R et al. IL-17 immunity in human type 1 diabetes. J Immunol 2010;185:1959-1967.
13. Cabrera SM, Rigby MR, Mirmira RG. Targeting regulatory T cells in the treatment of type 1 diabetes mellitus. Curr Mol Med 2012; 12:1261-1272.
14. GruessnerAC,SutherlandDE,GruessnerRW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant 2012;17:100-105.
15. Jamiolkowski RM, Guo LY, Li YR et al. Islet transplantation in type I diabetes mellitus. Yale J Biol Med 2012;85:37-43.
16. Huang X, Moore DJ, Ketchum RJ et al. Resolving the conundrum of islet transplantation by linking metabolic dysregulation, inflammation, and immune regulation. Endocr Rev 2008;29:603-630.
17. Chhabra P, Kensinger CD, Moore DJ et al. Present accomplishments and future prospects of cell-based therapies for type 1 diabetes mellitus. In: Wagner D, ed. Type 1 Diabetes: Pathogenesis, Genetics and Immunotherapy. Rijeka, Croatia: In Tech Open Access, 2011: 295-336.
18. Weir GC, Cavelti-Weder C, Bonner-Weir S. Stem cell approaches for diabetes: Towards beta cell replacement. Genome Med 2011;3: 61.
19. Granger A, Kushner JA. Cellular origins of beta-cell regeneration: A legacy view of historical controversies. J Intern Med 2009;266:325-338.
20. Fiorina P, Voltarelli J, Zavazava N. Immunological applications of stem cells in type 1 diabetes. Endocr Rev 2011;32:725-754.
21. Barcala Tabarrozzi AE, Castro CN, Dewey RA, Cell-based interventions to halt autoimmunity in type 1 diabetes mellitus. Clin Exp Immunol 2013;171:135-146.
22. Fändrich F, Ungefroren H. Customized cell-based treatment options to combat autoimmunity and restore beta-cell function in type 1 diabetes mellitus: Current protocols and future perspectives. Adv Exp Med Biol 2010;654: 641-665.
23. Sims E, Evans-Molina C. Stem cells as a tool to improve outcomes of islet transplantation. J Transplant 2012;2012:736491.
24. Madec AM, Mallone R, Afonso G et al. Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 2009;52:1391-1399.
25. Jurewicz M, Yang S, Augello A et al. Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes. Diabetes 2010;59:3139-3147.
26. Rackham CL, Chagastelles PC, Nardi NB et al. Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. Diabetologia 2011;54:1127-1135.
27. Furth ME, Atala A. Stem cell sources to treat diabetes. J Cell Biochem 2009;106:507-511.
28. Mfopou JK, Chen B, Sui L et al. Recent advances and prospects in the differentiation of pancreatic cells from human embryonic stem cells. Diabetes 2010;59:2094-2101.
29. Kroon E, Martinson LA, Kadoya K et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008;26:443-452.
30. Bose B, Shenoy PS, Konda S et al. Human embryonic stem cell differentiation into insulin secreting Β-cells for diabetes. Cell Biol Int 2012;36:1013-1020.
31. Lysy PA, Weir GC, Bonner-Weir S. Concise review: Pancreas regeneration: Recent advances and perspectives. STEM CELLS TRANSLA- TIONAL MEDICINE 2012;1:150-159.
32. Wang P, Rodriguez RT, Wang J et al. Targeting SOX17 in human embryonic stem cells creates unique strategies for isolating and analyzing developing endoderm. Cell Stem Cell 2011;8:335-346.
33. Kahan B, Magliocca J, Merriam F et al. Elimination of tumorigenic stem cells from differentiated progeny and selection of definitive endoderm reveals a Pdx1+ foregut endoderm stem cell lineage. Stem Cell Res 2011;6:143- 157.
34. Jiang W, Sui X, Zhang D et al. CD24: A novel surface marker for PDX1-positive pancreatic progenitors derived from human embryonic stem cells. STEM CELLS 2011;29:609-617.
35. Kelly OG, Chan MY, Martinson LA et al. Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol 2011;29:750-756.
36. Rezania A, Bruin JE, Riedel MJ et al. Maturation of human embryonic stem cell derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 2012;61:2016-2029.
37. Schulz TC, Young HY, Agulnick AD et al. A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PLoS One 2012;7:e37004.
38. O'Sullivan ES, Vegas A, Anderson DG et al. Islets transplanted in immunoisolation devices: A review of the progress and the challenges that remain. Endocr Rev 2011;32:827-844.
39. Tuch BE, Hughes TC, Evans MD. Encapsulated pancreatic progenitors derived from human embryonic stem cells as a therapy for insulin-dependent diabetes. Diabetes Metab Res Rev 2011;27:928-932.
40. Atala A. Human embryonic stem cells: Early hints on safety and efficacy. Lancet 2012; 379:689-690.
41. Maehr R. iPS cells in type 1 diabetes research and treatment. Clin Pharmacol Ther 2011;89:750-753.
42. Hosoya M. Preparation of pancreatic Β-cells from human iPS cells with small molecules. Islets 2012;4:249-252.
43. Alipio Z, Liao W, Roemer EJ et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci USA 2010;107:13426-13431.
44. Jeon K, Lim H, Kim JH et al. Differentiation and transplantation of functional pancreatic beta cells generated from induced pluripotent stem cells derived from a type 1 diabetes mouse model. Stem Cells Dev 2012;21:2642-2655.
45. Maehr R, Chen S, Snitow M et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA 2009;106:15768-15773.
46. Jang J, Yoo JE, Lee JA et al. Disease-specific induced pluripotent stem cells: A platform for human disease modeling and drug discovery. Exp Mol Med 2012;44:202-213.
47. Mayshar Y, Ben-David U, Lavon N et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 2010;7:521-531.
48. Stadtfeld M, Nagaya M, Utikal J et al. Induced pluripotent stem cells generated without viral integration. Science 2008;322:945-949.
49. Yu J, Hu K, Smuga-Otto K et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009;324: 797-801.
50. Hiratsuka M, Uno N, Ueda K. Integrationfree iPS cells engineered using human artificial chromosome vectors. PLoS One 2011;6: e25961.
51. Kaji K, Norrby K, Paca A et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009; 458:771-775.
52. Warren L, Manos PD, Ahfeldt T et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010;7:618-630.
53. Anokye-Danso F, Trivedi CM, Juhr D et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 2011;8:376-438.
54. Jia F, Wilson KD, Sun N et al. A nonviral minicircle vector for deriving human iPS cells. Nat Methods 2010;7:197-199.
55. Zhou H, Wu S, Joo JY et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009;4:381-384.
56. Nie B, Wang H, Laurent T et al. Cellular reprogramming: A small molecule perspective. Curr Opin Cell Biol 2012;24:784-792.
57. Feng B, Ng JH, Heng JC et al. Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell 2009;4:301-312.
58. Lu J, Kong X, Luo C et al. Application of epigenome-modifying small molecules in induced pluripotent stem cells. Med Res Rev 2012 [Epub ahead of print].
59. Haque R, Lei F, Xiong X et al. Programming of regulatory T cells from pluripotent stem cells and prevention of autoimmunity. J Immunol 2012;189:1228-1236.
60. Couri CE, Oliveira MC, Stracieri AB et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2009; 301:1573-1579.
61. Snarski E, Milczarczyk A, Torosian T et al. Independence of exogenous insulin following immunoablation and stem cell reconstitution in newly diagnosed diabetes type I. Bone Marrow Transplant 2011;46:562-566.
62. Gu W, Hu J, Wang W et al. Diabetic ketoacidosis at diagnosis influences complete remission after treatment with hematopoietic stem cell transplantation in adolescents with type 1 diabetes. Diabetes Care 2012;35:1413-1419.
63. Socié G, Salooja N, Cohen A et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003;101:3373-3385.
64. Couri CE, de Oliveira MC, Simões BP. Risks, benefits, and therapeutic potential of hematopoietic stem cell transplantation for autoimmune diabetes. Curr Diab Rep 2012;12: 604-611.
65. Voltarelli JC, Couri CE, Stracieri AB et al. Autologous hematopoietic stem cell transplantation for type 1 diabetes. Ann NY Acad Sci 2008;1150:220-229.
66. Zhang C, Todorov I, Lin CL et al. Elimination of insulitis and augmentation of islet beta cell regeneration via induction of chimerism in overtly diabetic NOD mice. Proc Natl Acad Sci USA 2007;104:2337-2342.
67. Mineo D, Ricordi C, Xu X et al. Combined islet and hematopoietic stem cell allotransplantation: A clinical pilot trial to induce chimerism and graft tolerance. Am J Transplant 2008; 8:1262-1274.
68. Xu H, Zhu Z, Huang Y et al. Innate and adaptive immune responses are tolerized in chimeras prepared with nonmyeloablative conditioning. Transplantation 2012;93:469-476.
69. Wang M, Racine JJ, Song X et al. Mixed chimerism and growth factors augment Β cell regeneration and reverse late-stage type 1 diabetes. Sci Transl Med 2012;4:133ra59.
70. Leventhal J, Abecassis M, Miller J et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med 2012;4:124ra28.
71. Gabr MM, Zakaria MM, Refaie AF et al. Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice. Cell Transplant 2012 [Epub ahead of print].
72. Domínguez-Bendala J, Lanzoni G, Inverardi L et al. Concise review: Mesenchymal stem cells for diabetes. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:59-63.
73. Volarevic V, Arsenijevic N, Lukic ML et al. Concise review: Mesenchymal stem cell treatment of the complications of diabetes mellitus. STEM CELLS 2011;29:5-10.
74. Chhabra P, Mirmira RG, Brayman KL. Regenerative medicine and tissue engineering: Contribution of stem cells in organ transplantation. Curr Opin Organ Transplant 2009;14:46-50.
75. Ho JH, Tseng TC, Ma WH et al. Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and Β-cell differentiation in streptozocin-induced diabetic mice. Cell Transplant 2012;21:997-1009.
76. Abdi R, Fiorina P, Adra CN et al. Immunomodulation by mesenchymal stem cells: A potential therapeutic strategy for type 1 diabetes. Diabetes 2008;57:1759-1567.
77. Davis NE, Hamilton D, Fontaine MJ. Harnessing the immunomodulatory and tissue repair properties of mesenchymal stem cells to restore Β cell function. Curr Diab Rep 2012;12: 612-622.
78. Ezquer FE, Ezquer ME, Parrau DB et al. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant 2008;14:631-640.
79. Bell GI, Broughton HC, Levac KD et al. Transplanted human bone marrow progenitor subtypes stimulate endogenous islet regeneration and revascularization. Stem Cells Dev 2012;21:97-109.
80. 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.
81. 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 USA 2006;103:17438-17443.
82. Lee RH, Pulin AA, Seo MJ et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009;5:54-63.
83. El Haddad N, Heathcote D, Moore R et al. Mesenchymal stem cells express serine protease inhibitor to evade the host immune response. Blood 2011;117:1176-1183.
84. Yeung TY, Seeberger KL, Kin T et al. Human mesenchymal stem cells protect human islets from pro-inflammatory cytokines. PLoS One 2012;7:e38189.
85. Figliuzzi M, Cornolti R, Perico N et al. Bone marrow-derived mesenchymal stem cells improve islet graft function in diabetic rats. Transplant Proc 2009;41:1797-1800.
86. Sakata N, Goto M, Yoshimatsu G et al. Utility of co-transplanting mesenchymal stem cells in islet transplantation. World J Gastroenterol 2011;17:5150-5155.
87. Ito T, Itakura S, Todorov I et al. Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function. Transplantation 2010;89:1438-1445.
88. Fiorina P, Jurewicz M, Augello A et al. Immunomodulatory function of bone marrowderived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 2009;183:993-1004.
89. Rubio D, Garcia-Castro J, Martin MC et al. Spontaneous human adult stem cell transformation. Cancer Res 2005;65:3035-3039.
90. Miura M, Miura Y, Hesed M et al. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. STEM CELLS 2006;24: 1095-1103.
91. Tolar J, Nauta AJ, Osborn MJ et al. Sarcoma derived from cultured mesenchymal stem cells. STEM CELLS 2007;25:371-379.
92. Djouad F, Plence P, Bony C et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003;102:3837-3844.
93. De Miguel MP, Fuentes-Julián S, Blázquez-Martínez A et al. Immunosuppressive properties of mesenchymal stem cells: Advances and applications. Curr Mol Med 2012; 12:574-591.
94. Han Z, Jing Y, Zhang S, The role of immunosuppression of mesenchymal stem cells in tissue repair and tumor growth. Cell Biosci 2012;2:8.
95. Hung SC, Deng WP, Yang WK et al. Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging. Clin Cancer Res 2005;11: 7749-7756.
96. Zhu W, Xu W, Jiang R et al. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol 2006; 80:267-274.
97. Suzuki K, Sun R, Origuchi M. Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization. Mol Med 2011;17:579-587.
98. Huang XP, Sun Z, Miyagi Y et al. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their longterm benefits for myocardial repair. Circulation 2010;122:2419-2429.
99. Eliopoulos N, Stagg J, Lejeune L et al. Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood 2005;106:4057-4065.
100. Sun Y, Chen L, Hou XG et al. Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin producing cells in vitro. Chin Med J 2007;120: 771-776.
101. Phadnis SM, Ghaskadbi SM, Hardikar AA et al. Mesenchymal stem cells derived from bone marrow of diabetic patients portrait unique markers influenced by the diabetic microenvironment. Rev Diabet Stud 2009;6:260-270.
102. Madhira SL, Challa SS, Chalasani M et al. Promise(s) of mesenchymal stem cells as an in vitro model system to depict pre-diabetic/diabetic milieu in WNIN/GR-Ob mutant rats. PLoS One 2012;7:e48061.
103. Shin L, Peterson DA. Impaired therapeutic capacity of autologous stem cells in a model of type 2 diabetes. STEM CELLS TRANSLA- TIONAL MEDICINE 2012;1:125-135.
104. Kume S, Kato S, Yamagishi S et al. Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone. J Bone Miner Res 2005;20: 1647-1658.
105. Mizuno H, Tobita M, Uysal AC. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine. STEM CELLS 2012;30:804-810.
106. Gir P, Oni G, Brown SA et al. Human adipose stem cells: Current clinical applications. Plast Reconstr Surg 2012;129:1277-1290.
107. Bassi EJ, Moraes-Vieira PM, Moreira-Sá CS et al. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes. Diabetes 2012;61:2534-2545.
108. Fan CG, Zhang QJ, Zhou JR. Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Stem Cell Rev 2011;7:195-207.
109. Zhao Y, Jiang Z, Zhao T et al. Reversal of type 1 diabetes via islet Β cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Med 2012; 10:3.
110. Zhao Y, Mazzone T. Human cord blood stem cells and the journey to a cure for type 1 diabetes. Autoimmun Rev 2010;10:103-107.
111. Chandra V, Swetha G, Muthyala S et al. Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice. PLoS One 2011;6:e20615.
112. Okura H, Komoda H, Fumimoto Y et al. Transdifferentiation of human adipose tissuederived stromal cells into insulin-producing clusters. J Artif Organs 2009;12:123-130.
113. Ohmura Y, Tanemura M, Kawaguchi N et al. Combined transplantation of pancreatic islets and adipose tissue-derived stem cells enhances the survival and insulin function of islet grafts in diabetic mice. Transplantation 2010; 90:1366-1373.
114. Cavallari G, Olivi E, Bianchi F et al. Mesenchymal stem cells and islet co-transplantation in diabetic rats: Improved islet graft revascularization and function by human adipose tissue-derived stem cells preconditioned with natural molecules. Cell Transplant 2012;21: 2771-2781.
115. Vanikar AV, Dave SD, Thakkar UG et al. Cotransplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: A novel therapy for insulin-dependent diabetes mellitus. Stem Cells Int 2010;2010:582382.
116. Mayani H. Umbilical cord blood: Lessons learned and lingering challenges after more than 20 years of basic and clinical research. Arch Med Res 2011;42:645-651.
117. Prabakar KR, Domínguez-Bendala J, Molano RD et al. Generation of glucose-responsive, insulin-producing cells from human umbilical cord blood-derived mesenchymal stem cells. Cell Transplant 2012;21:1321-1339.
118. Phuc PV, Nhung TH, Loan DT et al. Differentiating of banked human umbilical cord blood-derived mesenchymal stem cells into insulin-secreting cells. In Vitro Cell Dev Biol Anim 2011;47:54-63.
119. Forraz N, McGuckin CP. The umbilical cord: A rich and ethical stem cell source to ad vance regenerative medicine. Cell Prolif 2011; 44:60-69.
120. Hu J, Yu X, Wang Z et al. Long term effects of the implantation of Wharton's jelly-derived mesenchymal stem cells from the umbilical cord for newly onset type 1 diabetes mellitus. Endocr J 2012 [Epub ahead of print].