New Advances in Stem Cell Therapy for Diabetes Mellitus

Part of the Stem Cells in Clinical Applications book series (SCCA)


Intense research aimed to find solutions for the cure of diabetes mellitus, based on stem cell therapy to replace hypoglycemic drug or insulin administration, has been conducted over the past decades. A variety of stem cells, including induced pluripotent stem cells, embryonic stem cells, or adult stem cells such as bone marrow-, adipose tissue-, and Wharton jelly-derived stem cells, have demonstrated their ability to differentiate into insulin-producing cells and secret insulin in response to high-glucose stimulation. However, achievement of the final goal for routinely clinical application of stem cell therapy is still out of reach. In this chapter, new advances in stem cell therapy for diabetes mellitus were reviewed and discussed in attempt to clarify where we are and how we may go to reach the final goal of the cure of diabetes mellitus.


Diabetes mellitus Stem cells Therapy Insulin Beta cells 


  1. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH (2008) Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 57(7):1759–1767PubMedPubMedCentralCrossRefGoogle Scholar
  2. Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC et al (2010) Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci U S A 107(30):13426–13431PubMedPubMedCentralCrossRefGoogle Scholar
  3. American Diabetes A (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34(Suppl 1):S62–S69CrossRefGoogle Scholar
  4. Anzalone R, Lo Iacono M, Loria T, Di Stefano A, Giannuzzi P, Farina F et al (2011) Wharton’s jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes. Stem Cell Rev 7(2):342–363PubMedCrossRefGoogle Scholar
  5. Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K et al (2008) Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321(5889):699–702PubMedCrossRefGoogle Scholar
  6. Baksh D, Yao R, Tuan RS (2007) Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 25(6):1384–1392PubMedCrossRefGoogle Scholar
  7. Bar-Nur O, Russ HA, Efrat S, Benvenisty N (2011) Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9(1):17–23PubMedCrossRefGoogle Scholar
  8. Bassi EJ, Moraes-Vieira PM, Moreira-Sa CS, Almeida DC, Vieira LM, Cunha CS et al (2012) Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes. Diabetes 61(10):2534–2545PubMedPubMedCentralCrossRefGoogle Scholar
  9. Ber I, Shternhall K, Perl S, Ohanuna Z, Goldberg I, Barshack I et al (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. J Biol Chem 278(34):31950–31957PubMedCrossRefGoogle Scholar
  10. Blum B, Benvenisty N (2009) The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8(23):3822–3830PubMedCrossRefGoogle Scholar
  11. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE (1993) A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 42(12):1715–1720PubMedCrossRefGoogle Scholar
  12. Bonner-Weir S, Li WC, Ouziel-Yahalom L, Guo L, Weir GC, Sharma A (2010) Beta-cell growth and regeneration: replication is only part of the story. Diabetes 59(10):2340–2348PubMedPubMedCentralCrossRefGoogle Scholar
  13. Boumaza I, Srinivasan S, Witt WT, Feghali-Bostwick C, Dai Y, Garcia-Ocana A et al (2009) 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 32(1):33–42PubMedCrossRefGoogle Scholar
  14. Brennand K, Huangfu D, Melton D (2007) All beta cells contribute equally to islet growth and maintenance. PLoS Biol 5(7):e163PubMedPubMedCentralCrossRefGoogle Scholar
  15. Calafiore R, Basta G (2015) Stem cells for the cell and molecular therapy of type 1 diabetes mellitus (T1D): the gap between dream and reality. Am J Stem Cells 4(1):22–31PubMedPubMedCentralGoogle Scholar
  16. Cefalu WT (2012) American diabetes association-European association for the study of diabetes position statement: due diligence was conducted. Diabetes Care 35(6):1201–1203PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chandra V, Swetha G, Phadnis S, Nair PD, Bhonde RR (2009) Generation of pancreatic hormone-expressing islet-like cell aggregates from murine adipose tissue-derived stem cells. Stem Cells 27(8):1941–1953PubMedCrossRefGoogle Scholar
  18. Chao KC, Chao KF, Fu YS, Liu SH (2008) Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS One 3(1):e1451PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chen S, Borowiak M, Fox JL, Maehr R, Osafune K, Davidow L et al (2009) A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol 5(4):258–265PubMedCrossRefGoogle Scholar
  20. Chhabra P, Brayman KL (2013) Stem cell therapy to cure type 1 diabetes: from hype to hope. Stem Cells Transl Med 2(5):328–336PubMedPubMedCentralCrossRefGoogle Scholar
  21. D’Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG et al (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24(11):1392–1401PubMedCrossRefGoogle Scholar
  22. D’Souza DM, Al-Sajee D, Hawke TJ (2013) Diabetic myopathy: impact of diabetes mellitus on skeletal muscle progenitor cells. Front Physiol 4:379PubMedPubMedCentralGoogle Scholar
  23. Delorme B, Ringe J, Gallay N, Le Vern Y, Kerboeuf D, Jorgensen C et al (2008) Specific plasma membrane protein phenotype of culture-amplified and native human bone marrow mesenchymal stem cells. Blood 111(5):2631–2635PubMedCrossRefGoogle Scholar
  24. Deuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T et al (2011) Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant 20(5):655–667PubMedCrossRefGoogle Scholar
  25. Ding Y, Xu D, Feng G, Bushell A, Muschel RJ, Wood KJ (2009) Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58(8):1797–1806PubMedPubMedCentralCrossRefGoogle Scholar
  26. Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yanez AJ, Conget PA (2008) Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant 14(6):631–640CrossRefGoogle Scholar
  27. Fiorina P, Jurewicz M, Augello A, Vergani A, Dada S, La Rosa S et al (2009) Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 183(2):993–1004PubMedPubMedCentralCrossRefGoogle Scholar
  28. Fiorina P, Voltarelli J, Zavazava N (2011) Immunological applications of stem cells in type 1 diabetes. Endocr Rev 32(6):725–754PubMedPubMedCentralCrossRefGoogle Scholar
  29. Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T et al (2011) Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43(1):34–41PubMedCrossRefGoogle Scholar
  30. Gispen WH, Biessels GJ (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 23(11):542–549PubMedCrossRefGoogle Scholar
  31. Golestaneh N, Kokkinaki M, Pant D, Jiang J, DeStefano D, Fernandez-Bueno C et al (2009) Pluripotent stem cells derived from adult human testes. Stem Cells Dev 18(8):1115–1126PubMedPubMedCentralCrossRefGoogle Scholar
  32. Groop LC, Eriksson JG (1992) The etiology and pathogenesis of non-insulin-dependent diabetes. Ann Med 24(6):483–489PubMedCrossRefGoogle Scholar
  33. Group CR (2009) 2007 update on allogeneic islet transplantation from the Collaborative Islet Transplant Registry (CITR). Cell Transplant 18(7):753–767CrossRefGoogle Scholar
  34. Halban PA, German MS, Kahn SE, Weir GC (2010) Current status of islet cell replacement and regeneration therapy. J Clin Endocrinol Metab 95(3):1034–1043PubMedPubMedCentralCrossRefGoogle Scholar
  35. Hanna J, Markoulaki S, Schorderet P, Carey BW, Beard C, Wernig M et al (2008) Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133(2):250–264PubMedPubMedCentralCrossRefGoogle Scholar
  36. Hashemian SJ, Kouhnavard M, Nasli-Esfahani E (2015) Mesenchymal stem cells: rising concerns over their application in treatment of type one diabetes mellitus. J Diabetes Res 2015:675103PubMedPubMedCentralCrossRefGoogle Scholar
  37. He D, Wang J, Gao Y, Zhang Y (2011) Differentiation of PDX1 gene-modified human umbilical cord mesenchymal stem cells into insulin-producing cells in vitro. Int J Mol Med 28(6):1019–1024PubMedGoogle Scholar
  38. Hess D, Li L, Martin M, Sakano S, Hill D, Strutt B et al (2003) Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol 21(7):763–770PubMedCrossRefGoogle Scholar
  39. Ho JH, Tseng TC, Ma WH, Ong WK, Chen YF, Chen MH et al (2012) Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and beta-cell differentiation in streptozotocin-induced diabetic mice. Cell Transplant 21(5):997–1009PubMedCrossRefGoogle Scholar
  40. Hu J, Yu X, Wang Z, Wang F, Wang L, Gao H et al (2013) 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 60(3):347–357PubMedCrossRefGoogle Scholar
  41. Hua H, Shang L, Martinez H, Freeby M, Gallagher MP, Ludwig T et al (2013) iPSC-derived beta cells model diabetes due to glucokinase deficiency. J Clin Invest 123(7):3146–3153PubMedPubMedCentralCrossRefGoogle Scholar
  42. Hung SC, Chen NJ, Hsieh SL, Li H, Ma HL, Lo WH (2002) Isolation and characterization of size-sieved stem cells from human bone marrow. Stem Cells 20(3):249–258PubMedCrossRefGoogle Scholar
  43. Jeon K, Lim H, Kim JH, Thuan NV, Park SH, Lim YM et al (2012) 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 21(14):2642–2655PubMedPubMedCentralCrossRefGoogle Scholar
  44. Jurewicz M, Yang S, Augello A, Godwin JG, Moore RF, Azzi J et al (2010) Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes. Diabetes 59(12):3139–3147PubMedPubMedCentralCrossRefGoogle Scholar
  45. Karaoz E, Okcu A, Unal ZS, Subasi C, Saglam O, Duruksu G (2013) Adipose tissue-derived mesenchymal stromal cells efficiently differentiate into insulin-producing cells in pancreatic islet microenvironment both in vitro and in vivo. Cytotherapy 15(5):557–570PubMedCrossRefGoogle Scholar
  46. Kelly OG, Chan MY, Martinson LA, Kadoya K, Ostertag TM, Ross KG et al (2011) Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol 29(8):750–756PubMedCrossRefGoogle Scholar
  47. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24(5):1294–1301PubMedCrossRefGoogle Scholar
  48. Kim Y, Kim H, Cho H, Bae Y, Suh K, Jung J (2007) Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol 20(6):867–876CrossRefGoogle Scholar
  49. Kim SJ, Choi YS, Ko ES, Lim SM, Lee CW, Kim DI (2012) Glucose-stimulated insulin secretion of various mesenchymal stem cells after insulin-producing cell differentiation. J Biosci Bioeng 113(6):771–777PubMedCrossRefGoogle Scholar
  50. Knoepfler PS (2008) Why myc? An unexpected ingredient in the stem cell cocktail. Cell Stem Cell 2(1):18–21PubMedCrossRefGoogle Scholar
  51. Knoepfler PS (2009) Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells 27(5):1050–1056PubMedPubMedCentralCrossRefGoogle Scholar
  52. Kojima H, Fujimiya M, Matsumura K, Nakahara T, Hara M, Chan L (2004) Extrapancreatic insulin-producing cells in multiple organs in diabetes. Proc Natl Acad Sci U S A 101(8):2458–2463PubMedPubMedCentralCrossRefGoogle Scholar
  53. Kooreman NG, Wu JC (2010) Tumorigenicity of pluripotent stem cells: biological insights from molecular imaging. J R Soc Interface/R Soc 7(Suppl 6):S753–S763CrossRefGoogle Scholar
  54. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26(4):443–452PubMedCrossRefGoogle Scholar
  55. La Rocca G, Anzalone R, Corrao S, Magno F, Loria T, Lo Iacono M et al (2009) Isolation and characterization of Oct-4+/HLA-G+ mesenchymal stem cells from human umbilical cord matrix: differentiation potential and detection of new markers. Histochem Cell Biol 131(2):267–282PubMedCrossRefGoogle Scholar
  56. Larijani B, Esfahani EN, Amini P, Nikbin B, Alimoghaddam K, Amiri S et al (2012) Stem cell therapy in treatment of different diseases. Acta Med Iran 50(2):79–96PubMedGoogle Scholar
  57. Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K et al (2004) Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol 14(4–6):311–324CrossRefGoogle Scholar
  58. Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD et al (2006) 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 103(46):17438–17443PubMedPubMedCentralCrossRefGoogle Scholar
  59. Li M, Ikehara S (2013) Bone marrow stem cell as a potential treatment for diabetes. J Diabetes Res 2013:329596PubMedPubMedCentralGoogle Scholar
  60. Liew CG, Shah NN, Briston SJ, Shepherd RM, Khoo CP, Dunne MJ et al (2008) PAX4 enhances beta-cell differentiation of human embryonic stem cells. PLoS One 3(3):e1783PubMedPubMedCentralCrossRefGoogle Scholar
  61. Liu X, Wang Y, Li Y, Pei X (2013) Research status and prospect of stem cells in the treatment of diabetes mellitus. Sci China Life Sci 56(4):306–312PubMedCrossRefGoogle Scholar
  62. Lo B, Parham L (2009) Ethical issues in stem cell research. Endocr Rev 30(3):204–213PubMedPubMedCentralCrossRefGoogle Scholar
  63. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292(5520):1389–1394PubMedCrossRefGoogle Scholar
  64. Madec AM, Mallone R, Afonso G, Abou Mrad E, Mesnier A, Eljaafari A et al (2009) Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 52(7):1391–1399PubMedCrossRefGoogle Scholar
  65. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R et al (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A 106(37):15768–15773PubMedPubMedCentralCrossRefGoogle Scholar
  66. Matveyenko A, Vella A (2015) Regenerative medicine in diabetes. Mayo Clin Proc 90(4):546–554PubMedPubMedCentralCrossRefGoogle Scholar
  67. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H (2013) Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med 2(6):455–463PubMedPubMedCentralCrossRefGoogle Scholar
  68. Mfopou JK, Chen B, Sui L, Sermon K, Bouwens L (2010a) Recent advances and prospects in the differentiation of pancreatic cells from human embryonic stem cells. Diabetes 59(9):2094–2101PubMedPubMedCentralCrossRefGoogle Scholar
  69. Mfopou JK, Chen B, Mateizel I, Sermon K, Bouwens L (2010b) Noggin, retinoids, and fibroblast growth factor regulate hepatic or pancreatic fate of human embryonic stem cells. Gastroenterology 138(7):2233–2245. 45 e1–14PubMedCrossRefGoogle Scholar
  70. Montanucci P, Basta G, Pescara T, Pennoni I, Di Giovanni F, Calafiore R (2011) New simple and rapid method for purification of mesenchymal stem cells from the human umbilical cord Wharton jelly. Tissue Eng Part A 17(21–22):2651–2661PubMedCrossRefGoogle Scholar
  71. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T et al (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26(1):101–106PubMedCrossRefGoogle Scholar
  72. Nostro MC, Sarangi F, Ogawa S, Holtzinger A, Corneo B, Li X et al (2011) Stage-specific signaling through TGFbeta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development 138(5):861–871PubMedPubMedCentralCrossRefGoogle Scholar
  73. Oh SH, Muzzonigro TM, Bae SH, LaPlante JM, Hatch HM, Petersen BE (2004) Adult bone marrow-derived cells trans-differentiating into insulin-producing cells for the treatment of type I diabetes. Lab Invest; J Tech Methods Pathol 84(5):607–617CrossRefGoogle Scholar
  74. Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448(7151):313–317PubMedCrossRefGoogle Scholar
  75. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322(5903):949–953PubMedCrossRefGoogle Scholar
  76. Oswald J, Boxberger S, Jorgensen B, Feldmann S, Ehninger G, Bornhauser M et al (2004) Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22(3):377–384PubMedCrossRefGoogle Scholar
  77. Palmer JP (2009) C-peptide in the natural history of type 1 diabetes. Diabetes Metab Res Rev 25(4):325–328PubMedPubMedCentralCrossRefGoogle Scholar
  78. Pendleton C, Li Q, Chesler DA, Yuan K, Guerrero-Cazares H, Quinones-Hinojosa A (2013) Mesenchymal stem cells derived from adipose tissue vs bone marrow: in vitro comparison of their tropism towards gliomas. PLoS One 8(3):e58198PubMedPubMedCentralCrossRefGoogle Scholar
  79. Pileggi A (2012) Mesenchymal stem cells for the treatment of diabetes. Diabetes 61(6):1355–1356PubMedPubMedCentralCrossRefGoogle Scholar
  80. Pittenger MF, Martin BJ (2004) Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95(1):9–20PubMedCrossRefGoogle Scholar
  81. Reger RL, Tucker AH, Wolfe MR (2008) Differentiation and characterization of human MSCs. Methods Mol Biol 449:93–107PubMedGoogle Scholar
  82. Ren G, Su J, Zhang L, Zhao X, Ling W, L’Huillie A et al (2009) Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27(8):1954–1962PubMedCrossRefGoogle Scholar
  83. Ricordi C, Inverardi L, Dominguez-Bendala J (2012) From cellular therapies to tissue reprogramming and regenerative strategies in the treatment of diabetes. Regen Med 7(6 Suppl):41–48PubMedCrossRefGoogle Scholar
  84. Rolletschek A, Kania G, Wobus AM (2006) Generation of pancreatic insulin-producing cells from embryonic stem cells – ‘proof of principle’, but questions still unanswered. Diabetologia 49(11):2541–2545PubMedCrossRefGoogle Scholar
  85. Romanov YA, Svintsitskaya VA, Smirnov VN (2003) Searching for alternative sources of postnatal human mesenchymal stem cells: candidate MSC-like cells from umbilical cord. Stem Cells 21(1):105–110PubMedCrossRefGoogle Scholar
  86. Schaffler A, Buchler C (2007) Concise review: adipose tissue-derived stromal cells – basic and clinical implications for novel cell-based therapies. Stem Cells 25(4):818–827PubMedCrossRefGoogle Scholar
  87. Shim JH, Kim SE, Woo DH, Kim SK, Oh CH, McKay R et al (2007) Directed differentiation of human embryonic stem cells towards a pancreatic cell fate. Diabetologia 50(6):1228–1238PubMedCrossRefGoogle Scholar
  88. Sipione S, Eshpeter A, Lyon JG, Korbutt GS, Bleackley RC (2004) Insulin expressing cells from differentiated embryonic stem cells are not beta cells. Diabetologia 47(3):499–508PubMedCrossRefGoogle Scholar
  89. Smukler SR, Arntfield ME, Razavi R, Bikopoulos G, Karpowicz P, Seaberg R et al (2011) The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell 8(3):281–293PubMedCrossRefGoogle Scholar
  90. Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F (2000) Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49(2):157–162PubMedCrossRefGoogle Scholar
  91. Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K (2008) Induced pluripotent stem cells generated without viral integration. Science 322(5903):945–949PubMedPubMedCentralCrossRefGoogle Scholar
  92. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872PubMedCrossRefGoogle Scholar
  93. Tang DQ, Wang Q, Burkhardt BR, Litherland SA, Atkinson MA, Yang LJ (2012) In vitro generation of functional insulin-producing cells from human bone marrow-derived stem cells, but long-term culture running risk of malignant transformation. Am J Stem Cells 1(2):114–127PubMedPubMedCentralGoogle Scholar
  94. Tateishi K, He J, Taranova O, Liang G, D’Alessio AC, Zhang Y (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 283(46):31601–31607PubMedCrossRefGoogle Scholar
  95. Teo AK, Wagers AJ, Kulkarni RN (2013) New opportunities: harnessing induced pluripotency for discovery in diabetes and metabolism. Cell Metab 18(6):775–791PubMedCrossRefGoogle Scholar
  96. Thatava T, Nelson TJ, Edukulla R, Sakuma T, Ohmine S, Tonne JM et al (2011) Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny. Gene Ther 18(3):283–293PubMedCrossRefGoogle Scholar
  97. Thatava T, Kudva YC, Edukulla R, Squillace K, De Lamo JG, Khan YK et al (2013) Intrapatient variations in type 1 diabetes-specific iPS cell differentiation into insulin-producing cells. Mol Ther: J Am Soc Gene Ther 21(1):228–239CrossRefGoogle Scholar
  98. Timper K, Seboek D, Eberhardt M, Linscheid P, Christ-Crain M, Keller U et al (2006) Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun 341(4):1135–1140PubMedCrossRefGoogle Scholar
  99. Tsai PJ, Wang HS, Shyr YM, Weng ZC, Tai LC, Shyu JF et al (2012) Transplantation of insulin-producing cells from umbilical cord mesenchymal stem cells for the treatment of streptozotocin-induced diabetic rats. J Biomed Sci 19:47PubMedPubMedCentralCrossRefGoogle Scholar
  100. Turnovcova K, Ruzickova K, Vanecek V, Sykova E, Jendelova P (2009) Properties and growth of human bone marrow mesenchymal stromal cells cultivated in different media. Cytotherapy 11(7):874–885PubMedCrossRefGoogle Scholar
  101. Urban VS, Kiss J, Kovacs J, Gocza E, Vas V, Monostori E et al (2008) Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 26(1):244–253PubMedCrossRefGoogle Scholar
  102. Vajdic CM, van Leeuwen MT (2009) Cancer incidence and risk factors after solid organ transplantation. Int J Cancer J Int Cancer 125(8):1747–1754CrossRefGoogle Scholar
  103. Wang HS, Shyu JF, Shen WS, Hsu HC, Chi TC, Chen CP et al (2011) Transplantation of insulin-producing cells derived from umbilical cord stromal mesenchymal stem cells to treat NOD mice. Cell Transplant 20(3):455–466PubMedCrossRefGoogle Scholar
  104. Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M, Merchav S et al (2006) Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease. Stem Cells 24(3):781–792PubMedCrossRefGoogle Scholar
  105. Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, Vander Werff I et al (2008) Immune properties of human umbilical cord Wharton’s jelly-derived cells. Stem Cells 26(11):2865–2874PubMedCrossRefGoogle Scholar
  106. Wernig M, Meissner A, Cassady JP, Jaenisch R (2008) c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2(1):10–12PubMedCrossRefGoogle Scholar
  107. Wu H, Mahato RI (2014) Mesenchymal stem cell-based therapy for type 1 diabetes. Discov Med 17(93):139–143PubMedGoogle Scholar
  108. Xie QP, Huang H, Xu B, Dong X, Gao SL, Zhang B et al (2009) Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro. Differ Res Biol Divers 77(5):483–491CrossRefGoogle Scholar
  109. Xu X, Browning VL, Odorico JS (2011) Activin, BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells. Mech Dev 128(7–10):412–427PubMedPubMedCentralCrossRefGoogle Scholar
  110. Yamanaka S (2007) Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1(1):39–49PubMedCrossRefGoogle Scholar
  111. Yang LJ (2006) Liver stem cell-derived beta-cell surrogates for treatment of type 1 diabetes. Autoimmun Rev 5(6):409–413PubMedCrossRefGoogle Scholar
  112. Yechoor V, Liu V, Espiritu C, Paul A, Oka K, Kojima H et al (2009) Neurogenin3 is sufficient for transdetermination of hepatic progenitor cells into neo-islets in vivo but not transdifferentiation of hepatocytes. Dev Cell 16(3):358–373PubMedPubMedCentralCrossRefGoogle Scholar
  113. Zaret KS, Grompe M (2008) Generation and regeneration of cells of the liver and pancreas. Science 322(5907):1490–1494PubMedPubMedCentralCrossRefGoogle Scholar
  114. Zhang D, Jiang W, Liu M, Sui X, Yin X, Chen S et al (2009) Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res 19(4):429–438PubMedCrossRefGoogle Scholar
  115. Zhao W, Wang Y, Wang D, Sun B, Wang G, Wang J et al (2008) 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 253(1–2):23–30PubMedCrossRefGoogle Scholar
  116. Zhu FF, Zhang PB, Zhang DH, Sui X, Yin M, Xiang TT et al (2011) Generation of pancreatic insulin-producing cells from rhesus monkey induced pluripotent stem cells. Diabetologia 54(9):2325–2336PubMedCrossRefGoogle Scholar
  117. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13(12):4279–4295PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Endocrinology, Aerospace Center HospitalPeking University AffiliateBeijingChina
  2. 2.Department of MedicineCleveland Clinic Akron General Medical CenterAkronUSA

Personalised recommendations