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Pluripotent Stem Cell-Derived Pancreatic β Cells: From In Vitro Maturation to Clinical Application

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Recent Advances in Stem Cells

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Obtaining a large number of pancreatic β cells, which are fully functional in vitro, provides the opportunity to study the pathophysiology of diabetes and gives cells to replace the damaged β cells in the patient body. Recently, pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), showed a great ability to differentiate into pancreatic β cells as a way to model several forms of diabetes in vitro. Interestingly, the first clinical trial to treat type 1 diabetes (T1D) using hESC-derived pancreatic progenitors has been approved in 2014, indicating the rapid progress toward treating diabetes using PSCs. However, several questions remain and further studies are still required to improve the process of patient-specific PSC generation and to enhance the efficiency of the differentiation process into mature pancreatic β cells in the years to come. In the current chapter, we will discuss the progress and challenges in the differentiation of PSCs into pancreatic β cells and their therapeutic potentials. Also, we will describe how the use of PSCs and patient-specific PSCs can improve our understanding of the pathophysiology of diabetes and pancreatic β cell development.

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References

  1. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.

    Article  CAS  PubMed  Google Scholar 

  2. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    Article  CAS  PubMed  Google Scholar 

  3. Hanna J, Markoulaki S, Schorderet P, Carey BW, Beard C, Wernig M, et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell. 2008;133(2):250–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.

    Article  CAS  PubMed  Google Scholar 

  5. Abdelalim EM. Molecular mechanisms controlling the cell cycle in embryonic stem cells. Stem Cell Rev. 2013;9(6):764–73.

    Article  CAS  PubMed  Google Scholar 

  6. Ruiz S, Panopoulos AD, Herrerias A, Bissig KD, Lutz M, Berggren WT, et al. A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity. Curr Biol. 2011;21(1):45–52.

    Article  CAS  PubMed  Google Scholar 

  7. Gillespie KM. Type 1 diabetes: pathogenesis and prevention. Can Med Assoc J. 2006;175(2):165–70.

    Article  Google Scholar 

  8. Joost HG. Pathogenesis, risk assessment and prevention of type 2 diabetes mellitus. Obes Facts. 2008;1(3):128–37.

    Article  CAS  PubMed  Google Scholar 

  9. Yang L, Calay ES, Fan J, Arduini A, Kunz RC, Gygi SP, et al. Metabolism. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science. 2015;349(6247):500–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Doria A, Patti ME, Kahn CR. The emerging genetic architecture of type 2 diabetes. Cell Metab. 2008;8(3):186–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mathis D, Vence L, Benoist C. Beta-cell death during progression to diabetes. Nature. 2001;414(6865):792–8.

    Article  CAS  PubMed  Google Scholar 

  12. Donath MY, Halban PA. Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia. 2004;47(3):581–9.

    Article  CAS  PubMed  Google Scholar 

  13. Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev. 2008;29(3):254–64.

    Article  CAS  PubMed  Google Scholar 

  14. Bonnefond A, Froguel P, Vaxillaire M. The emerging genetics of type 2 diabetes. Trends Mol Med. 2010;16(9):407–16.

    Article  CAS  PubMed  Google Scholar 

  15. Martello G, Smith A. The nature of embryonic stem cells. Annu Rev Cell Dev Biol. 2014;30:647–75.

    Article  CAS  PubMed  Google Scholar 

  16. Abdelalim EM, Emara MM. Advances and challenges in the differentiation of pluripotent stem cells into pancreatic β cells. World J Stem Cells. 2015; 7(1):174-81.

    Google Scholar 

  17. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  CAS  PubMed  Google Scholar 

  18. Evans M. Discovering pluripotency: 30 years of mouse embryonic stem cells. Nat Rev Mol Cell Biol. 2011;12(10):680–6.

    Article  CAS  PubMed  Google Scholar 

  19. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A. 2009;106(37):15768–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tateishi K, He J, Taranova O, Liang G, D’Alessio AC, Zhang Y. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem. 2008;283(46):31601–7.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang D, Jiang W, Liu M, Sui X, Yin X, Chen S, et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res. 2009;19(4):429–38.

    Article  CAS  PubMed  Google Scholar 

  22. Thatava T, Kudva YC, Edukulla R, Squillace K, De Lamo JG, Khan YK, et al. Intrapatient variations in type 1 diabetes-specific iPS cell differentiation into insulin-producing cells. Mol Ther. 2013;21(1):228–39.

    Article  CAS  PubMed  Google Scholar 

  23. Hua H, Shang L, Martinez H, Freeby M, Gallagher MP, Ludwig T, et al. iPSC-derived beta cells model diabetes due to glucokinase deficiency. J Clin Invest. 2013;123(7):3146–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pagliuca FW, Millman JR, Gurtler M, Segel M, Van Dervort A, Ryu JH, et al. Generation of functional human pancreatic beta cells in vitro. Cell. 2014;159(2):428–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Haegel H, Larue L, Ohsugi M, Fedorov L, Herrenknecht K, Kemler R. Lack of beta-catenin affects mouse development at gastrulation. Development. 1995;121(11):3529–37.

    CAS  PubMed  Google Scholar 

  26. Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR, Bradley A. Requirement for Wnt3 in vertebrate axis formation. Nat Genet. 1999;22(4):361–5.

    Article  CAS  PubMed  Google Scholar 

  27. Kelly OG, Pinson KI, Skarnes WC. The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development. 2004;131(12):2803–15.

    Article  CAS  PubMed  Google Scholar 

  28. Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, Herrmann B, et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development. 1994;120(7):1919–28.

    CAS  PubMed  Google Scholar 

  29. Osada SI, Wright CV. Xenopus nodal-related signaling is essential for mesendodermal patterning during early embryogenesis. Development. 1999;126(14):3229–40.

    CAS  PubMed  Google Scholar 

  30. Vincent SD, Dunn NR, Hayashi S, Norris DP, Robertson EJ. Cell fate decisions within the mouse organizer are governed by graded Nodal signals. Genes Dev. 2003;17(13):1646–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol. 2005;23(12):1534–41.

    Article  PubMed  CAS  Google Scholar 

  32. Jiang J, Au M, Lu K, Eshpeter A, Korbutt G, Fisk G, et al. Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells. 2007;25(8):1940–53.

    Article  CAS  PubMed  Google Scholar 

  33. Chen S, Borowiak M, Fox JL, Maehr R, Osafune K, Davidow L, et al. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol. 2009;5(4):258–65.

    Article  CAS  PubMed  Google Scholar 

  34. Osafune K, Caron L, Borowiak M, Martinez RJ, Fitz-Gerald CS, Sato Y, et al. Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol. 2008;26(3):313–5.

    Article  CAS  PubMed  Google Scholar 

  35. Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell. 2009;5(1):111–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. D’Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 2006;24(11):1392–401.

    Article  PubMed  CAS  Google Scholar 

  37. Jiang W, Shi Y, Zhao D, Chen S, Yong J, Zhang J, et al. In vitro derivation of functional insulin-producing cells from human embryonic stem cells. Cell Res. 2007;17(4):333–44.

    Article  CAS  PubMed  Google Scholar 

  38. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26(4):443–52.

    Article  CAS  PubMed  Google Scholar 

  39. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science. 2001;292(5520):1389–94.

    Article  CAS  PubMed  Google Scholar 

  40. Thatava T, Nelson TJ, Edukulla R, Sakuma T, Ohmine S, Tonne JM, et al. Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny. Gene Ther. 2011;18(3):283–93.

    Article  CAS  PubMed  Google Scholar 

  41. Kunisada Y, Tsubooka-Yamazoe N, Shoji M, Hosoya M. Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells. Stem Cell Res. 2012;8(2):274–84.

    Article  CAS  PubMed  Google Scholar 

  42. Nostro MC, Sarangi F, Ogawa S, Holtzinger A, Corneo B, Li X, et al. Stage-specific signaling through TGFbeta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development. 2011;138(5):861–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Micallef SJ, Janes ME, Knezevic K, Davis RP, Elefanty AG, Stanley EG. Retinoic acid induces Pdx1-positive endoderm in differentiating mouse embryonic stem cells. Diabetes. 2005;54(2):301–5.

    Article  CAS  PubMed  Google Scholar 

  44. Schulz TC, Young HY, Agulnick AD, Babin MJ, Baetge EE, Bang AG, et al. A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PLoS One. 2012;7(5):e37004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Micallef SJ, Li X, Schiesser JV, Hirst CE, Yu QC, Lim SM, et al. INS(GFP/w) human embryonic stem cells facilitate isolation of in vitro derived insulin-producing cells. Diabetologia. 2012;55(3):694–706.

    Article  CAS  PubMed  Google Scholar 

  46. Shahjalal HM, Shiraki N, Sakano D, Kikawa K, Ogaki S, Baba H, et al. Generation of insulin-producing beta-like cells from human iPS cells in a defined and completely xeno-free culture system. J Mol Cell Biol. 2014;6(5):394–408.

    Article  PubMed  Google Scholar 

  47. Shim JH, Kim SE, Woo DH, Kim SK, Oh CH, McKay R, et al. Directed differentiation of human embryonic stem cells towards a pancreatic cell fate. Diabetologia. 2007;50(6):1228–38.

    Article  CAS  PubMed  Google Scholar 

  48. Hammar EB, Irminger JC, Rickenbach K, Parnaud G, Ribaux P, Bosco D, et al. Activation of NF-kappaB by extracellular matrix is involved in spreading and glucose-stimulated insulin secretion of pancreatic beta cells. J Biol Chem. 2005;280(34):30630–7.

    Article  CAS  PubMed  Google Scholar 

  49. Weber LM, Hayda KN, Anseth KS. Cell–matrix interactions improve beta-cell survival and insulin secretion in three-dimensional culture. Tissue Eng Part A. 2008;14(12):1959–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Parnaud G, Hammar E, Ribaux P, Donath MY, Berney T, Halban PA. Signaling pathways implicated in the stimulation of beta-cell proliferation by extracellular matrix. Mol Endocrinol. 2009;23(8):1264–71.

    Article  CAS  PubMed  Google Scholar 

  51. Speier S, Gjinovci A, Charollais A, Meda P, Rupnik M. Cx36-mediated coupling reduces beta-cell heterogeneity, confines the stimulating glucose concentration range, and affects insulin release kinetics. Diabetes. 2007;56(4):1078–86.

    Article  CAS  PubMed  Google Scholar 

  52. Lu CC, Brennan J, Robertson EJ. From fertilization to gastrulation: axis formation in the mouse embryo. Curr Opin Genet Dev. 2001;11(4):384–92.

    Article  CAS  PubMed  Google Scholar 

  53. Lawson KA, Meneses JJ, Pedersen RA. Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development. 1991;113(3):891–911.

    CAS  PubMed  Google Scholar 

  54. Rodaway A, Patient R. Mesendoderm. An ancient germ layer? Cell. 2001;105(2):169–72.

    Article  CAS  PubMed  Google Scholar 

  55. Rodaway A, Takeda H, Koshida S, Broadbent J, Price B, Smith JC, et al. Induction of the mesendoderm in the zebrafish germ ring by yolk cell-derived TGF-beta family signals and discrimination of mesoderm and endoderm by FGF. Development. 1999;126(14):3067–78.

    CAS  PubMed  Google Scholar 

  56. Tada S, Era T, Furusawa C, Sakurai H, Nishikawa S, Kinoshita M, et al. Characterization of mesendoderm: a diverging point of the definitive endoderm and mesoderm in embryonic stem cell differentiation culture. Development. 2005;132(19):4363–74.

    Article  CAS  PubMed  Google Scholar 

  57. Kubo A, Shinozaki K, Shannon JM, Kouskoff V, Kennedy M, Woo S, et al. Development of definitive endoderm from embryonic stem cells in culture. Development. 2004;131(7):1651–62.

    Article  CAS  PubMed  Google Scholar 

  58. Bakre MM, Hoi A, Mong JC, Koh YY, Wong KY, Stanton LW. Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation. J Biol Chem. 2007;282(43):31703–12.

    Article  CAS  PubMed  Google Scholar 

  59. Shiraki N, Harada S, Ogaki S, Kume K, Kume S. Identification of DAF1/CD55, a novel definitive endoderm marker. Cell Struct Funct. 2010;35(2):73–80.

    Article  CAS  PubMed  Google Scholar 

  60. Wang P, McKnight KD, Wong DJ, Rodriguez RT, Sugiyama T, Gu X, et al. A molecular signature for purified definitive endoderm guides differentiation and isolation of endoderm from mouse and human embryonic stem cells. Stem Cells Dev. 2012;21(12):2273–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mfopou JK, Chen B, Mateizel I, Sermon K, Bouwens L. Noggin, retinoids, and fibroblast growth factor regulate hepatic or pancreatic fate of human embryonic stem cells. Gastroenterology. 2010;138(7):2233–45. 45 e1-14.

    Article  CAS  PubMed  Google Scholar 

  62. Johannesson M, Stahlberg A, Ameri J, Sand FW, Norrman K, Semb H. FGF4 and retinoic acid direct differentiation of hESCs into PDX1-expressing foregut endoderm in a time- and concentration-dependent manner. PLoS One. 2009;4(3):e4794.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Niakan KK, Ji H, Maehr R, Vokes SA, Rodolfa KT, Sherwood RI, et al. Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal. Genes Dev. 2010;24(3):312–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Koutsourakis M, Langeveld A, Patient R, Beddington R, Grosveld F. The transcription factor GATA6 is essential for early extraembryonic development. Development. 1999;126(4):723–32.

    CAS  Google Scholar 

  65. Cai KQ, Capo-Chichi CD, Rula ME, Yang DH, Xu XX. Dynamic GATA6 expression in primitive endoderm formation and maturation in early mouse embryogenesis. Dev Dyn. 2008;237(10):2820–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Champeris TS, Jones PM. Generating pancreatic beta-cells from embryonic stem cells by manipulating signaling pathways. J Endocrinol. 2010;206(1):13–26.

    Article  CAS  Google Scholar 

  67. Tian T, Meng AM. Nodal signals pattern vertebrate embryos. Cell Mol Life Sci. 2006;63(6):672–85.

    Article  CAS  PubMed  Google Scholar 

  68. Zhou X, Sasaki H, Lowe L, Hogan BL, Kuehn MR. Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation. Nature. 1993;361(6412):543–7.

    Article  CAS  PubMed  Google Scholar 

  69. Pfendler KC, Catuar CS, Meneses JJ, Pedersen RA. Overexpression of Nodal promotes differentiation of mouse embryonic stem cells into mesoderm and endoderm at the expense of neuroectoderm formation. Stem Cells Dev. 2005;14(2):162–72.

    Article  CAS  PubMed  Google Scholar 

  70. Barrow JR, Howell WD, Rule M, Hayashi S, Thomas KR, Capecchi MR, et al. Wnt3 signaling in the epiblast is required for proper orientation of the anteroposterior axis. Dev Biol. 2007;312(1):312–20.

    Article  CAS  PubMed  Google Scholar 

  71. McLean AB, D’Amour KA, Jones KL, Krishnamoorthy M, Kulik MJ, Reynolds DM, et al. Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. Stem Cells. 2007;25(1):29–38.

    Article  CAS  PubMed  Google Scholar 

  72. Sui L, Mfopou JK, Geens M, Sermon K, Bouwens L. FGF signaling via MAPK is required early and improves Activin A-induced definitive endoderm formation from human embryonic stem cells. Biochem Biophys Res Commun. 2012;426(3):380–5.

    Article  CAS  PubMed  Google Scholar 

  73. Vallier L, Touboul T, Chng Z, Brimpari M, Hannan N, Millan E, et al. Early cell fate decisions of human embryonic stem cells and mouse epiblast stem cells are controlled by the same signalling pathways. PLoS One. 2009;4(6):e6082.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Hansson M, Olesen DR, Peterslund JM, Engberg N, Kahn M, Winzi M, et al. A late requirement for Wnt and FGF signaling during activin-induced formation of foregut endoderm from mouse embryonic stem cells. Dev Biol. 2009;330(2):286–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, et al. Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol. 2005;23(12):1542–50.

    Article  CAS  PubMed  Google Scholar 

  76. Gadue P, Huber TL, Paddison PJ, Keller GM. Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc Natl Acad Sci U S A. 2006;103(45):16806–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tam PP, Kanai-Azuma M, Kanai Y. Early endoderm development in vertebrates: lineage differentiation and morphogenetic function. Curr Opin Genet Dev. 2003;13(4):393–400.

    Article  CAS  PubMed  Google Scholar 

  78. Schier AF. Nodal signaling in vertebrate development. Annu Rev Cell Dev Biol. 2003;19:589–621.

    Article  CAS  PubMed  Google Scholar 

  79. Hay DC, Fletcher J, Payne C, Terrace JD, Gallagher RC, Snoeys J, et al. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci U S A. 2008;105(34):12301–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Xu X, Browning VL, Odorico JS. Activin, BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells. Mech Dev. 2011;128(7–10):412–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Teo AK, Ali Y, Wong KY, Chipperfield H, Sadasivam A, Poobalan Y, et al. Activin and BMP4 synergistically promote formation of definitive endoderm in human embryonic stem cells. Stem Cells. 2012;30(4):631–42.

    Article  CAS  PubMed  Google Scholar 

  82. Bruin JE, Erener S, Vela J, Hu X, Johnson JD, Kurata HT, et al. Characterization of polyhormonal insulin-producing cells derived in vitro from human embryonic stem cells. Stem Cell Res. 2014;12(1):194–208.

    Article  CAS  PubMed  Google Scholar 

  83. Bone HK, Nelson AS, Goldring CE, Tosh D, Welham MJ. A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3. J Cell Sci. 2011;124(Pt 12):1992–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Takeuchi H, Nakatsuji N, Suemori H. Endodermal differentiation of human pluripotent stem cells to insulin-producing cells in 3D culture. Sci Rep. 2014;4:4488.

    PubMed  PubMed Central  Google Scholar 

  85. Borowiak M, Maehr R, Chen S, Chen AE, Tang W, Fox JL, et al. Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem Cell. 2009;4(4):348–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wandzioch E, Zaret KS. Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science. 2009;324(5935):1707–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bernardo AS, Cho CH, Mason S, Docherty HM, Pedersen RA, Vallier L, et al. Biphasic induction of Pdx1 in mouse and human embryonic stem cells can mimic development of pancreatic beta-cells. Stem Cells. 2009;27(2):341–51.

    Article  CAS  PubMed  Google Scholar 

  88. Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 1994;371(6498):606–9.

    Article  CAS  PubMed  Google Scholar 

  89. Grapin-Botton A, Majithia AR, Melton DA. Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes. Genes Dev. 2001;15(4):444–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L, et al. Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci U S A. 2003;100(3):998–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Miyazaki S, Yamato E, Miyazaki J. Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes. 2004;53(4):1030–7.

    Article  CAS  PubMed  Google Scholar 

  92. Mfopou JK, Bouwens L. Hedgehog signals in pancreatic differentiation from embryonic stem cells: revisiting the neglected. Differentiation. 2008;76(2):107–17.

    Article  CAS  PubMed  Google Scholar 

  93. Mfopou JK, Willems E, Leyns L, Bouwens L. Expression of regulatory genes for pancreas development during murine embryonic stem cell differentiation. Int J Dev Biol. 2005;49(8):915–22.

    Article  CAS  PubMed  Google Scholar 

  94. Mfopou JK, De Groote V, Xu X, Heimberg H, Bouwens L. Sonic hedgehog and other soluble factors from differentiating embryoid bodies inhibit pancreas development. Stem Cells. 2007;25(5):1156–65.

    Article  CAS  PubMed  Google Scholar 

  95. Skoudy A, Rovira M, Savatier P, Martin F, Leon-Quinto T, Soria B, et al. Transforming growth factor (TGF)beta, fibroblast growth factor (FGF) and retinoid signalling pathways promote pancreatic exocrine gene expression in mouse embryonic stem cells. Biochem J. 2004;379(Pt 3):749–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Segev H, Fishman B, Ziskind A, Shulman M, Itskovitz-Eldor J. Differentiation of human embryonic stem cells into insulin-producing clusters. Stem Cells. 2004;22(3):265–74.

    Article  CAS  PubMed  Google Scholar 

  97. Hebrok M, Kim SK, Melton DA. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 1998;12(11):1705–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Frandsen U, Porneki AD, Floridon C, Abdallah BM, Kassem M. Activin B mediated induction of Pdx1 in human embryonic stem cell derived embryoid bodies. Biochem Biophys Res Commun. 2007;362(3):568–74.

    Article  CAS  PubMed  Google Scholar 

  99. Hart A, Papadopoulou S, Edlund H. Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells. Dev Dyn. 2003;228(2):185–93.

    Article  CAS  PubMed  Google Scholar 

  100. Shiraki N, Lai CJ, Hishikari Y, Kume S. TGF-beta signaling potentiates differentiation of embryonic stem cells to Pdx-1 expressing endodermal cells. Genes Cells. 2005;10(6):503–16.

    Article  CAS  PubMed  Google Scholar 

  101. Sanvito F, Herrera PL, Huarte J, Nichols A, Montesano R, Orci L, et al. TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development. 1994;120(12):3451–62.

    CAS  PubMed  Google Scholar 

  102. Rezania A, Bruin JE, Riedel MJ, Mojibian M, Asadi A, Xu J, 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(8):2016–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gradwohl G, Dierich A, LeMeur M, Guillemot F. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A. 2000;97(4):1607–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development. 2002;129(10):2447–57.

    CAS  PubMed  Google Scholar 

  105. Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, et al. Notch signalling controls pancreatic cell differentiation. Nature. 1999;400(6747):877–81.

    Article  CAS  PubMed  Google Scholar 

  106. Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, et al. Control of endodermal endocrine development by Hes-1. Nat Genet. 2000;24(1):36–44.

    Article  CAS  PubMed  Google Scholar 

  107. Hald J, Hjorth JP, German MS, Madsen OD, Serup P, Jensen J. Activated notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development. Dev Biol. 2003;260(2):426–37.

    Article  CAS  PubMed  Google Scholar 

  108. Murtaugh LC, Stanger BZ, Kwan KM, Melton DA. Notch signaling controls multiple steps of pancreatic differentiation. Proc Natl Acad Sci U S A. 2003;100(25):14920–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lee JC, Smith SB, Watada H, Lin J, Scheel D, Wang J, et al. Regulation of the pancreatic pro-endocrine gene neurogenin3. Diabetes. 2001;50(5):928–36.

    Article  CAS  PubMed  Google Scholar 

  110. Shih HP, Kopp JL, Sandhu M, Dubois CL, Seymour PA, Grapin-Botton A, et al. A notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development. 2012;139(14):2488–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhu FF, Zhang PB, Zhang DH, Sui X, Yin M, Xiang TT, et al. Generation of pancreatic insulin-producing cells from rhesus monkey induced pluripotent stem cells. Diabetologia. 2011;54(9):2325–36.

    Article  CAS  PubMed  Google Scholar 

  112. Sakano D, Shiraki N, Kikawa K, Yamazoe T, Kataoka M, Umeda K, et al. VMAT2 identified as a regulator of late-stage beta-cell differentiation. Nat Chem Biol. 2013;10(2):141–8.

    Article  PubMed  CAS  Google Scholar 

  113. Gage BK, Webber TD, Kieffer TJ. Initial cell seeding density influences pancreatic endocrine development during in vitro differentiation of human embryonic stem cells. PLoS One. 2013;8(12):e82076.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Kubo A, Stull R, Takeuchi M, Bonham K, Gouon-Evans V, Sho M, et al. Pdx1 and Ngn3 overexpression enhances pancreatic differentiation of mouse ES cell-derived endoderm population. PLoS One. 2011;6(9):e24058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Nelson SB, Schaffer AE, Sander M. The transcription factors Nkx6.1 and Nkx6.2 possess equivalent activities in promoting beta-cell fate specification in Pdx1+ pancreatic progenitor cells. Development. 2007;134(13):2491–500.

    Article  CAS  PubMed  Google Scholar 

  116. Rezania A, Bruin JE, Xu J, Narayan K, Fox JK, O’Neil JJ, et al. Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo. Stem Cells. 2013;31(11):2432–42.

    Article  CAS  PubMed  Google Scholar 

  117. Taylor BL, Liu FF, Sander M. Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Rep. 2013;4(6):1262–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Nostro MC, Sarangi F, Yang C, Holland A, Elefanty AG, Stanley EG, et al. Efficient generation of NKX6-1+ pancreatic progenitors from multiple human pluripotent stem cell lines. Stem Cell Reports. 2015;4(4):591–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tessem JS, Moss LG, Chao LC, Arlotto M, Lu D, Jensen MV, et al. Nkx6.1 regulates islet beta-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. Proc Natl Acad Sci U S A. 2014;111(14):5242–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, et al. Inactivation of specific beta cell transcription factors in type 2 diabetes. J Clin Invest. 2013;123(8):3305–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kwon YD, Oh SK, Kim HS, Ku SY, Kim SH, Choi YM, et al. Cellular manipulation of human embryonic stem cells by TAT-PDX1 protein transduction. Mol Ther. 2005;12(1):28–32.

    Article  CAS  PubMed  Google Scholar 

  122. Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes. 2000;49(2):157–62.

    Article  CAS  PubMed  Google Scholar 

  123. St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature. 1997;387(6631):406–9.

    Article  CAS  PubMed  Google Scholar 

  124. Greenwood AL, Li S, Jones K, Melton DA. Notch signaling reveals developmental plasticity of Pax4(+) pancreatic endocrine progenitors and shunts them to a duct fate. Mech Dev. 2007;124(2):97–107.

    Article  CAS  PubMed  Google Scholar 

  125. Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature. 1997;386(6623):399–402.

    Article  CAS  PubMed  Google Scholar 

  126. Wang J, Elghazi L, Parker SE, Kizilocak H, Asano M, Sussel L, et al. The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation. Dev Biol. 2004;266(1):178–89.

    Article  CAS  PubMed  Google Scholar 

  127. Collombat P, Hecksher-Sorensen J, Broccoli V, Krull J, Ponte I, Mundiger T, et al. The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development. 2005;132(13):2969–80.

    Article  CAS  PubMed  Google Scholar 

  128. Collombat P, Mansouri A, Hecksher-Sorensen J, Serup P, Krull J, Gradwohl G, et al. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev. 2003;17(20):2591–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gage BK, Baker RK, Kieffer TJ. Overexpression of PAX4 reduces glucagon expression in differentiating hESCs. Islets. 2014;6(2):e29236.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Liew CG, Shah NN, Briston SJ, Shepherd RM, Khoo CP, Dunne MJ, et al. PAX4 enhances beta-cell differentiation of human embryonic stem cells. PLoS One. 2008;3(3):e1783.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lavon N, Yanuka O, Benvenisty N. The effect of overexpression of Pdx1 and Foxa2 on the differentiation of human embryonic stem cells into pancreatic cells. Stem Cells. 2006;24(8):1923–30.

    Article  CAS  PubMed  Google Scholar 

  132. Gong ZC, Huang Q, Dai XP, Lei GH, Lu HB, Yin JY, et al. NeuroD1 A45T and PAX4 R121W polymorphisms are associated with plasma glucose level of repaglinide monotherapy in Chinese patients with type 2 diabetes. Br J Clin Pharmacol. 2012;74(3):501–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jo W, Endo M, Ishizu K, Nakamura A, Tajima T. A novel PAX4 mutation in a Japanese patient with maturity-onset diabetes of the young. Tohoku J Exp Med. 2011;223(2):113–8.

    Article  CAS  PubMed  Google Scholar 

  134. Plengvidhya N, Kooptiwut S, Songtawee N, Doi A, Furuta H, Nishi M, et al. PAX4 mutations in Thais with maturity onset diabetes of the young. J Clin Endocrinol Metab. 2007;92(7):2821–6.

    Article  CAS  PubMed  Google Scholar 

  135. Tokuyama Y, Matsui K, Ishizuka T, Egashira T, Kanatsuka A. The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus. Metabolism. 2006;55(2):213–6.

    Article  CAS  PubMed  Google Scholar 

  136. Zhang Y, Xiao XH, Wang H, Wang T, Sun Q, Yang GH, et al. Association between A1168C polymorphism in PAX4 gene and type 1 diabetes in Han Chinese. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2007;29(3):370–3.

    CAS  PubMed  Google Scholar 

  137. Brun T, Gauthier BR. A focus on the role of Pax4 in mature pancreatic islet beta-cell expansion and survival in health and disease. J Mol Endocrinol. 2008;40(2):37–45.

    Article  CAS  PubMed  Google Scholar 

  138. Hu He KH, Lorenzo PI, Brun T, Jimenez Moreno CM, Aeberhard D, Vallejo Ortega J, et al. In vivo conditional Pax4 overexpression in mature islet beta-cells prevents stress-induced hyperglycemia in mice. Diabetes. 2011;60(6):1705–15.

    Article  PubMed  CAS  Google Scholar 

  139. Lorenzo PI, Fuente-Martin E, Brun T, Cobo-Vuilleumier N, Jimenez-Moreno CM, G Herrera Gomez I, et al. PAX4 defines an expandable beta-cell subpopulation in the adult pancreatic islet. Sci Rep. 2015;5:15672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Ohmine S, Squillace KA, Hartjes KA, Deeds MC, Armstrong AS, Thatava T, et al. Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency. Aging. 2012;4(1):60–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kelly OG, Chan MY, Martinson LA, Kadoya K, Ostertag TM, Ross KG, et al. Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol. 2011;29(8):750–6.

    Article  CAS  PubMed  Google Scholar 

  142. Cai J, Yu C, Liu Y, Chen S, Guo Y, Yong J, et al. Generation of homogeneous PDX1(+) pancreatic progenitors from human ES cell-derived endoderm cells. J Mol Cell Biol. 2010;2(1):50–60.

    Article  CAS  PubMed  Google Scholar 

  143. Teo AK, Wagers AJ, Kulkarni RN. New opportunities: harnessing induced pluripotency for discovery in diabetes and metabolism. Cell Metab. 2013;18(6):775–91.

    Article  CAS  PubMed  Google Scholar 

  144. Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32(11):1121–33.

    Article  CAS  PubMed  Google Scholar 

  145. Russ HA, Parent AV, Ringler JJ, Hennings TG, Nair GG, Shveygert M, et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 2015;34(13):1759–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hrvatin S, O’Donnell CW, Deng F, Millman JR, Pagliuca FW, DiIorio P, et al. Differentiated human stem cells resemble fetal, not adult, beta cells. Proc Natl Acad Sci U S A. 2014;111(8):3038–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Blum B, Hrvatin SS, Schuetz C, Bonal C, Rezania A, Melton DA. Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3. Nat Biotechnol. 2012;30(3):261–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Jermendy A, Toschi E, Aye T, Koh A, Aguayo-Mazzucato C, Sharma A, et al. Rat neonatal beta cells lack the specialised metabolic phenotype of mature beta cells. Diabetologia. 2011;54(3):594–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Bruin JE, Rezania A, Xu J, Narayan K, Fox JK, O’Neil JJ, et al. Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia. 2013;56(9):1987–98.

    Article  PubMed  Google Scholar 

  150. Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC, et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci U S A. 2010;107(30):13426–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Jeon K, Lim H, Kim JH, Thuan NV, Park SH, Lim YM, 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(14):2642–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Rezania A, Riedel MJ, Wideman RD, Karanu F, Ao Z, Warnock GL, et al. Production of functional glucagon-secreting alpha-cells from human embryonic stem cells. Diabetes. 2011;60(1):239–47.

    Article  CAS  PubMed  Google Scholar 

  153. Basford CL, Prentice KJ, Hardy AB, Sarangi F, Micallef SJ, Li X, et al. The functional and molecular characterisation of human embryonic stem cell-derived insulin-positive cells compared with adult pancreatic beta cells. Diabetologia. 2012;55(2):358–71.

    Article  CAS  PubMed  Google Scholar 

  154. Xie R, Everett LJ, Lim HW, Patel NA, Schug J, Kroon E, et al. Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell. 2013;12(2):224–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Artner I, Blanchi B, Raum JC, Guo M, Kaneko T, Cordes S, et al. MafB is required for islet beta cell maturation. Proc Natl Acad Sci U S A. 2007;104(10):3853–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner-Weir S, et al. A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol. 2006;293(2):526–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Artner I, Hang Y, Mazur M, Yamamoto T, Guo M, Lindner J, et al. MafA and MafB regulate genes critical to beta-cells in a unique temporal manner. Diabetes. 2010;59(10):2530–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Gu C, Stein GH, Pan N, Goebbels S, Hornberg H, Nave KA, et al. Pancreatic beta cells require NeuroD to achieve and maintain functional maturity. Cell Metab. 2010;11(4):298–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Aguayo-Mazzucato C, Zavacki AM, Marinelarena A, Hollister-Lock J, El Khattabi I, Marsili A, et al. Thyroid hormone promotes postnatal rat pancreatic beta-cell development and glucose-responsive insulin secretion through MAFA. Diabetes. 2013;62(5):1569–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Blum B, Roose AN, Barrandon O, Maehr R, Arvanites AC, Davidow LS, et al. Reversal of beta cell de-differentiation by a small molecule inhibitor of the TGFbeta pathway. Elife. 2014;3:e02809.

    PubMed  PubMed Central  Google Scholar 

  161. Schaffer AE, Taylor BL, Benthuysen JR, Liu J, Thorel F, Yuan W, et al. Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic beta cell identity. PLoS Genet. 2013;9(1):e1003274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Li C, Chen P, Vaughan J, Lee KF, Vale W. Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis. Proc Natl Acad Sci U S A. 2007;104(10):4206–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Yamada M, Johannesson B, Sagi I, Burnett LC, Kort DH, Prosser RW, et al. Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells. Nature. 2014;510(7506):533–6.

    Article  CAS  PubMed  Google Scholar 

  164. Abdelalim EM, Bonnefond A, Bennaceur-Griscelli A, Froguel P. Pluripotent stem cells as a potential tool for disease modelling and cell therapy in diabetes. Stem Cell Rev. 2014;10(3):327–37.

    Article  CAS  PubMed  Google Scholar 

  165. Teo AK, Windmueller R, Johansson BB, Dirice E, Njolstad PR, Tjora E, et al. Derivation of human induced pluripotent stem cells from patients with maturity onset diabetes of the young. J Biol Chem. 2013;288(8):5353–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Kudva YC, Ohmine S, Greder LV, Dutton JR, Armstrong A, De Lamo JG, et al. Transgene-free disease-specific induced pluripotent stem cells from patients with type 1 and type 2 diabetes. Stem Cells Transl Med. 2012;1(6):451–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Yabe SG, Iwasaki N, Yasuda K, Hamazaki TS, Konno M, Fukuda S, et al. Establishment of maturity-onset diabetes of the young-induced pluripotent stem cells from a Japanese patient. J Diabetes Investig. 2015;6(5):543–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bhatt S, Gupta MK, Khamaisi M, Martinez R, Gritsenko MA, Wagner BK, et al. Preserved DNA damage checkpoint pathway protects against complications in long-standing type 1 diabetes. Cell Metab. 2015;22(2):239–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Iovino S, Burkart AM, Kriauciunas K, Warren L, Hughes KJ, Molla M, et al. Genetic insulin resistance is a potent regulator of gene expression and proliferation in human iPS cells. Diabetes. 2014;63(12):4130–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Shang L, Hua H, Foo K, Martinez H, Watanabe K, Zimmer M, et al. Beta-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. Diabetes. 2014;63(3):923–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Hanna J, Markoulaki S, Mitalipova M, Cheng AW, Cassady JP, Staerk J, et al. Metastable pluripotent states in NOD-mouse-derived ESCs. Cell Stem Cell. 2009;4(6):513–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448(7151):313–7.

    Article  CAS  PubMed  Google Scholar 

  173. Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science. 2008;322(5903):945–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322(5903):949–53.

    Article  CAS  PubMed  Google Scholar 

  175. Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell. 2009;136(5):964–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature. 2009;458(7239):771–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hamalainen R, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature. 2009;458(7239):766–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell. 2009;4(5):381–4.

    Article  CAS  PubMed  Google Scholar 

  179. Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell. 2009;4(6):472–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Kirk K, Hao E, Lahmy R, Itkin-Ansari P. Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape. Stem Cell Res. 2014;12(3):807–14.

    Article  CAS  PubMed  Google Scholar 

  181. Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell. 2007;1(1):39–49.

    Article  CAS  PubMed  Google Scholar 

  182. Knoepfler PS. Why myc? An unexpected ingredient in the stem cell cocktail. Cell Stem Cell. 2008;2(1):18–21.

    Article  CAS  PubMed  Google Scholar 

  183. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26(1):101–6.

    Article  CAS  PubMed  Google Scholar 

  184. Wernig M, Meissner A, Cassady JP, Jaenisch R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell. 2008;2(1):10–2.

    Article  CAS  PubMed  Google Scholar 

  185. Yakhnenko I, Wong WK, Katkov II, Itkin-Ansari P. Cryopreservation of human insulin expressing cells macro-encapsulated in a durable therapeutic immunoisolating device theracyte. Cryo Letters. 2012;33(6):518–31.

    PubMed  Google Scholar 

  186. Tachibana M, Amato P, Sparman M, Gutierrez NM, Tippner-Hedges R, Ma H, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell. 2013;153(6):1228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Servitja JM, Ferrer J. Transcriptional networks controlling pancreatic development and beta cell function. Diabetologia. 2004;47(4):597–613.

    Article  CAS  PubMed  Google Scholar 

  188. Riggs AC, Bernal-Mizrachi E, Ohsugi M, Wasson J, Fatrai S, Welling C, et al. Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia. 2005;48(11):2313–21.

    Article  CAS  PubMed  Google Scholar 

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    Essam M. Abdelalim Ph.D. & Mohamed M. Emara

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Abdelalim, E.M., Emara, M.M. (2016). Pluripotent Stem Cell-Derived Pancreatic β Cells: From In Vitro Maturation to Clinical Application. In: Abdelalim, E. (eds) Recent Advances in Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-33270-3_6

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