Insulin-producing surrogate β-cells from embryonic stem cells: Are we there yet

Molecular Therapy

Volumn 19, Issue 10, 2011, Pages 1759-1768

  Naujok, Ortwin ^a   Burns, Chris ^b   Jones, Peter M ^c   Lenzen, Sigurd ^a  

^a HANNOVER MEDICAL SCHOOL   (Germany)

^b NATIONAL INSTITUTE FOR BIOLOGICAL STANDARDS AND CONTROL   (United Kingdom)

^c KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

INSULIN;

CELL ACTIVITY; CELL COUNT; CELL DIFFERENTIATION; CELL FUNCTION; CELL LINE; CELL MATURATION; CELL MEMBRANE POTENTIAL; CELL THERAPY; DIABETES MELLITUS; EMBRYONIC STEM CELL; HUMAN; IMMUNE SYSTEM; IN VITRO STUDY; INSULIN RELEASE; INSULIN SYNTHESIS; NONHUMAN; PANCREAS ISLET BETA CELL; PHENOTYPE; PLURIPOTENT STEM CELL; REGENERATIVE MEDICINE; REVIEW; STREPTOZOCIN DIABETES;

EID: 80053560933     PISSN: 15250016     EISSN: 15250024     Source Type: Journal    
DOI: 10.1038/mt.2011.165     Document Type: Review

References (115)

1. Shaw, JE, Sicree, RA and Zimmet, PZ (2010). Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87: 4-14.
2. Feltbower, RG, Bodansky, HJ, Patterson, CC, Parslow, RC, Stephenson, CR, Reynolds, C et al. (2008). Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire Register of diabetes in children and young adults. Diabetes Care 31: 922-926.
3. Huang, ES, Basu, A, O'Grady, M and Capretta, JC (2009). Projecting the future diabetes population size and related costs for the U.S. Diabetes Care 32: 2225-2229.
4. Borowiak, M and Melton, DA (2009). How to make cells? Curr Opin Cell Biol 21: 727-732.
5. Guo, T and Hebrok, M (2009). Stem cells to pancreatic cells: new sources for diabetes cell therapy. Endocr Rev 30: 214-227.
6. Aguayo-Mazzucato, C and Bonner-Weir, S (2010). Stem cell therapy for type 1 diabetes mellitus. Nat Rev Endocrinol 6: 139-148.
7. Halban, PA, German, MS, Kahn, SE and Weir, GC (2010). Current status of islet cell replacement and regeneration therapy. J Clin Endocrinol Metab 95: 1034-1043.
8. Lechner, A, Nolan, AL, Blacken, RA and Habener, JF (2005). Redifferentiation of insulinsecreting cells after in vitro expansion of adult human pancreatic islet tissue. Biochem Biophys Res Commun 327: 581-588. (Pubitemid 40040514)
9. Yatoh, S, Dodge, R, Akashi, T, Omer, A, Sharma, A, Weir, GC et al. (2007). Differentiation of affinity-purified human pancreatic duct cells to cells. Diabetes 56: 1802-1809. (Pubitemid 47025448)
10. Ferber, S, Halkin, A, Cohen, H, Ber, I, Einav, Y, Goldberg, I et al. (2000). Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 6: 568-572. (Pubitemid 30305908)
11. Elsner, M, Jörns, A and Lenzen, S (2008). Diabetes therapy by lentiviral hepatic insulin gene expression without transformation of liver. Diabetologia 51: 694-5; author reply 696.
12. Ianus, A, Holz, GG, Theise, ND and Hussain, MA (2003). In vivo derivation of glucosecompetent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111: 843-850. (Pubitemid 37074959)
13. Assady, S, Maor, G, Amit, M, Itskovitz-Eldor, J, Skorecki, KL and Tzukerman, M (2001). Insulin production by human embryonic stem cells. Diabetes 50: 1691-1697. (Pubitemid 33641584)
14. Lumelsky, N, Blondel, O, Laeng, P, Velasco, I, Ravin, R and McKay, R (2001). Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292: 1389-1394. (Pubitemid 32476228)
15. Lenzen, S (1992). Glucokinase: signal recognition enzyme for glucose-induced insulin secretion. In Flatt PR (ed.). Nutrient Regulation of Insulin Secretion. Portland Press Ltd: Chapel Hill. pp. 101-124.
16. Soria, B, Roche, E, Berná, G, León-Quinto, T, Reig, JA and Martín, F (2000). Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49: 157-162. (Pubitemid 30070992)
17. León-Quinto, T, Jones, J, Skoudy, A, Burcin, M and Soria, B (2004). In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia 47: 1442-1451. (Pubitemid 39232431)
18. Lee, SH, Lumelsky, N, Studer, L, Auerbach, JM and McKay, RD (2000). Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 18: 675-679. (Pubitemid 30415305)
19. Zulewski, H, Abraham, EJ, Gerlach, MJ, Daniel, PB, Moritz, W, Müller, B et al. (2001). Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50: 521-533. (Pubitemid 32195216)
20. Bai, L, Meredith, G and Tuch, BE (2005). Glucagon-like peptide-1 enhances production of insulin in insulin-producing cells derived from mouse embryonic stem cells. J Endocrinol 186: 343-352. (Pubitemid 41167403)
21. Blyszczuk, P, Czyz, J, Kania, G, Wagner, M, Roll, U, St-Onge, L et al. (2003). Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci USA 100: 998-1003. (Pubitemid 36183944)
22. Hansson, M, Tonning, A, Frandsen, U, Petri, A, Rajagopal, J, Englund, MC et al. (2004). Artifactual insulin release from differentiated embryonic stem cells. Diabetes 53: 2603-2609. (Pubitemid 39299268)
23. Hori, Y, Rulifson, IC, Tsai, BC, Heit, JJ, Cahoy, JD and Kim, SK (2002). Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci USA 99: 16105-16110. (Pubitemid 35462756)
24. Moritoh, Y, Yamato, E, Yasui, Y, Miyazaki, S and Miyazaki, J (2003). Analysis of insulinproducing cells during in vitro differentiation from feeder-free embryonic stem cells. Diabetes 52: 1163-1168. (Pubitemid 36523351)
25. Paek, HJ, Morgan, JR and Lysaght, MJ (2005). Sequestration and synthesis: the source of insulin in cell clusters differentiated from murine embryonic stem cells. Stem Cells 23: 862-867. (Pubitemid 41170941)
26. Rajagopal, J, Anderson, WJ, Kume, S, Martinez, OI and Melton, DA (2003). Insulin staining of ES cell progeny from insulin uptake. Science 299: 363. (Pubitemid 36120032)
27. Sipione, S, Eshpeter, A, Lyon, JG, Korbutt, GS and Bleackley, RC (2004). Insulin expressing cells from differentiated embryonic stem cells are not cells. Diabetologia 47: 499-508. (Pubitemid 38491246)
28. Naujok, O, Francini, F, Picton, S, Jörns, A, Bailey, CJ and Lenzen, S (2008). A new experimental protocol for preferential differentiation of mouse embryonic stem cells into insulin-producing cells. Cell Transplant 17: 1231-1242.
29. Segev, H, Fishman, B, Ziskind, A, Shulman, M and Itskovitz-Eldor, J (2004). Differentiation of human embryonic stem cells into insulin-producing clusters. Stem Cells 22: 265-274. (Pubitemid 38736611)
30. Bhushan, A, Itoh, N, Kato, S, Thiery, JP, Czernichow, P, Bellusci, S et al. (2001). Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development 128: 5109-5117. (Pubitemid 34083036)
31. 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: 1392-1401. (Pubitemid 44722103)
32. Kroon, E, Martinson, LA, Kadoya, K, Bang, AG, Kelly, OG, Eliazer, S et al. (2008). Pancreatic endoderm derived from human embryonic stem cells generates glucoseresponsive insulin-secreting cells in vivo. Nat Biotechnol 26: 443-452. (Pubitemid 351501814)
33. 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 insulinproducing cells. Cell Res 19: 429-438.
34. Jeon, J, Correa-Medina, M, Ricordi, C, Edlund, H and Diez, JA (2009). Endocrine cell clustering during human pancreas development. J Histochem Cytochem 57: 811-824.
35. Kubo, A, Shinozaki, K, Shannon, JM, Kouskoff, V, Kennedy, M, Woo, S et al. (2004). Development of definitive endoderm from embryonic stem cells in culture. Development 131: 1651-1662. (Pubitemid 38559291)
36. D'Amour, KA, Agulnick, AD, Eliazer, S, Kelly, OG, Kroon, E and Baetge, EE (2005). Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23: 1534-1541. (Pubitemid 41752931)
37. Adewumi, O, Aflatoonian, B, Ahrlund-Richter, L, Amit, M, Andrews, PW, Beighton, G et al.; International Stem Cell Initiative. (2007). Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol 25: 803-816. (Pubitemid 47052190)
38. Osafune, K, Caron, L, Borowiak, M, Martinez, RJ, Fitz-Gerald, CS, Sato, Y et al. (2008). Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol 26: 313-315. (Pubitemid 351355125)
39. Cho, YM, Lim, JM, Yoo, DH, Kim, JH, Chung, SS, Park, SG et al. (2008). Cellulin and nicotinamide sustain PDX1 expression and induce pancreatic cell differentiation in human embryonic stem cells. Biochem Biophys Res Commun 366: 129-134. (Pubitemid 350297223)
40. Ahlgren, U, Jonsson, J, Jonsson, L, Simu, K and Edlund, H (1998). Cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the cell phenotype and maturity onset diabetes. Genes Dev 12: 1763-1768. (Pubitemid 28304328)
41. Courtney, ML, Jones, PM and Burns, CJ (2010). Importance of quantitative analysis in the generation of insulin-expressing cells from human embryonic stem cells. Pancreas 39: 105-107.
42. 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: 1228-1238. (Pubitemid 46701546)
43. Jiang, J, Au, M, Lu, K, Eshpeter, A, Korbutt, G, Fisk, G et al. (2007). Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25: 1940-1953. (Pubitemid 47258172)
44. Jiang, W, Shi, Y, Zhao, D, Chen, S, Yong, J, Zhang, J et al. (2007). In vitro derivation of functional insulin-producing cells from human embryonic stem cells. Cell Res 17: 333-344. (Pubitemid 46639938)
45. Luther, MJ, Hauge-Evans, A, Souza, KL, Jörns, A, Lenzen, S, Persaud, SJ et al. (2006). MIN6 cell cell interactions influence insulin secretory responses to nutrients and non-nutrients. Biochem Biophys Res Commun 343: 99-104.
46. Barrientos, R, Baltrusch, S, Sigrist, S, Legeay, G, Belcourt, A and Lenzen, S (2009). Kinetics of insulin secretion from MIN6 pseudoislets after encapsulation in a prototype device of a bioartificial pancreas. Horm Metab Res 41: 5-9.
47. Fujikawa, T, Oh, SH, Pi, L, Hatch, HM, Shupe, T and Petersen, BE (2005). Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cellderived insulin-producing cells. Am J Pathol 166: 1781-1791. (Pubitemid 40734401)
48. Eshpeter, A, Jiang, J, Au, M, Rajotte, RV, Lu, K, Lebkowski, JS et al. (2008). In vivo characterization of transplanted human embryonic stem cell-derived pancreatic endocrine islet cells. Cell Prolif 41: 843-858.
49. Naujok, O, Francini, F, Picton, S, Bailey, CJ, Lenzen, S and Jörns, A (2009). Changes in gene expression and morphology of mouse embryonic stem cells on differentiation into insulin-producing cells in vitro and in vivo. Diabetes Metab Res Rev 25: 464-476.
50. Matveyenko, AV, Georgia, S, Bhushan, A and Butler, PC (2010). Inconsistent formation and nonfunction of insulin-positive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats. Am J Physiol Endocrinol Metab 299: E713-E720.
51. Zhu, S, Wurdak, H, Wang, J, Lyssiotis, CA, Peters, EC, Cho, CY et al. (2009). A small molecule primes embryonic stem cells for differentiation. Cell Stem Cell 4: 416-426.
52. 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: 258-265.
53. Borowiak, M, Maehr, R, Chen, S, Chen, AE, Tang, W, Fox, JL et al. (2009). Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem Cell 4: 348-358.
54. Yanagita, RC, Nakagawa, Y, Yamanaka, N, Kashiwagi, K, Saito, N and Irie, K (2008). Synthesis, conformational analysis, and biological evaluation of 1-hexylindolactam-V10 as a selective activator for novel protein kinase C isozymes. J Med Chem 51: 46-56.
55. Nakagawa, Y, Irie, K, Yanagita, RC, Ohigashi, H and Tsuda, K (2005). Indolactam-V is involved in the CH/pi interaction with Pro-11 of the PKC C1B domain: application for the structural optimization of the PKC ligand. J Am Chem Soc 127: 5746-5747. (Pubitemid 40577606)
56. Nitti, M, Furfaro, AL, Cevasco, C, Traverso, N, Marinari, UM, Pronzato, MA et al. (2010). PKC and NADPH oxidase in retinoic acid-induced neuroblastoma cell differentiation. Cell Signal 22: 828-835.
57. Kambhampati, S, Li, Y, Verma, A, Sassano, A, Majchrzak, B, Deb, DK et al. (2003). Activation of protein kinase C by all-trans-retinoic acid. J Biol Chem 278: 32544-32551. (Pubitemid 37055692)
58. Leitges, M, Plomann, M, Standaert, ML, Bandyopadhyay, G, Sajan, MP, Kanoh, Y et al. (2002). Knockout of PKC enhances insulin signaling through PI3K. Mol Endocrinol 16: 847-858. (Pubitemid 34297752)
59. Standaert, ML, Bandyopadhyay, G, Galloway, L, Soto, J, Ono, Y, Kikkawa, U et al. (1999). Effects of knockout of the protein kinase C gene on glucose transport and glucose homeostasis. Endocrinology 140: 4470-4477. (Pubitemid 30666110)
60. Hennige, AM, Ranta, F, Heinzelmann, I, Düfer, M, Michael, D, Braumüller, H et al. (2010). Overexpression of kinase-negative protein kinase C in pancreatic cells protects mice from diet-induced glucose intolerance and cell dysfunction. Diabetes 59: 119-127.
61. Uchida, T, Iwashita, N, Ohara-Imaizumi, M, Ogihara, T, Nagai, S, Choi, JB et al. (2007). Protein kinase C plays a non-redundant role in insulin secretion in pancreatic cells. J Biol Chem 282: 2707-2716. (Pubitemid 47076769)
62. Champeris Tsaniras, S and Jones, PM (2010). Generating pancreatic cells from embryonic stem cells by manipulating signaling pathways. J Endocrinol 206: 13-26.
63. Mfopou, JK, Chen, B, Sui, L, Sermon, K and Bouwens, L (2010). Recent advances and prospects in the differentiation of pancreatic cells from human embryonic stem cells. Diabetes 59: 2094-2101.
64. Takahashi, K and Yamanaka, S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676. (Pubitemid 44233629)
65. 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: 861-872. (Pubitemid 350138099)
66. Yu, J, Vodyanik, MA, Smuga-Otto, K, Antosiewicz-Bourget, J, Frane, JL, Tian, S et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917-1920.
67. Shi, Y, Do, JT, Desponts, C, Hahm, HS, Schöler, HR and Ding, S (2008). A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2: 525-528. (Pubitemid 351729222)
68. Aasen, T, Raya, A, Barrero, MJ, Garreta, E, Consiglio, A, Gonzalez, F et al. (2008). Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26: 1276-1284.
69. Loh, YH, Agarwal, S, Park, IH, Urbach, A, Huo, H, Heffner, GC et al. (2009). Generation of induced pluripotent stem cells from human blood. Blood 113: 5476-5479.
70. Stadtfeld, M, Brennand, K and Hochedlinger, K (2008). Reprogramming of pancreatic cells into induced pluripotent stem cells. Curr Biol 18: 890-894.
71. 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: 699-702.
72. Huangfu, D, Maehr, R, Guo, W, Eijkelenboom, A, Snitow, M, Chen, AE et al. (2008). Induction of pluripotent stem cells by defined factors is greatly improved by smallmolecule compounds. Nat Biotechnol 26: 795-797. (Pubitemid 351961456)
73. Okita, K, Ichisaka, T and Yamanaka, S (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448: 313-317. (Pubitemid 47080336)
74. Yu, J, Hu, K, Smuga-Otto, K, Tian, S, Stewart, R, Slukvin, II et al. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science 324: 797-801.
75. Woltjen, K, Michael, IP, Mohseni, P, Desai, R, Mileikovsky, M, Hämäläinen, R et al. (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458: 766-770.
76. Soldner, F, Hockemeyer, D, Beard, C, Gao, Q, Bell, GW, Cook, EG et al. (2009). Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136: 964-977.
77. Voelkel, C, Galla, M, Maetzig, T, Warlich, E, Kuehle, J, Zychlinski, D et al. (2010). Protein transduction from retroviral Gag precursors. Proc Natl Acad Sci USA 107: 7805-7810.
78. Zhou, H, Wu, S, Joo, JY, Zhu, S, Han, DW, Lin, T et al. (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4: 381-384.
79. Kim, D, Kim, CH, Moon, JI, Chung, YG, Chang, MY, Han, BS et al. (2009). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4: 472-476.
80. Tateishi, K, He, J, Taranova, O, Liang, G, D'Alessio, AC and Zhang, Y (2008). Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 283: 31601-31607.
81. 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 USA 106: 15768-15773.
82. Yamanaka, S (2009). Elite and stochastic models for induced pluripotent stem cell generation. Nature 460: 49-52.
83. Guenther, MG, Frampton, GM, Soldner, F, Hockemeyer, D, Mitalipova, M, Jaenisch, R et al. (2010). Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7: 249-257.
84. Polo, JM, Liu, S, Figueroa, ME, Kulalert, W, Eminli, S, Tan, KY et al. (2010). Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol 28: 848-855.
85. Kim, K, Doi, A, Wen, B, Ng, K, Zhao, R, Cahan, P et al. (2010). Epigenetic memory in induced pluripotent stem cells. Nature 467: 285-290.
86. Doi, A, Park, IH, Wen, B, Murakami, P, Aryee, MJ, Irizarry, R et al. (2009). Differential methylation of tissue-and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41: 1350-1353.
87. Deng, J, Shoemaker, R, Xie, B, Gore, A, LeProust, EM, Antosiewicz-Bourget, J et al. (2009). Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol 27: 353-360.
88. Stadtfeld, M, Apostolou, E, Akutsu, H, Fukuda, A, Follett, P, Natesan, S et al. (2010). Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465: 175-181.
89. Lister, R, Pelizzola, M, Kida, YS, Hawkins, RD, Nery, JR, Hon, G et al. (2011). Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471: 68-73.
90. Hu, BY, Weick, JP, Yu, J, Ma, LX, Zhang, XQ, Thomson, JA et al. (2010). Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci USA 107: 4335-4340.
91. Jozefczuk, J, Prigione, A, Chavez, L and Adjaye, J (2011). Comparative analysis of human embryonic stem cell and induced pluripotent stem cell-derived hepatocyte-like cells reveals current drawbacks and possible strategies for improved differentiation. Stem Cells Dev 20: 1259-1275.
92. Laurent, LC, Ulitsky, I, Slavin, I, Tran, H, Schork, A, Morey, R et al. (2011). Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8: 106-118.
93. Hussein, SM, Batada, NN, Vuoristo, S, Ching, RW, Autio, R, Närvä, E et al. (2011). Copy number variation and selection during reprogramming to pluripotency. Nature 471: 58-62.
94. Gore, A, Li, Z, Fung, HL, Young, JE, Agarwal, S, Antosiewicz-Bourget, J et al. (2011). Somatic coding mutations in human induced pluripotent stem cells. Nature 471: 63-67.
95. Mayshar, Y, Ben-David, U, Lavon, N, Biancotti, JC, Yakir, B, Clark, AT et al. (2010). Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7: 521-531.
96. Miura, K, Okada, Y, Aoi, T, Okada, A, Takahashi, K, Okita, K et al. (2009). Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 27: 743-745.
97. Zhao, T, Zhang, ZN, Rong, Z and Xu, Y (2011). Immunogenicity of induced pluripotent stem cells. Nature 474: 212-215.
98. Evans, MJ and Kaufman, MH (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature 292: 154-156. (Pubitemid 11050741)
99. Thomson, JA, Itskovitz-Eldor, J, Shapiro, SS, Waknitz, MA, Swiergiel, JJ, Marshall, VS et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282: 1145-1147. (Pubitemid 28516247)
100. Blum, B and Benvenisty, N (2008). The tumorigenicity of human embryonic stem cells. Adv Cancer Res 100: 133-158. (Pubitemid 351932182)
101. Knoepfler, PS (2009). Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells 27: 1050-1056.
102. Klug, MG, Soonpaa, MH, Koh, GY and Field, LJ (1996). Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest 98: 216-224. (Pubitemid 26243839)
103. Drobinskaya, I, Linn, T, Saric, T, Bretzel, RG, Bohlen, H, Hescheler, J et al. (2008). Scalable selection of hepatocyte-and hepatocyte precursor-like cells from culture of differentiating transgenically modified murine embryonic stem cells. Stem Cells 26: 2245-2256.
104. Naujok, O, Kaldrack, J, Taivankhuu, T, Jörns, A and Lenzen, S (2010). Selective removal of undifferentiated embryonic stem cells from differentiation cultures through HSV1 thymidine kinase and ganciclovir treatment. Stem Cell Rev 6: 450-461.
105. Choo, AB, Tan, HL, Ang, SN, Fong, WJ, Chin, A, Lo, J et al. (2008). Selection against undifferentiated human embryonic stem cells by a cytotoxic antibody recognizing podocalyxin-like protein-1. Stem Cells 26: 1454-1463.
106. Tan, HL, Fong, WJ, Lee, EH, Yap, M and Choo, A (2009). mAb 84, a cytotoxic antibody that kills undifferentiated human embryonic stem cells via oncosis. Stem Cells 27: 1792-1801.
107. Vierbuchen, T, Ostermeier, A, Pang, ZP, Kokubu, Y, Südhof, TC and Wernig, M (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463: 1035-1041.
108. Szabo, E, Rampalli, S, Risueño, RM, Schnerch, A, Mitchell, R, Fiebig-Comyn, A et al. (2010). Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468: 521-526.
109. Efe, JA, Hilcove, S, Kim, J, Zhou, H, Ouyang, K, Wang, G et al. (2011). Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 13: 215-222.
110. Huang, P, He, Z, Ji, S, Sun, H, Xiang, D, Liu, C et al. (2011). Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475:386-389.
111. Zhou, Q, Brown, J, Kanarek, A, Rajagopal, J and Melton, DA (2008). In vivo reprogramming of adult pancreatic exocrine cells to cells. Nature 455: 627-632.
112. Sibley, RK, Sutherland, DE, Goetz, F and Michael, AF (1985). Recurrent diabetes mellitus in the pancreas iso-and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest 53: 132-144. (Pubitemid 15049005)
113. Shiroi, A, Yoshikawa, M, Yokota, H, Fukui, H, Ishizaka, S, Tatsumi, K, et al. (2002). Identification of insulin-producing cells derived from embryonic stem cells by zincchelating dithizone. Stem Cells 20: 284-292. (Pubitemid 34765087)
114. Houard, N, Rousseau, GG and Lemaigre, FP (2003). HNF-6-independent differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia 46: 378-385. (Pubitemid 36547593)
115. Miyazaki, S, Yamato, E and Miyazaki, J (2004). Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes 53: 1030-1037. (Pubitemid 38436615)