How to make a functional β-cell

Development (Cambridge)

Volumn 140, Issue 12, 2013, Pages 2472-2483

  Pagliuca, Felicia W ^a,b   Melton, Douglas A ^a,b  

^a Harvard University   (United States)

^b HARVARD STEM CELL INSTITUTE   (United States)

Author keywords

; Cell; Diabetes mellitus; Mammalian metabolism

Indexed keywords

GLUCOSE; HEPATOCYTE NUCLEAR FACTOR 3BETA; INSULIN; NEUROGENIC DIFFERENTIATION FACTOR; NEUROGENIN 3; PROTEIN; PTF1A PROTEIN; TRANSCRIPTION FACTOR NKX6.1; TRANSCRIPTION FACTOR PDX 1; TRANSCRIPTION FACTOR SOX17; TRANSCRIPTION FACTOR SOX9; UNCLASSIFIED DRUG;

ARTICLE; CELL DIFFERENTIATION; CELL DIVISION; CELL FUNCTION; CELL TYPE; ECTODERM; ENDOCRINE CELL; ENDODERM; GLUCOSE BLOOD LEVEL; HUMAN; INSULIN RELEASE; MESODERM; MOLECULAR MECHANICS; NONHUMAN; PANCREAS ISLET ALPHA CELL; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL;

Β CELL; DIABETES MELLITUS; MAMMALIAN METABOLISM;

ACINAR CELLS; ANIMALS; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL TRANSDIFFERENTIATION; DIABETES MELLITUS; ENDODERM; GLUCAGON-SECRETING CELLS; GLUCOSE; HUMANS; INSULIN RESISTANCE; INSULIN-SECRETING CELLS; NUCLEAR REPROGRAMMING; PLURIPOTENT STEM CELLS;

MAMMALIA;

EID: 84878340278     PISSN: 09501991     EISSN: 14779129     Source Type: Journal    
DOI: 10.1242/dev.093187     Document Type: Article

References (135)

1. Ang, S. L. and Rossant, J. (1994). HNF-3 beta is essential for node and notochord formation in mouse development. Cell 78, 561-574.
2. Annes, J. P., Ryu, J. H., Lam, K., Carolan, P. J., Utz, K., Hollister-Lock, J., Arvanites, A. C., Rubin, L. L., Weir, G. and Melton, D. A. (2012). Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication. Proc. Natl. Acad. Sci. USA 109, 3915-3920.
3. Apelqvist, A., Ahlgren, U. and Edlund, H. (1997). Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr. Biol. 7, 801-804.
4. Apelqvist, A., Li, H., Sommer, L., Beatus, P., Anderson, D. J., Honjo, T., Hrabe de Angelis, M., Lendahl, U. and Edlund, H. (1999). Notch signalling controls pancreatic cell differentiation. Nature 400, 877-881.
5. Araki, R., Uda, M., Hoki, Y., Sunayama, M., Nakamura, M., Ando, S., Sugiura, M., Ideno, H., Shimada, A., Nifuji, A. et al. (2013). Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494, 100-104.
6. Ashcroft, F. M. and Rorsman, P. (2012). Diabetes mellitus and the β cell: the last ten years. Cell 148, 1160-1171.
7. Bellin, M. D., Barton, F. B., Heitman, A., Harmon, J. V., Kandaswamy, R., Balamurugan, A. N., Sutherland, D. E., Alejandro, R. and Hering, B. J. (2012). Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am. J. Transplant. 12, 1576-1583.
8. Bhushan, A., Itoh, N., Kato, S., Thiery, J. P., Czernichow, P., Bellusci, S. and Scharfmann, R. (2001). Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development 128, 5109-5117.
9. Blum, B., Hrvatin, S., Schuetz, C., Bonal, C., Rezania, A., and Melton, D. A. (2012). Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3. Nat. Biotechnol. 30, 261-264.
10. Bonner-Weir, S., Deery, D., Leahy, J. L. and Weir, G. C. (1989). Compensatory growth of pancreatic β-cells in adult rats after short-term glucose infusion. Diabetes 38, 49-53.
11. Bramswig, N. C., Everett, L. J., Schug, J., Dorrell, C., Liu, C., Luo, Y., Streeter, P. R., Naji, A., Grompe, M. and Kaestner, K. H. (2013). Epigenomic plasticity enables human pancreatic α to β cell reprogramming. J. Clin. Invest. 123, 1275-1284.
12. Brelje, T. C., Stout, L. E., Bhagroo, N. V. and Sorenson, R. L. (2004). Distinctive roles for prolactin and growth hormone in the activation of signal transducer and activator of transcription 5 in pancreatic islets of langerhans. Endocrinology 145, 4162-4175.
13. Brennan, J., Lu, C. C., Norris, D. P., Rodriguez, T. A., Beddington, R. S. and Robertson, E. J. (2001). Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411, 965-969.
14. Butler, A. E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R. A. and Butler, P. C. (2003). β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102-110.
15. Butler, A. E., Cao-Minh, L., Galasso, R., Rizza, R. A., Corradin, A., Cobelli, C. and Butler, P. C. (2010). Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 53, 2167-2176.
16. Caballero, F., Siniakowicz, K., Hollister-Lock, J., Duran, L., Katsuta, H., Yamada, T., Lei, J., Deng, S., Westermark, G. T., Markmann, J. et al. (2013). Birth and death of human β-cells in pancreas from cadaver donors, autopsies, surgical specimens, and islets transplanted into mice. Cell Transplant doi:10.3727/096368912X659916.
17. Caro, J. J., Ward, A. J. and O'Brien, J. A. (2002). Lifetime costs of complications resulting from type 2 diabetes in the U.S. Diabetes Care 25, 476-481.
18. Chen, C. Z., Li, L., Lodish, H. F. and Bartel, D. P. (2004). MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83-86.
19. Chen, S., Borowiak, M., Fox, J. L., Maehr, R., Osafune, K., Davidow, L., Lam, K., Peng, L. F., Schreiber, S. L., Rubin, L. L. et al. (2009). A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat. Chem. Biol. 5, 258-265.
20. Chen, A. E., Borowiak, M., Sherwood, R. I., Kweudjeu, A. and Melton, D. A. (2013). Functional evaluation of ES cell-derived endodermal populations reveals differences between Nodal and Activin A-guided differentiation. Development 140, 675-686.
21. Cheng, X., Ying, L., Lu, L., Galvao, A. M., Mills, J. A., Lin, H. C., Kotton, D. N., Shen, S. S., Nostro, M. C., Choi, J. K. et al. (2012). Self-renewing endodermal progenitor lines generated from human pluripotent stem cells. Cell Stem Cell 10, 371-384.
22. Chintinne, M., Stange, G., Denys, B., Ling, Z., In 't Veld, P. and Pipeleers, D. (2012). Beta cell count instead of beta cell mass to assess and localize growth in beta cell population following pancreatic duct ligation in mice. PLoS ONE 7, e43959.
23. Collombat, P., Xu, X., Ravassard, P., Sosa-Pineda, B., Dussaud, S., Billestrup, N., Madsen, O. D., Serup, P., Heimberg, H. and Mansouri, A. (2009). The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 138, 449-462.
24. Collombat, P., Xu, X., Heimberg, H. and Mansouri, A. (2010). Pancreatic betacells: from generation to regeneration. Semin. Cell Dev. Biol. 21, 838-844.
25. D'Amour, K. A., Agulnick, A. D., Eliazer, S., Kelly, O. G., Kroon, E. and Baetge, E. E. (2005). Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23, 1534-1541.
26. D'Amour, K. A., Bang, A. G., Eliazer, S., Kelly, O. G., Agulnick, A. D., Smart, N. G., Moorman, M. A., Kroon, E., Carpenter, M. K. and Baetge, E. E. (2006). Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392-1401.
27. Desgraz, R., Bonal, C. and Herrera, P. L. (2011). β-cell regeneration: the pancreatic intrinsic faculty. Trends Endocrinol. Metab. 22, 34-43.
28. Ding, Q., Lee, Y.-K., Schaefer, E. A., Peters, D. T., Veres, A., Kim, K., Kuperwasser, N., Motola, D. L., Meissner, T. B., Hendriks, W. T. et al. (2013). A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell 12, 238-251.
29. Dor, Y. and Melton, D. A. (2004). How important are adult stem cells for tissue maintenance? Cell Cycle 3, 1104-1106.
30. El Ouaamari, A., Kawamori, D., Dirice, E., Liew, C. W., Shadrach, J. L., Hu, J. et al. (2013). Liver-derived systemic factors drive β cell hyperplasia in insulin-resistant states. Cell Reports 3, 401-410.
31. Eng, J., Kleinman, W. A., Singh, L., Singh, G. and Raufman, J. P. (1992). Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J. Biol. Chem. 267, 7402-7405.
32. Fonseca, V. (2003). Clinical significance of targeting postprandial and fasting hyperglycemia in managing type 2 diabetes mellitus. Curr. Med. Res. Opin. 19, 635-641.
33. Gaber, A. O., Fraga, D. W., Callicutt, C. S., Gerling, I. C., Sabek, O. M. and Kotb, M. Y. (2001). Improved in vivo pancreatic islet function after prolonged in vitro islet culture. Transplantation 72, 1730-1736.
34. Gannon, M., Herrera, P. L. and Wright, C. V. (2000). Mosaic Cre-mediated recombination in pancreas using the pdx-1 enhancer/promoter. Genesis 26, 143-144.
35. Gao, N., LeLay, J., Vatamaniuk, M. Z., Rieck, S., Friedman, J. R. and Kaestner, K. H. (2008). Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev. 22, 3435-3448.
36. Gradwohl, G., Dierich, A., LeMeur, M. and Guillemot, F. (2000). neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc. Natl. Acad. Sci. USA 97, 1607-1611.
37. Gu, G., Dubauskaite, J. and Melton, D. A. (2002). Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, 2447-2457.
38. Guha, P., Morgan, J. W., Mostoslavsky, G., Rodrigues, N. P. and Boyd, A. S. (2013). Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell 12, 407-412.
39. Hanna, J., Wernig, M., Markoulaki, S., Sun, C.-W., Meissner, A., Cassady, J. P., Beard, C., Brambrink, T., Wu, L. C., Townes, T. M. et al. (2007). Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920-1923.
40. Hebrok, M., Kim, S. K. and Melton, D. A. (1998). Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 12, 1705-1713.
41. Huang, P., He, Z., Ji, S., Sun, H., Xiang, D., Liu, C., Hu, Y., Wang, X. and Hui, L. (2011). Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475, 386-389.
42. Ieda, M., Fu, J. D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B. G. and Srivastava, D. (2010). Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375-386.
43. Jensen, J., Pedersen, E. E., Galante, P., Hald, J., Heller, R. S., Ishibashi, M., Kageyama, R., Guillemot, F., Serup, P. and Madsen, O. D. (2000). Control of endodermal endocrine development by Hes-1. Nat. Genet. 24, 36-44.
44. Jonsson, J., Carlsson, L., Edlund, T. and Edlund, H. (1994). Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371, 606-609.
45. Kanai-Azuma, M., Kanai, Y., Gad, J. M., Tajima, Y., Taya, C., Kurohmaru, M., Sanai, Y., Yonekawa, H., Yazaki, K., Tam, P. P. et al. (2002). Depletion of definitive gut endoderm in Sox17-null mutant mice. Development 129, 2367-2379.
46. Karnik, S. K., Chen, H., McLean, G. W., Heit, J. J., Gu, X., Zhang, A. Y., Fontaine, M., Yen, M. H. and Kim, S. K. (2007). Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus. Science 318, 806-809.
47. Kassem, S. A., Ariel, I., Thornton, P. S., Scheimberg, I. and Glaser, B. (2000). Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49, 1325-1333.
48. Kassem, S., Bhandari, S., Rodriguez-Bada, P., Motaghedi, R., Heyman, M., Garcia-Gimeno, M. A., Cobo-Vuilleumier, N., Sanz, P., Maclaren, N. K., Rahier, J. et al. (2010). Large islets, beta-cell proliferation, and a glucokinase mutation. N. Engl. J. Med. 362, 1348-1350.
49. Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R. J. and Wright, C. V. (2002). The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat. Genet. 32, 128-134.
50. Keirstead, H. S., Nistor, G., Bernal, G., Totoiu, M., Cloutier, F., Sharp, K. and Steward, O. (2005). Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J. Neurosci. 25, 4694-4705.
51. Keymeulen, B., Gillard, P., Mathieu, C., Movahedi, B., Maleux, G., Delvaux, G., Ysebaert, D., Roep, B., Vandemeulebroucke, E., Marichal, M. et al. (2006). Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft. Proc. Natl. Acad. Sci. USA 103, 17444-17449.
52. Kim, S. K. and Melton, D. A. (1998). Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc. Natl. Acad. Sci. USA 95, 13036-13041.
53. Kim, S. K., Hebrok, M. and Melton, D. A. (1997). Notochord to endoderm signaling is required for pancreas development. Development 124, 4243-4252.
54. Kopp, J. L., Dubois, C. L., Hao, E., Thorel, F., Herrera, P. L. and Sander, M. (2011a). Progenitor cell domains in the developing and adult pancreas. Cell Cycle 10, 1921-1927.
55. Kopp, J. L., Dubois, C. L., Schaffer, A. E., Hao, E., Shih, H. P., Seymour, P. A., Ma, J. and Sander, M. (2011b). Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138, 653-665.
56. Krapp, A., Knofler, M., Ledermann, B., Burki, K., Berney, C., Zoerkler, N., Hagenbuchle, O. and Wellauer, P. K. (1998). The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 12, 3752-3763.
57. Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J. et al. (2008). Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26, 443-452.
58. Lacy, P. E. L. and Scharp, D. W. S. (1986). Islet transplantation in treating diabetes. Annu. Rev. Med. 37, 33-40.
59. Lammert, E., Cleaver, O. and Melton, D. (2001). Induction of pancreatic differentiation by signals from blood vessels. Science 294, 564-567.
60. Lee, S. H., Hao, E., Savinov, A. Y., Geron, I., Strongin, A. Y. and Itkin-Ansari, P. (2009). Human β-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies. Transplantation 87, 983-991.
61. Levitt, H. E., Cyphert, T. J., Pascoe, J. L., Hollern, D. A., Abraham, N., Lundell, R. J., Rosa, T., Romano, L. C., Zou, B., O'Donnell, C. P. et al. (2011). Glucose stimulates human beta cell replication in vivo in islets transplanted into NODsevere combined immunodeficiency (SCID) mice. Diabetologia 54, 572-582.
62. Li, Z., Gadue, P., Chen, K., Jiao, Y., Tuteja, G., Schug, J., Li, W. and Kaestner, K. H. (2012). Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation. Cell 151, 1608-1616.
63. Lowry, W. E., Richter, L., Yachechko, R., Pyle, A. D., Tchieu, J., Sridharan, R., Clark, A. T. and Plath, K. (2008). Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl. Acad. Sci. USA 105, 2883-2888.
64. Lynn, F. C., Skewes-Cox, P., Kosaka, Y., McManus, M. T., Harfe, B. D. and German, M. S. (2007). MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes 56, 2938-2945.
65. Martin, M., Gallego-Llamas, J., Ribes, V., Kedinger, M., Niederreither, K., Chambon, P., Dolle, P. and Gradwohl, G. (2005). Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. Dev. Biol. 284, 399-411.
66. Matschinsky, F. M. (2009). Assessing the potential of glucokinase activators in diabetes therapy. Nat. Rev. Drug Discov. 8, 399-416.
67. McCracken, K. W. and Wells, J. M. (2012). Molecular pathways controlling pancreas induction. Semin. Cell Dev. Biol. 23, 656-662.
68. Melkman-Zehavi, T., Oren, R., Kredo-Russo, S., Shapira, T., Mandelbaum, A. D., Rivkin, N., Nir, T., Lennox, K. A., Behlke, M. A., Dor, Y. et al. (2011). miRNAs control insulin content in pancreatic β-cells via downregulation of transcriptional repressors. EMBO J. 30, 835-845.
69. Michael, M. D., Kulkarni, R. N., Postic, C., Previs, S. F., Shulman, G. I., Magnuson, M. A. and Kahn, C. R. (2000). Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87-97.
70. Molotkov, A., Molotkova, N. and Duester, G. (2005). Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Dev. Dyn. 232, 950-957.
71. Moran, I., Akerman, I., van de Bunt, M., Xie, R., Benazra, M., Nammo, T., Arnes, L., Nakić, N., Garcia-Hurtado, J., Rodriguez-Segui, S. et al. (2012). Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab. 16, 435-448.
72. Mullen, Y. S., Clark, W. R., Molnar, I. G. and Brown, J. (1977). Complete reversal of experimental diabetes mellitus in rats by a single fetal pancreas. Science 195, 68-70.
73. Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N. and Yamanaka, S. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 26, 101-106.
74. Nathan, D. M., Zinman, B., Cleary, P. A., Backlund, J. Y., Genuth, S., Miller, R., Orchard, T. J. and Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group (2009). Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005). Arch. Intern. Med. 169, 1307-1316.
75. Nikolova, G., Jabs, N., Konstantinova, I., Domogatskaya, A., Tryggvason, K., Sorokin, L., Fassler, R., Gu, G., Gerber, H. P., Ferrara, N. et al. (2006). The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Dev. Cell 10, 397-405.
76. Noguchi, H., Naziruddin, B., Jackson, A., Shimoda, M., Ikemoto, T., Fujita, Y., Chujo, D., Takita, M., Peng, H., Sugimoto, K. et al. (2012). Fresh islets are more effective for islet transplantation than cultured islets. Cell Transplant. 21, 517-523.
77. Nostro, M. C., Sarangi, F., Ogawa, S., Holtzinger, A., Corneo, B., Li, X., Micallef, S. J., Park, I. H., Basford, C., Wheeler, M. B. et al. (2011). Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development 138, 861-871.
78. Offield, M. F., Jetton, T. L., Labosky, P. A., Ray, M., Stein, R. W., Magnuson, M. A., Hogan, B. L. and Wright, C. V. (1996). PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983-995.
79. Ohlsson, H., Karlsson, K. and Edlund, T. (1993). IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 12, 4251-4259.
80. Okita, K., Ichisaka, T. and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317.
81. Okita, K., Hong, H., Takahashi, K. and Yamanaka, S. (2010). Generation of mouse-induced pluripotent stem cells with plasmid vectors. Nat. Protoc. 5, 418-428.
82. Pan, F. C. and Wright, C. (2011). Pancreas organogenesis: from bud to plexus to gland. Dev. Dyn. 240, 530-565.
83. Pan, F. C., Bankaitis, E. D., Boyer, D., Xu, X., Van de Casteele, M., Magnuson, M. A., Heimberg, H. and Wright, C. V. (2013). Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140, 751-764.
84. Parsons, J. A., Brelje, T. C. and Sorenson, R. L. (1992). Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology 130, 1459-1466.
85. Perl, S., Kushner, J. A., Buchholz, B. A., Meeker, A. K., Stein, G. M., Hsieh, M., Kirby, M., Pechhold, S., Liu, E. H., Harlan, D. M. et al. (2010). Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating. J. Clin. Endocrinol. Metab. 95, E234-E239.
86. Porat, S., Weinberg-Corem, N., Tornovsky-Babaey, S., Schyr-Ben-Haroush, R., Hija, A., Stolovich-Rain, M., Dadon, D., Granot, Z., Ben-Hur, V., White, P. et al. (2011). Control of pancreatic β cell regeneration by glucose metabolism. Cell Metab. 13, 440-449.
87. Powers, A. C. and D'Alessio, D. (2011). Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edn (ed. B. A. Chabner, L. L. Brunton and B. C. Knollman). New York: McGraw-Hill.
88. Poy, M. N., Eliasson, L., Krutzfeldt, J., Kuwajima, S., Ma, X., Macdonald, P. E., Pfeffer, S., Tuschl, T., Rajewsky, N., Rorsman, P. et al. (2004). A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226-230.
89. Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C. and Henquin, J. C. (2008). Pancreatic β-cell mass in European subjects with type 2 diabetes. Diabetes Obes. Metab. 10 Suppl. 4, 32-42.
90. Rankin, M. M., Wilbur, C. J., Rak, K., Shields, E. J., Granger, A. and Kushner, J. A. (2013). Beta cells are not generated in pancreatic duct ligation induced injury in adult mice. Diabetes 62, 1634-1645.
91. Rezania, A., Bruin, J. E., Riedel, M. J., Mojibian, M., Asadi, A., Xu, J., Gauvin, R., Narayan, K., Karanu, F., O'Neil, J. J. et al. (2012). Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 61, 2016-2029.
92. Schaffer, L., Brissette, R. E., Spetzler, J. C., Pillutla, R. C., Ostergaard, S., Lennick, M., Brandt, J., Fletcher, P. W., Danielsen, G. M., Hsiao, K. C. et al. (2003). Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks. Proc. Natl. Acad. Sci. USA 100, 4435-4439.
93. Schaffer, L., Brand, C. L., Hansen, B. F., Ribel, U., Shaw, A. C., Slaaby, R. and Sturis, J. (2008). A novel high-affinity peptide antagonist to the insulin receptor. Biochem. Biophys. Res. Commun. 376, 380-383.
94. Schaffer, A. E., Freude, K. K., Nelson, S. B. and Sander, M. (2010). Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev. Cell 18, 1022-1029.
95. Scholin, A., Bjorklund, L., Borg, H., Arnqvist, H., Bjork, E., Blohme, G., Bolinder, J., Eriksson, J. W., Gudbjornsdottir, S., Nystrom, L. et al. (2004). Islet antibodies and remaining β-cell function 8 years after diagnosis of diabetes in young adults: a prospective follow-up of the nationwide Diabetes Incidence Study in Sweden. J. Intern. Med. 255, 384-391.
96. Schulz, T. C., Young, H. Y., Agulnick, A. D., Babin, M. J., Baetge, E. E., Bang, A. G., Bhoumik, A., Cepa, I., Cesario, R. M., Haakmeester, C. et al. (2012). A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PLoS ONE 7, e37004.
97. Shapiro, A. M., Lakey, J. R., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M. and Rajotte, R. V. (2000). Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230-238.
98. Shapiro, A. M., Ricordi, C., Hering, B. J., Auchincloss, H., Lindblad, R., Robertson, R. P., Secchi, A., Brendel, M. D., Berney, T., Brennan, D. C. et al. (2006). International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med. 355, 1318-1330.
99. Shen, W., Tremblay, M. S., Deshmukh, V. A., Wang, W., Filippi, C. M., Harb, G., Zhang, Y. Q., Kamireddy, A., Baaten, J. E., Jin, Q. et al. (2013). Smallmolecule inducer of β cell proliferation identified by high-throughput screening. J. Am. Chem. Soc. 135, 1669-1672.
100. Shiba, Y., Fernandes, S., Zhu, W. Z., Filice, D., Muskheli, V., Kim, J., Palpant, N. J., Gantz, J., Moyes, K. W., Reinecke, H. et al. (2012). Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489, 322-325.
101. Sneddon, J. B., Borowiak, M. and Melton, D. A. (2012). Self-renewal of embryonic-stem-cell-derived progenitors by organ-matched mesenchyme. Nature 491, 765-768.
102. Solar, M., Cardalda, C., Houbracken, I., Martin, M., Maestro, M. A., De Medts, N., Xu, X., Grau, V., Heimberg, H., Bouwens, L. et al. (2009). Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev. Cell 17, 849-860.
103. Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G., and Gruss, P. (1997). The pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature 386, 399-402.
104. Stafford, D. and Prince, V. E. (2002). Retinoic acid signaling is required for a critical early step in zebrafish pancreatic development. Curr. Biol. 12, 1215-1220.
105. Stoffers, D. A., Zinkin, N. T., Stanojevic, V., Clarke, W. L. and Habener, J. F. (1997). Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat. Genet. 15, 106-110.
106. Stoffers, D. A., Kieffer, T. J., Hussain, M. A., Drucker, D. J., Bonner-Weir, S., Habener, J. F. and Egan, J. M. (2000). Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 49, 741-748.
107. Stolovich-Rain, M., Hija, A., Grimsby, J., Glaser, B. and Dor, Y. (2012). Pancreatic beta cells in very old mice retain capacity for compensatory proliferation. J. Biol. Chem. 287, 27407-27414.
108. 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.
109. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872.
110. Talchai, C., Xuan, S., Lin, H. V., Sussel, L. and Accili, D. (2012). Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150, 1223-1234.
111. Terauchi, Y., Takamoto, I., Kubota, N., Matsui, J., Suzuki, R., Komeda, K., Hara, A., Toyoda, Y., Miwa, I., Aizawa, S. et al. (2007). Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. J. Clin. Invest. 117, 246-257.
112. Teta, M., Long, S. Y., Wartschow, L. M., Rankin, M. M. and Kushner, J. A. (2005). Very slow turnover of β-cells in aged adult mice. Diabetes 54, 2557-2567.
113. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S. and Jones, J. M. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145-1147.
114. Thorel, F., Nepote, V., Avril, I., Kohno, K., Desgraz, R., Chera, S. and Herrera, P. L. (2010). Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149-1154.
115. Tian, L., Gao, J., Weng, G., Yi, H., Tian, B., O'Brien, T. D. and Guo, Z. (2011). Comparison of exendin-4 on beta-cell replication in mouse and human islet grafts. Transpl. Int. 24, 856-864.
116. Tremblay, K. D. (2010). Formation of the murine endoderm: lessons from the mouse, frog, fish, and chick. Prog. Mol. Biol. Transl. Sci. 96, 1-34.
117. Van Assche, F. A., Aerts, L. and De Prins, F. (1978). A morphological study of the endocrine pancreas in human pregnancy. Br. J. Obstet. Gynaecol. 85, 818-820.
118. van der Meulen, T., Xie, R., Kelly, O. G., Vale, W. W., Sander, M. and Huising, M. O. (2012). Urocortin 3 marks mature human primary and embryonic stem cell-derived pancreatic alpha and beta cells. PLoS ONE 7, e52181.
119. Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Sudhof, T. C. and Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035-1041.
120. Vikram, A. and Jena, G. (2010). S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats. Biochem. Biophys. Res. Commun. 398, 260-265.
121. Wandzioch, E. and Zaret, K. S. (2009). Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science 324, 1707-1710.
122. Wang, R. N., Kloppel, G. and Bouwens, L. (1995). Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia 38, 1405-1411.
123. Wang, W., Walker, J. R., Wang, X., Tremblay, M. S., Lee, J. W., Wu, X. and Schultz, P. G. (2009). Identification of small-molecule inducers of pancreatic β-cell expansion. Proc. Natl. Acad. Sci. USA 106, 1427-1432.
124. Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A. et al. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618-630.
125. Weinstein, D. C., Ruiz i Altaba, A., Chen, W. S., Hoodless, P., Prezioso, V. R., Jessell, T. M. and Darnell, J. E., Jr (1994). The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell 78, 575-588.
126. Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B. E. and Jaenisch, R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318-324.
127. Xie, R., Everett, L. J., Lim, H. W., Patel, N. A., Schug, J., Kroon, E. et al. (2013). Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell 12, 224-237.
128. Xu, G., Stoffers, D. A., Habener, J. F. and Bonner-Weir, S. (1999). Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48, 2270-2276.
129. Xu, X., D'Hoker, J., Stange, G., Bonne, S., De Leu, N., Xiao, X., Van de Casteele, M., Mellitzer, G., Ling, Z., Pipeleers, D. et al. (2008). Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132, 197-207.
130. Yi, P. Y., Park, J. and Melton, D. M. (2013). Betatrophin: a hormone that controls pancreatic beta cell proliferation. Cell 153, 747-758.
131. Yoshitomi, H. and Zaret, K. S. (2004). Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131, 807-817.
132. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R. et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.
133. Zhao, T., Zhang, Z. N., Rong, Z. and Xu, Y. (2011). Immunogenicity of induced pluripotent stem cells. Nature 474, 212-215.
134. Zhou, Q. and Melton, D. A. (2008). Extreme makeover: converting one cell into another. Cell Stem Cell 3, 382-388.
135. Zhou, Q., Law, A. C., Rajagopal, J., Anderson, W. J., Gray, P. A. and Melton, D. A. (2007). A multipotent progenitor domain guides pancreatic organogenesis. Dev. Cell 13, 103-114.