Cano, David A., Rulifson, Ingrid C., Heiser, Patrick W., Swigart, Lamorna B., Pelengaris, Stella, German, Mike, Evan, Gerard I., Bluestone, Jeffrey A. and Hebrok, Matthias. (2008) Regulated beta-cell regeneration in the adult mouse pancreas. Diabetes, Vol.57 (No.4). pp. 958-966. ISSN 0012-1797

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Abstract

Several studies have shown that the adult pancreas possesses a limited potential for beta-cell regeneration upon tissue injury. One of the difficulties in studying P-cell regeneration has been the lack of a robust, synchronized animal model system that would allow controlled regulation of beta-cell loss and subsequent proliferation in adult pancreas. Here we present a transgenic mouse regeneration model in which the c-Myc transcription factor/mutant estrogen receptor (cMycER(TAM)) fusion protein can be specifically activated in mature P-cells. We have studied these transgenic mice by immunohistochemical and biochemical methods to assess the ablation and posterior regeneration of P-cells. Activation of the cMycER(TAM) fusion protein results in synchronous and selective P-cell apoptosis followed by the onset of acute diabetes. Inactivation of c-Myc leads to gradual regeneration of insulin-expressing cells and reversal of diabetes. Our results demonstrate that the mature pancreas has the ability to fully recover from almost complete ablation of all existing beta-cells. Our results also suggest the regeneration of beta-cells is mediated by replication of P-cells rather than neogenesis from pancreatic ducts.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology
Divisions:	Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Mice -- Cytology, Pancreatic beta cells, Regeneration (Biology)
Journal or Publication Title:	Diabetes
Publisher:	American Diabetes Association
ISSN:	0012-1797
Date:	April 2008
Volume:	Vol.57
Number:	No.4
Number of Pages:	9
Page Range:	pp. 958-966
Identification Number:	10.2337/db07-0913
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Sandler Family Supporting Foundation, Juvenile Diabetes Research Foundation (U.K.), University of California, San Francisco. Diabetes and Endocrinology Research Center, National Institutes of Health (U.S.) (NIH), California Institute for Regenerative Medicine
Grant number:	4-2004-372 (JDRF), P30-DK63720 (DERC), 5T32-A107334-13 (NIH)
References:	1. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230 –238, 2000 2. Jiang J, Au M, Lu K, Eshpeter A, Korbutt G, Fisk G, Majumdar AS: Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25:1940 –1953, 2007 3. Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, Nishikawa S, Chiba T, Era T, Nishikawa S: Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol 23:1542–1550, 2005 4. 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 23:1534 –1541, 2005 5. D’Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE: Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392–1401, 2006 6. Kubo A, Shinozaki K, Shannon JM, Kouskoff V, Kennedy M, Woo S, Fehling HJ, Keller G: Development of definitive endoderm from embryonic stem cells in culture. Development 131:1651–1662, 2004 7. Georgia S, Bhushan A: Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest 114:963–968, 2004 8. Kushner JA, Ciemerych MA, Sicinska E, Wartschow LM, Teta M, Long SY, Sicinski P, White MF: Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol 25:3752–3762, 2005 9. Georgia S, Bhushan A: p27 regulates the transition of beta-cells from quiescence to proliferation. Diabetes 55:2950 –2956, 2006 10. Teta M, Long SY, Wartschow LM, Rankin MM, Kushner JA: Very slow turnover of beta-cells in aged adult mice. Diabetes 54:2557–2567, 2005 11. Brennand K, Huangfu D, Melton D: All beta cells contribute equally to islet growth and maintenance. PLoS Biol 5:e163, 2007 12. Dor Y, Brown J, Martinez OI, Melton DA: Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41– 46, 2004 13. Teta M, Rankin MM, Long SY, Stein GM, Kushner JA: Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell 12:817– 826, 2007 14. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE: A second pathway for regeneration of adult exocrine and endocrine pancreas: a possible recapitulation of embryonic development. Diabetes 42:1715–1720, 1993 15. Dudek RW, Lawrence IE, Hill RS, Johnson RC: Induction of islet cytodifferentiation by fetal mesenchyme in adult pancreatic ductal epithelium. Diabetes 40:1041–1048, 1991 16. Kadison AS, Maldonado TS, Crisera CA, Longaker MT, Gittes GK: In vitro validation of duct differentiation in developing embryonic mouse pancreas. J Surg Res 90:126 –130, 2000 17. Pelengaris S, Khan M, Evan GI: Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109:321–334, 2002 18. Kawahira H, Ma NH, Tzanakakis ES, McMahon AP, Chuang PT, Hebrok M: Combined activities of Hedgehog signaling inhibitors regulate pancreas development. Development 130:4871– 4879, 2003 19. Sussel L, Kalamaras J, Hartigan-O’Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS: Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development 125:2213–2221, 1998 20. Cano DA, Sekine S, Hebrok M: Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. Gastroenterology 131:1856 –1869, 2006 21. Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF: Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12:2424 –2433, 1998 22. Lawlor ER, Soucek L, Brown-Swigart L, Shchors K, Bialucha CU, Evan GI: Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis. Cancer Res 66:4591– 4601, 2006 23. Laybutt DR, Weir GC, Kaneto H, Lebet J, Palmiter RD, Sharma A, Bonner-Weir S: Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. Diabetes 51:1793–1804, 2002 24. Edlund H: Transcribing pancreas. Diabetes 47:1817–1823, 1998 25. Sharma A, Zangen DH, Reitz P, Taneja M, Lissauer ME, Miller CP, Weir GC, Habener JF, Bonner-Weir S: The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes 48:507–513, 1999 26. Kritzik MR, Jones E, Chen Z, Krakowski M, Krahl T, Good A, Wright C, Fox H, Sarvetnick N: PDX-1 and Msx-2 expression in the regenerating and developing pancreas. J Endocrinol 163:523–530, 1999 27. Holland AM, Gonez LJ, Naselli G, Macdonald RJ, Harrison LC: Conditional expression demonstrates the role of the homeodomain transcription factor Pdx1 in maintenance and regeneration of beta-cells in the adult pancreas. Diabetes 54:2586 –2595, 2005 28. Rosenberg L: In vivo cell transformation: neogenesis of beta cells from pancreatic ductal cells. Cell Transplant 4:371–383, 1995 29. Bonner-Weir S, Trent DF, Weir GC: Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J Clin Invest 71: 1544–1553, 1983 30. Kritzik MR, Krahl T, Good A, Krakowski M, St-Onge L, Gruss P, Wright C, Sarvetnick N: Transcription factor expression during pancreatic islet regeneration. Mol Cell Endocrinol 164:99 –107, 2000 31. Nir T, Melton DA, Dor Y: Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117:2553–2561, 2007 32. Olson LK, Sharma A, Peshavaria M, Wright CV, Towle HC, Rodertson RP, Stein R: Reduction of insulin gene transcription in HIT-T15 beta cells chronically exposed to a supraphysiologic glucose concentration is associated with loss of STF-1 transcription factor expression. Proc Natl Acad Sci U S A 92:9127–9131, 1995 33. Zangen DH, Bonner-Weir S, Lee CH, Latimer JB, Miller CP, Habener JF, Weir GC: Reduced insulin, GLUT2, and IDX-1 in beta-cells after partial pancreatectomy. Diabetes 46:258 –264, 1997 34. Waguri M, Yamamoto K, Miyagawa JI, Tochino Y, Yamamori K, Kajimoto Y, Nakajima H, Watada H, Yoshiuchi I, Itoh N, Imagawa A, Namba M, Kuwajima M, Yamasaki Y, Hanafusa T, Matsuzawa Y: Demonstration of two different processes of beta-cell regeneration in a new diabetic mouse model induced by selective perfusion of alloxan. Diabetes 46:1281–1290, 1997 35. Bonner-Weir S, Weir GC: New sources of pancreatic beta-cells. Nat Biotechnol 23:857– 861, 2005 36. Trucco M: Regeneration of the pancreatic beta cell. J Clin Invest 115:5–12, 2005 37. Gu D, Sarvetnick N: Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development 118:33– 46, 1993 38. Park SY, Wang X, Chen Z, Powers AC, Magnuson MA, Head WS, Piston DW, Bell GI: Optical imaging of pancreatic beta cells in living mice expressing a mouse insulin I promoter-firefly luciferase transgene. Genesis 43:80–86, 2005 39. Marsh BJ, Mastronarde DN, Buttle KF, Howell KE, McIntosh JR: Organellar relationships in the Golgi region of the pancreatic beta cell line, HIT-T15, visualized by high resolution electron tomography. Proc Natl Acad Sci U S A 98:2399 –2406, 2001 40. Marsh BJ, Soden C, Alarcon C, Wicksteed BL, Yaekura K, Costin AJ, Morgan GP, Rhodes CJ: Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine beta-cells. Mol Endocrinol 21: 2255–2269, 2007
URI:	http://wrap.warwick.ac.uk/id/eprint/30303

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