Skip to main content

Advertisement

Log in

β-cell regeneration: Neogenesis, replication or both?

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Both type I and type II diabetes are characterized by β-cell loss and dysfunction. Therefore, a major goal of diabetes therapy is to promote the formation of new β-cells, either in vitro for transplantation or in vivo, i.e., β-cell regeneration. The question of whether β-cell regeneration occurs by replication of preexisting β-cells or by neogenesis from a precursor within the pancreas is a major focus of interest. Lineage-tracing studies have found evidence only for β-cell replication, while earlier studies based upon the appearance of insulin-positive cells in areas outside of islets formed the basis for the belief that neogenesis from precursors can occur in adult animals. Recently, we found that nonendocrine pancreatic epithelial cells could be induced to undergo endocrine differentiation under the influence of inductive factors from the human fetal pancreas. One possibility is that, similar to models of hepatocyte regeneration, β-cells can arise either by neogenesis or replication, depending on the particular stimulus. Clearly, understanding the nature and control of β-cell regeneration is critical for success in efforts to treat diabetes by β-cell replacement.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Shih DQ, Stoffel M (2002) Molecular etiologies of MODY and other early-onset forms of diabetes. Curr Diab Rep 2:125–134

    Article  PubMed  Google Scholar 

  2. Tourrel C, Bailbe D, Lacorne M, Meile MJ, Kergoat M, Portha B (2002) Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes 51:1443–1452

    Article  PubMed  CAS  Google Scholar 

  3. Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC (2005) Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48:2221–2228

    Article  PubMed  CAS  Google Scholar 

  4. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110

    Article  PubMed  CAS  Google Scholar 

  5. Hummel KP, Coleman DL, Lane PW (1972) The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL-KsJ and C57BL-6J strains. Biochem Genet 7:1–13

    Article  PubMed  CAS  Google Scholar 

  6. Hummel KP, Dickie MM, Coleman DL (1966) Diabetes, a new mutation in the mouse. Science 153:1127–1128

    Article  PubMed  CAS  Google Scholar 

  7. Clee SM, Attie AD (2007) The genetic landscape of type 2 diabetes in mice. Endocr Rev 28:48–83

    Article  PubMed  CAS  Google Scholar 

  8. Nakagami T, Qiao Q, Carstensen B, Nhr-Hansen C, Hu G, Tuomilehto J, Balkau B, Borch-Johnsen K (2003) Age, body mass index and Type 2 diabetes-associations modified by ethnicity. Diabetologia 46:1063–1070

    Article  PubMed  CAS  Google Scholar 

  9. Kuroe A, Fukushima M, Usami M, Ikeda M, Nakai Y, Taniguchi A, Matsuura T, Suzuki H, Kurose T, Yasuda K, Yamada Y, Seino Y (2003) Impaired beta-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance. Diabetes Res Clin Pract 59:71–77

    Article  PubMed  CAS  Google Scholar 

  10. Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, Shizuru JA, Weissman IL (2003) Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol 21:759–806

    Article  PubMed  CAS  Google Scholar 

  11. Deutsch G, Jung J, Zheng M, Lora J, Zaret KS (2001) A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development 128:871–881

    PubMed  CAS  Google Scholar 

  12. Fausto N, Riehle KJ (2005) Mechanisms of liver regeneration and their clinical implications. J Hepatobiliary Pancreat Surg 12:181–189

    Article  PubMed  Google Scholar 

  13. Weber LW, Boll M, Stampfl A (2003) Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 33:105–136

    Article  PubMed  CAS  Google Scholar 

  14. Lemire JM, Shiojiri N, Fausto N (1991) Oval cell proliferation and the origin of small hepatocytes in liver injury induced by d-galactosamine. Am J Pathol 139:535–552

    PubMed  CAS  Google Scholar 

  15. Akhurst B, Croager EJ, Farley-Roche CA, Ong JK, Dumble ML, Knight B, Yeoh GC (2001) A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology 34:519–522

    Article  PubMed  CAS  Google Scholar 

  16. Evarts RP, Nagy P, Nakatsukasa H, Marsden E, Thorgeirsson SS (1989) In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res 49:1541–1547

    PubMed  CAS  Google Scholar 

  17. Evarts RP, Nagy P, Marsden E, Thorgeirsson SS (1987) A precursor–product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 8:1737–1740

    Article  PubMed  CAS  Google Scholar 

  18. Teta M, Rankin MM, Long SY, Stein GM, Kushner JA (2007) Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell 12:817–826

    Article  PubMed  CAS  Google Scholar 

  19. Like AA, Chick WL (1969) Mitotic division in pancreatic beta cells. Science 163:941–943

    Article  PubMed  CAS  Google Scholar 

  20. Like AA, Chick WL (1970) Studies in the diabetic mutant mouse. I. Light microscopy and radioautography of pancreatic islets. Diabetologia 6:207–215

    Article  PubMed  CAS  Google Scholar 

  21. Logothetopoulos J, Bell EG (1966) Histological and autoradiographic studies of the islets of mice injected with insulin antibody. Diabetes 15:205–211

    PubMed  CAS  Google Scholar 

  22. Davidson PM, Campbell IL, Oxbrow L, Hutson JM, Harrison LC (1989) Pancreatic beta cell proliferation in rabbits demonstrated by bromodeoxyuridine labeling. Pancreas 4:594–600

    Article  PubMed  CAS  Google Scholar 

  23. Meier JJ, Lin JC, Butler AE, Galasso R, Martinez DS, Butler PC (2006) Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia

  24. Sorenson RL, Brelje TC (1997) Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm Metab Res 29:301–307

    PubMed  CAS  Google Scholar 

  25. Steil GM, Trivedi N, Jonas JC, Hasenkamp WM, Sharma A, Bonner-Weir S, Weir GC (2001) Adaptation of beta-cell mass to substrate oversupply: enhanced function with normal gene expression. Am J Physiol Endocrinol Metab 280:E788–E796

    PubMed  CAS  Google Scholar 

  26. Vasavada RC, Gonzalez-Pertusa JA, Fujinaka Y, Fiaschi-Taesch N, Cozar-Castellano I, Garcia-Ocana A (2006) Growth factors and beta cell replication. Int J Biochem Cell Biol 38:931–950

    Article  PubMed  CAS  Google Scholar 

  27. Brelje TC, Parsons JA, Sorenson RL (1994) Regulation of islet beta-cell proliferation by prolactin in rat islets. Diabetes 43:263–273

    Article  PubMed  CAS  Google Scholar 

  28. Meier JJ, Butler AE, Galasso R, Rizza RA, Butler PC (2006) Increased islet beta cell replication adjacent to intrapancreatic gastrinomas in humans. Diabetologia 49:2689–2696

    Article  PubMed  CAS  Google Scholar 

  29. Brand SJ, Tagerud S, Lambert P, Magil SG, Tatarkiewicz K, Doiron K, Yan Y (2002) Pharmacological treatment of chronic diabetes by stimulating pancreatic beta-cell regeneration with systemic co-administration of EGF and gastrin. Pharmacol Toxicol 91:414–420

    Article  PubMed  CAS  Google Scholar 

  30. Xu G, Stoffers DA, Habener JF, 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

    Article  PubMed  CAS  Google Scholar 

  31. Path G, Opel A, Gehlen M, Rothhammer V, Niu X, Limbert C, Romfeld L, Hugl S, Knoll A, Brendel MD, Bretzel RG, Seufert J (2006) Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo. Am J Physiol Endocrinol Metab 291:E1168–E1176

    Article  PubMed  CAS  Google Scholar 

  32. Rabinovitch A, Quigley C, Rechler MM (1983) Growth hormone stimulates islet B-cell replication in neonatal rat pancreatic monolayer cultures. Diabetes 32:307–312

    Article  PubMed  CAS  Google Scholar 

  33. Hayek A, Beattie GM, Cirulli V, Lopez AD, Ricordi C, Rubin JS (1995) Growth factor/matrix-induced proliferation of human adult beta-cells. Diabetes 44:1458–1460

    Article  PubMed  CAS  Google Scholar 

  34. Garcia-Ocana A, Takane KK, Syed MA, Philbrick WM, Vasavada RC, Stewart AF (2000) Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia. J Biol Chem 275:1226–1232

    Article  PubMed  CAS  Google Scholar 

  35. Beattie GM, Itkin-Ansari P, Cirulli V, Leibowitz G, Lopez AD, Bossie S, Mally MI, Levine F, Hayek A (1999) Sustained proliferation of PDX-1+ cells derived from human islets. Diabetes 48:1013–1019

    Article  PubMed  CAS  Google Scholar 

  36. Halvorsen TL, Beattie GM, Lopez AD, Hayek A, Levine F (2000) Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro. J Endocrinol 166:103–109

    Article  PubMed  CAS  Google Scholar 

  37. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457

    Article  PubMed  CAS  Google Scholar 

  38. Maedler K, Schumann DM, Schulthess F, Oberholzer J, Bosco D, Berney T, Donath MY (2006) Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1. Diabetes 55:2455–2462

    Article  PubMed  CAS  Google Scholar 

  39. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney AS, Burton PR, Clayton DG, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Davison D, Easton D, Evans D, Leung HT, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskvina V, Nikolov I, O’Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop DT, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Mathew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop GM, Connell J, Dominiczak A, Braga Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hider SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Ferreira T, Pereira-Gale J, Hallgrimsdottir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Compston A, Ouwehand NJ, Samani MR, Isaacs JD, Morgan AW, Wilson GD, Ardern-Jones A, Berg J, Brady A, Bradshaw N, Brewer C, Brice G, Bullman B, Campbell J, Castle B, Cetnarsryj R, Chapman C, Chu C, Coates N, Cole T, Davidson R, Donaldson A, Dorkins H, Douglas F, Eccles D, Eeles R, Elmslie F, Evans DG, Goff S, Goodman S, Goudie D, Gray J, Greenhalgh L, Gregory H, Hodgson SV, Homfray T, Houlston RS, Izatt L, Jackson L, Jeffers L, Johnson-Roffey V, Kavalier F, Kirk C, Lalloo F, Langman C, Locke I, Longmuir M, Mackay J, Magee A, Mansour S, Miedzybrodzka Z, Miller J, Morrison P, Murday V, Paterson J, Pichert G, Porteous M, Rahman N, Rogers M, Rowe S, Shanley S, Saggar A, Scott G, Side L, Snadden L, Steel M, Thomas M, Thomas S, McCarthy MI, Hattersley AT (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341

    Article  PubMed  CAS  Google Scholar 

  40. Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22:44–52

    Article  PubMed  CAS  Google Scholar 

  41. Cebrian A, Garcia-Ocana A, Takane KK, Sipula D, Stewart AF, Vasavada RC (2002) Overexpression of parathyroid hormone-related protein inhibits pancreatic beta-cell death in vivo and in vitro. Diabetes 51:3003–3013

    Article  PubMed  CAS  Google Scholar 

  42. Garcia-Ocana A, Vasavada RC, Cebrian A, Reddy V, Takane KK, Lopez-Talavera JC, Stewart AF (2001) Transgenic overexpression of hepatocyte growth factor in the beta-cell markedly improves islet function and islet transplant outcomes in mice. Diabetes 50:2752–2762

    Article  PubMed  CAS  Google Scholar 

  43. Krakowski ML, Kritzik MR, Jones EM, Krahl T, Lee J, Arnush M, Gu D, Mroczkowski B, Sarvetnick N (1999) Transgenic expression of epidermal growth factor and keratinocyte growth factor in beta-cells results in substantial morphological changes. J Endocrinol 162:167–175

    Article  PubMed  CAS  Google Scholar 

  44. Rachdi L, Balcazar N, Elghazi L, Barker DJ, Krits I, Kiyokawa H, Bernal-Mizrachi E (2006) Differential effects of p27 in regulation of beta-cell mass during development, neonatal period, and adult life. Diabetes 55:3520–3528

    Article  PubMed  CAS  Google Scholar 

  45. Levine F (1997) Gene therapy for diabetes: strategies for beta-cell modification and replacement. Diabetes Metab Rev 13:209–246

    Article  PubMed  CAS  Google Scholar 

  46. Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:33–40

    Article  Google Scholar 

  47. Wang S, Beattie GM, Mally MI, Cirulli V, Itkin-Ansari P, Lopez AD, Hayek A, Levine F (1997) Isolation and characterization of a cell line from the epithelial cells of the human fetal pancreas. Cell Transplant 6:59–67

    Article  PubMed  CAS  Google Scholar 

  48. Halvorsen TL, Leibowitz G, Levine F (1999) Telomerase activity is sufficient to allow transformed cells to escape from crisis. Mol Cell Biol 19:1864–1870

    PubMed  CAS  Google Scholar 

  49. Demeterco C, Itkin-Ansari P, Tyrberg B, Ford L, Jarvis R, Yoo S-J, Levine F (2002) c-Myc controls proliferation versus differentiation in human pancreatic endocrine cells. J Clin Endocrinol Metab 87:3475–3485

    Article  PubMed  CAS  Google Scholar 

  50. Dufayet de la Tour D, Halvorsen T, Demeterco C, Tyrberg B, Itkin-Ansari P, Loy M, Yoo S-J, Hao E, Bossie S, Levine F (2001) β-cell differentiation from a human pancreatic cell line in vitro and in vivo. Mol Endocrinol 15:476–483

    Article  Google Scholar 

  51. Itkin-Ansari P, Demeterco C, Bossie S, de la Tour DD, Beattie GM, Movassat J, Mally MI, Hayek A, Levine F (2000) PDX-1 and cell–cell contact act in synergy to promote delta-cell development in a human pancreatic endocrine precursor cell line. Mol Endocrinol 14:814–822

    Article  PubMed  CAS  Google Scholar 

  52. Karnik SK, Hughes CM, Gu X, Rozenblatt-Rosen O, McLean GW, Xiong Y, Meyerson M, Kim SK (2005) Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci U S A 102:14659–14664

    Article  PubMed  CAS  Google Scholar 

  53. Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, Schnepp RW, Krankel C, Livolsi VA, Gibbs D, Hua X, Roeder RG, Meyerson M, Hess JL (2005) Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci U S A 102:749–754

    Article  PubMed  CAS  Google Scholar 

  54. Bertolino P, Tong WM, Herrera PL, Casse H, Zhang CX, Wang ZQ (2003) Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Cancer Res 63:4836–4841

    PubMed  CAS  Google Scholar 

  55. Schnepp RW, Chen YX, Wang H, Cash T, Silva A, Diehl JA, Brown E, Hua X (2006) Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells. Cancer Res 66:5707–5715

    Article  PubMed  CAS  Google Scholar 

  56. Cozar-Castellano I, Fiaschi-Taesch N, Bigatel TA, Takane KK, Garcia-Ocana A, Vasavada R, Stewart AF (2006) Molecular control of cell cycle progression in the pancreatic beta-cell. Endocr Rev 27:356–370

    Article  PubMed  CAS  Google Scholar 

  57. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512

    Article  PubMed  CAS  Google Scholar 

  58. Kassem SA, Ariel I, Thornton PS, Hussain K, Smith V, Lindley KJ, Aynsley-Green A, Glaser B (2001) p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy. Diabetes 50:2763–2769

    Article  PubMed  CAS  Google Scholar 

  59. Uchida T, Nakamura T, Hashimoto N, Matsuda T, Kotani K, Sakaue H, Kido Y, Hayashi Y, Nakayama KI, White MF, Kasuga M (2005) Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med 11:175–182

    Article  PubMed  CAS  Google Scholar 

  60. Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA, Elledge SJ (1997) Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 387:151–158

    Article  PubMed  CAS  Google Scholar 

  61. Cozar-Castellano I, Haught M, Stewart AF (2006) The cell cycle inhibitory protein p21cip is not essential for maintaining beta-cell cycle arrest or beta-cell function in vivo. Diabetes 55:3271–3278

    Article  PubMed  CAS  Google Scholar 

  62. Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ (1999) The p21(Cip1) and p27(Kip1) CDK ’inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 18:1571–1583

    Article  PubMed  CAS  Google Scholar 

  63. Cozar-Castellano I, Takane KK, Bottino R, Balamurugan AN, Stewart AF (2004) Induction of beta-cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenovirus-mediated transfer of cyclin-dependent kinase-4 and cyclin D1. Diabetes 53:149–159

    Article  PubMed  CAS  Google Scholar 

  64. Brennand K, Huangfu D, Melton D (2007) All beta Cells Contribute Equally to Islet Growth and Maintenance. PLoS biology 5:e163

    Article  PubMed  Google Scholar 

  65. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE (1993) A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 42:1715–1720

    Article  PubMed  CAS  Google Scholar 

  66. Rosenberg L (1998) Induction of islet cell neogenesis in the adult pancreas: the partial duct obstruction model. Microsc Res Tech 43:337–346

    Article  PubMed  CAS  Google Scholar 

  67. Page BJ, du Toit DF, Muller CJ, Mattysen J, Lyners R (2000) An immunocytochemical profile of the endocrine pancreas using an occlusive duct ligation model. Jop 1:191–203

    PubMed  CAS  Google Scholar 

  68. Rosenberg L (1995) In vivo cell transformation: neogenesis of beta cells from pancreatic ductal cells. Cell Transplant 4:371–383

    Article  PubMed  CAS  Google Scholar 

  69. Gu D, Sarvetnick N (1993) Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development 117:1–14

    Google Scholar 

  70. Lardon J, Huyens N, Rooman I, Bouwens L (2004) Exocrine cell transdifferentiation in dexamethasone-treated rat pancreas. Virchows Arch 444:61–65

    Article  PubMed  Google Scholar 

  71. Suzuki T, Kadoya Y, Sato Y, Handa K, Takahashi T, Kakita A, Yamashina S (2003) The expression of pancreatic endocrine markers in centroacinar cells of the normal and regenerating rat pancreas: their possible transformation to endocrine cells. Arch Histol Cytol 66:347–358

    Article  PubMed  CAS  Google Scholar 

  72. Nagasao J, Yoshioka K, Amasaki H, Mutoh K (2003) Centroacinar and intercalated duct cells as potential precursors of pancreatic endocrine cells in rats treated with streptozotocin. Ann Anat 185:211–216

    Article  PubMed  Google Scholar 

  73. Guz Y, Nasir I, Teitelman G (2001) Regeneration of Pancreatic beta Cells from Intra-Islet Precursor Cells in an Experimental Model of Diabetes. Endocrinology 142:4956–4968

    Article  PubMed  CAS  Google Scholar 

  74. Bertelli E, Bendayan M (1997) Intermediate endocrine-acinar pancreatic cells in duct ligation conditions. Am J Physiol 273:C1641–C1649

    PubMed  CAS  Google Scholar 

  75. Gu D, Arnush M, Sarvetnick N (1997) Endocrine/exocrine intermediate cells in streptozotocin-treated Ins-IFN-gamma transgenic mice. Pancreas 15:246–250

    Article  PubMed  CAS  Google Scholar 

  76. Baeyens L, De Breuck S, Lardon J, Mfopou JK, Rooman I, Bouwens L (2005) in vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells. Diabetologia 48:49–57

    Article  PubMed  CAS  Google Scholar 

  77. Kerr-Conte J, Pattou F, Lecomte-Houcke M, Xia Y, Boilly B, Proye C, Lefebvre J (1996) Ductal cyst formation in collagen-embedded adult human islet preparations. A means to the reproduction of nesidioblastosis in vitro. Diabetes 45:1108–1114

    Article  PubMed  CAS  Google Scholar 

  78. Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O’Neil JJ (2000) In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci U S A 97:7999–8004

    Article  PubMed  CAS  Google Scholar 

  79. Verrou C, Zhang Y, Zurn C, Schamel WW, Reth M (1999) Comparison of the tamoxifen regulated chimeric Cre recombinases MerCreMer and CreMer. Biol Chem 380:1435–1438

    Article  PubMed  CAS  Google Scholar 

  80. Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46

    Article  PubMed  CAS  Google Scholar 

  81. Bonner-Weir S, Sharma A (2006) Are there pancreatic progenitor cells from which new islets form after birth? Nature Clin Prac 2:240–241

    Article  Google Scholar 

  82. Levine F, Mercola M (2004) No pancreatic endocrine stem cells? N Engl J Med 351:1024–1026

    Article  PubMed  CAS  Google Scholar 

  83. Desai B, Farzad C, De Leon DD, Guoping S, Leach SD, Stoffers DA (2005) Mature pancreatic acinar cells do not transdifferentiate into islet endocrine cells after partial pancreatectomy or duct ligation in mice. Diabetes 54:A56

    Google Scholar 

  84. Means AL, Meszoely IM, Suzuki K, Miyamoto Y, Rustgi AK, Coffey RJ, Jr, Wright CV, Stoffers DA, Leach SD (2005) Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132:3767–3776

    Article  PubMed  CAS  Google Scholar 

  85. Inada A, Nienaber C, Fonseca S, Bonner-Weir S (2006) Timing and expression pattern of carbonic anhydrase II in pancreas. Dev Dyn 235:1571–1577

    Article  PubMed  CAS  Google Scholar 

  86. Inada A, Nienaber C, Sharma A, Bonner-Weir S (2006) Lineage Tracing Shows Pancreatic Ductal Cells as Islet Progenitors in Postnatal Mice. Diabetes 55:Abstract 131-OR

  87. Teta M, Long SY, Wartschow LM, Rankin MM, Kushner JA (2005) Very slow turnover of beta-cells in aged adult mice. Diabetes 54:2557–2567

    Article  PubMed  CAS  Google Scholar 

  88. Swenne I (1983) Effects of aging on the regenerative capacity of the pancreatic B-cell of the rat. Diabetes 32:14–19

    Article  PubMed  CAS  Google Scholar 

  89. Guo C, Yang W, Lobe CG (2002) A Cre recombinase transgene with mosaic, widespread tamoxifen-inducible action. Genesis 32:8–18

    Article  PubMed  CAS  Google Scholar 

  90. Bonner-Weir S, Toschi E, Inada A, Reitz P, Fonseca SY, Aye T, Sharma A (2004) The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes 5(Suppl 2):16–22

    Article  PubMed  Google Scholar 

  91. Finegood DT, Scaglia L, Bonner-Weir S (1995) Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44:249–256

    Article  PubMed  CAS  Google Scholar 

  92. Tyrberg B, Andersson A, Borg LAH (2001) Species differences in susceptibility of transplanted and cultured pancreatic islets to the β-cell toxin alloxan. Gen Comp Endocrinol 122:238–251

    Article  PubMed  CAS  Google Scholar 

  93. Castaing M, Duvillie B, Quemeneur E, Basmaciogullari A, Scharfmann R (2005) Ex vivo analysis of acinar and endocrine cell development in the human embryonic pancreas. Dev Dyn 234:339–345

    Article  PubMed  CAS  Google Scholar 

  94. Hao E, Tyrberg B, Itkin-Ansari P, Lakey J, Monosov E, Barcova M, Mercola M, Levine F (2006) Beta-cell differentiation from non-endocrine epithelial cells of the adult human pancreas. Nat Med 12:310–316

    Article  PubMed  CAS  Google Scholar 

  95. Heimberg H, Bouwens L, Heremans Y, Van De Casteele M, Lefebvre V, Pipeleers D (2000) Adult human pancreatic duct and islet cells exhibit similarities in expression and differences in phosphorylation and complex formation of the homeodomain protein Ipf-1. Diabetes 49:571–579

    Article  PubMed  CAS  Google Scholar 

  96. Heremans Y, Van De Casteele M, in’t Veld P, Gradwohl G, Serup P, Madsen O, Pipeleers D, Heimberg H (2002) Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3. J Cell Biol 159:303–312

    Article  PubMed  CAS  Google Scholar 

  97. Street CN, Lakey JR, Rajotte RV, Shapiro AM, Kieffer TJ, Lyon JG, Kin T, Korbutt GS (2004) Enriched human pancreatic ductal cultures obtained from selective death of acinar cells express pancreatic and duodenal homeobox gene-1 age-dependently. Rev Diabetic Stud 1:66–79

    Article  PubMed  Google Scholar 

  98. Beattie G, M, Levine F, Mally MI, Otonkoski T, O’Brien JS, Salomon DR, Hayek A (1994) Acid beta-galactosidase: a developmentally regulated marker of endocrine cell precursors in the human fetal pancreas. J Clin Endocrinol Metab 78:1232–1240

    Article  PubMed  CAS  Google Scholar 

  99. Bogdani M, Lefebvre V, Buelens N, Bock T, Pipeleers-Marichal M, In’t Veld P, Pipeleers D (2003) Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors. Diabetologia 46:830–838

    Article  PubMed  CAS  Google Scholar 

  100. Leibowitz G, Beattie GM, Kafri T, Cirulli V, Lopez AD, Hayek A, Levine F (1999) Gene transfer to human pancreatic endocrine cells using viral vectors. Diabetes 48:745–753

    Article  PubMed  CAS  Google Scholar 

  101. Gershengorn MC, Hardikar AA, Wei C, Geras-Raaka E, Marcus-Samuels B, Raaka BM (2004) Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science 306:2261–2264

    Article  PubMed  CAS  Google Scholar 

  102. Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK, Habener JF (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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the NIDDK and JDRF for funding.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fred Levine.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levine, F., Itkin-Ansari, P. β-cell regeneration: Neogenesis, replication or both?. J Mol Med 86, 247–258 (2008). https://doi.org/10.1007/s00109-007-0259-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-007-0259-1

Keywords

Navigation