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Regulated β-Cell Regeneration in the Adult Mouse Pancreas

¹ Diabetes Center, University of California San Francisco, San Francisco, California
² Comprehensive Cancer Center, University of California San Francisco, San Francisco, California
³ Biological Sciences, University of Warwick, Coventry, U.K

Address correspondence and reprint requests to Jeffrey A. Bluestone, jbluest{at}diabetes.ucsf.edu, or Matthias Hebrok, mhebrok{at}diabetes.ucsf.edu

Abbreviations: AP, alkaline phosphatase; cMycER^TAM, c-Myc transcription factor/mutant estrogen receptor; ER, estrogen receptor; IAPP, islet amyloid polypeptide; Isl1, Islet1; Nkx6.1, NK6 homeobox 1; Pdx1, pancreatic duodenal homeobox 1; pINS, insulin promoter; PP, pancreatic polypeptide; TAM, tamoxifen

Several studies have shown that the adult pancreas possesses a limited potential for β-cell regeneration upon tissue injury. One of the difficulties in studying β-cell regeneration has been the lack of a robust, synchronized animal model system that would allow controlled regulation of β-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 β-cells. We have studied these transgenic mice by immunohistochemical and biochemical methods to assess the ablation and posterior regeneration of β-cells. Activation of the cMycER^TAM fusion protein results in synchronous and selective β-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 β-cells. Our results also suggest the regeneration of β-cells is mediated by replication of β-cells rather than neogenesis from pancreatic ducts.

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