Regulated beta-cell regeneration in the adult mouse pancreas.
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 beta-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 beta-cells. We have studied these transgenic mice by immunohistochemical and biochemical methods to assess the ablation and posterior regeneration of beta-cells. Activation of the cMycER(TAM) fusion protein results in synchronous and selective beta-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 beta-cells rather than neogenesis from pancreatic ducts.
Cano
David A
DA
Diabetes Center, University of California San Francisco, California, USA.
Rulifson
Ingrid C
IC
Heiser
Patrick W
PW
Swigart
Lamorna B
LB
Pelengaris
Stella
S
German
Mike
M
Evan
Gerard I
GI
Bluestone
Jeffrey A
JA
Hebrok
Matthias
M
D000818:Animals; D002455:Cell Division; D003433:Crosses, Genetic; D005934:Glucagon / Q000032:analysis; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010179:Pancreas / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012038:Regeneration
D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D005934:Glucagon