PDGF signalling controls age-dependent proliferation in pancreatic ?-cells.

ABSTRACT: Determining the signalling pathways that direct tissue expansion is a principal goal of regenerative biology. Vigorous pancreatic ?-cell replication in juvenile mice and humans declines with age, and elucidating the basis for this decay may reveal strategies for inducing ?-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-derived growth factor receptor (Pdgfr) signalling controls age-dependent ?-cell proliferation in mouse and human pancreatic islets. With age, declining ?-cell Pdgfr levels were accompanied by reductions in ?-cell enhancer of zeste homologue 2 (Ezh2) levels and ?-cell replication. Conditional inactivation of the Pdgfra gene in ?-cells accelerated these changes, preventing mouse neonatal ?-cell expansion and adult ?-cell regeneration. Targeted human PDGFR-? activation in mouse ?-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult ?-cells. Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated ?-cell proliferation. The discovery of a conserved pathway controlling age-dependent ?-cell proliferation indicates new strategies for ?-cell expansion.

SUBMITTER: Chen H 

PROVIDER: S-EPMC3503246 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature