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

ABSTRACT

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