PDGF signalling controls age-dependent proliferation in pancreatic β-cells

H Chen, X Gu, Y Liu, J Wang, SE Wirt, R Bottino… - Nature, 2011 - nature.com
H Chen, X Gu, Y Liu, J Wang, SE Wirt, R Bottino, H Schorle, J Sage, SK Kim
Nature, 2011nature.com
Determining the signalling pathways that direct tissue expansion is a principal goal of
regenerative biology. Vigorous pancreatic β-cell replication in juvenile mice and humans
declines with age, and elucidating the basis for this decay may reveal strategies for inducing
β-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-
derived growth factor receptor (Pdgfr) signalling controls age-dependent β-cell proliferation
in mouse and human pancreatic islets. With age, declining β-cell Pdgfr levels were …
Abstract
Determining the signalling pathways that direct tissue expansion is a principal goal of regenerative biology. Vigorous pancreatic β-cell replication in juvenile mice and humans declines with age, and elucidating the basis for this decay may reveal strategies for inducing β-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-derived growth factor receptor (Pdgfr) signalling controls age-dependent β-cell proliferation in mouse and human pancreatic islets. With age, declining β-cell Pdgfr levels were accompanied by reductions in β-cell enhancer of zeste homologue 2 (Ezh2) levels and β-cell replication. Conditional inactivation of the Pdgfra gene in β-cells accelerated these changes, preventing mouse neonatal β-cell expansion and adult β-cell regeneration. Targeted human PDGFR-α activation in mouse β-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult β-cells. Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated β-cell proliferation. The discovery of a conserved pathway controlling age-dependent β-cell proliferation indicates new strategies for β-cell expansion.
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