Journal
NATURE
Volume 478, Issue 7369, Pages 349-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10502
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Funding
- NIH
- NIH-NCI [RO1 CA114102]
- Stem Cell Network NRW
- Deutsche Krebshilfe
- Dewey family fund
- Juvenile Diabetes Research Foundation
- Snyder Foundation
- Stinehart Foundation
- NIH Beta Cell Biology Consortium [UO1 DK89532, UO1 DK89572]
- Howard Hughes Medical Institute (HHMI)
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Determining the signalling pathways that direct tissue expansion is a principal goal of regenerative biology. Vigorous pancreatic beta-cell replication in juvenile mice and humans declines with age, and elucidating the basis for this decay may reveal strategies for inducing beta-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-derived growth factor receptor (Pdgfr) signalling controls age-dependent beta-cell proliferation in mouse and human pancreatic islets. With age, declining beta-cell Pdgfr levels were accompanied by reductions in beta-cell enhancer of zeste homologue 2 (Ezh2) levels and beta-cell replication. Conditional inactivation of the Pdgfra gene in beta-cells accelerated these changes, preventing mouse neonatal beta-cell expansion and adult beta-cell regeneration. Targeted human PDGFR-a activation in mouse beta-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult beta-cells. Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated beta-cell proliferation. The discovery of a conserved pathway controlling age-dependent beta-cell proliferation indicates new strategies for beta-cell expansion.
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