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

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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Figure 1: Age-dependent attenuation of Pdgfr-α limits β-cell Ezh2 expression and proliferation in neonatal and juvenile mice.
Figure 2: Pdgfra loss impairs β-cell regeneration in STZ-induced diabetes.
Figure 3: Activated PDGFR-α delays age-dependent Ezh2 loss and replication failure in pancreatic β-cells.
Figure 4: PDGFR-α promotes β-cell expansion through Ezh2.
Figure 5: Pdgfr signalling governs Erk and Rb/E2f regulation of Ezh2 in islet β-cells.
Figure 6: PDGFR-α regulates human β-cell EZH2 expression and proliferation.

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Acknowledgements

We thank A. Bhushan, A. Stewart, A. Powers, P. Beachy, M. White, X. Chen and X. Li for helpful discussions and advice, A. Tarakhovsky, P. Herrera and M. Hara for mice, A. Powers, A. Thompson and S. Bryant for human islet sample procurement, and members of the S.K.K. laboratory for comments on the manuscript. H.C. was supported by the NIH Ruth L. Kirschstein NRSA/Stanford Regenerative Medicine Training Program. J.S. was supported by NIH-NCI RO1 CA114102. H.S. was supported by the Stem Cell Network NRW and Deutsche Krebshilfe. Work in the S.K.K. laboratory was supported by a gift from the Dewey family fund, and grants from the Juvenile Diabetes Research Foundation, Snyder Foundation, Stinehart Foundation, the NIH Beta Cell Biology Consortium (UO1 DK89532 to S.K.K. and UO1 DK89572 to A. Powers) and by the Howard Hughes Medical Institute (HHMI). S.K.K. is an Investigator of the HHMI.

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H.C., X G., Y.L. and J.W. performed experiments. H.C., S.E.W., J.S. and H.S. generated mice. R.B. isolated human islets. H.C. and S.K.K. conceived the project, generated hypotheses, analysed data and wrote the manuscript.

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Correspondence to Seung K. Kim.

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Chen, H., Gu, X., Liu, Y. et al. PDGF signalling controls age-dependent proliferation in pancreatic β-cells. Nature 478, 349–355 (2011). https://doi.org/10.1038/nature10502

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