PDGF Signalling Controls Age-Dependent Proliferation in Pancreatic β-cells

Nature. 2011 Oct 12;478(7369):349-55. doi: 10.1038/nature10502.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / pathology
  • E2F Transcription Factors / metabolism
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Knockout Techniques
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / enzymology
  • Insulin-Secreting Cells / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Polycomb Repressive Complex 2
  • Receptors, Platelet-Derived Growth Factor / metabolism*
  • Retinoblastoma Protein / metabolism
  • Signal Transduction*

Substances

  • E2F Transcription Factors
  • Retinoblastoma Protein
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2
  • Receptors, Platelet-Derived Growth Factor
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3