title: 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.
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Hainan
authors: H
authors: Chen
authors: Xueying
authors: X
authors: Gu
authors: Yinghua
authors: Y
authors: Liu
authors: Jing
authors: J
authors: Wang
authors: Stacey E
authors: SE
authors: Wirt
authors: Rita
authors: R
authors: Bottino
authors: Hubert
authors: H
authors: Schorle
authors: Julien
authors: J
authors: Sage
authors: Seung K
authors: SK
authors: Kim
mesh_terms: D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D050684:E2F Transcription Factors / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D017479:Receptors, Platelet-Derived Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3