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

Nature volume 478, pages 349–355 (2011)Cite this article

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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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References

  1. Heit, J. J., Karnik, S. K. & Kim, S. K. Intrinsic regulators of pancreatic β-cell proliferation. Annu. Rev. Cell Dev. Biol. 22, 311–338 (2006)

    Article  CAS  Google Scholar 

  2. Vasavada, R. C. et al. Growth factors and β-cell replication. Int. J. Biochem. Cell Biol. 38, 931–950 (2006)

    Article  CAS  Google Scholar 

  3. Vasavada, R. C. et al. Targeted expression of placental lactogen in the β-cells of transgenic mice results in β-cell proliferation, islet mass augmentation, and hypoglycemia. J. Biol. Chem. 275, 15399–15406 (2000)

    Article  CAS  Google Scholar 

  4. Garcia-Ocana, A. et al. Hepatocyte growth factor overexpression in the islet of transgenic mice increases β-cell proliferation, enhances islet mass, and induces mild hypoglycemia. J. Biol. Chem. 275, 1226–1232 (2000)

    Article  CAS  Google Scholar 

  5. Beattie, G. M. et al. A novel approach to increase human islet cell mass while preserving β-cell function. Diabetes 51, 3435–3439 (2002)

    Article  CAS  Google Scholar 

  6. Parnaud, G. et al. Proliferation of sorted human and rat β-cells. Diabetologia 51, 91–100 (2008)

    Article  CAS  Google Scholar 

  7. Dor, Y. et al. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004)

    Article  ADS  CAS  Google Scholar 

  8. Kushner, J. A. et al. Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth. Mol. Cell. Biol. 25, 3752–3762 (2005)

    Article  CAS  Google Scholar 

  9. Teta, M. et al. Very slow turnover of β-cells in aged adult mice. Diabetes 54, 2557–2567 (2005)

    Article  CAS  Google Scholar 

  10. Meier, J. J. et al. β-Cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes 57, 1584–1594 (2008)

    Article  CAS  Google Scholar 

  11. Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006)

    Article  ADS  CAS  Google Scholar 

  12. Zindy, F. et al. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15, 203–211 (1997)

    Article  CAS  Google Scholar 

  13. Chen, H. et al. Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 23, 975–985 (2009)

    Article  CAS  Google Scholar 

  14. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002)

    Article  ADS  CAS  Google Scholar 

  15. van der Vlag, J. & Otte, A. P. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nature Genet. 23, 474–478 (1999)

    Article  CAS  Google Scholar 

  16. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000)

    Article  CAS  Google Scholar 

  17. Swenne, I. et al. Effects of platelet-derived growth factor and somatomedin-C/insulin-like growth factor I on the deoxyribonucleic acid replication of fetal rat islets of Langerhans in tissue culture. Endocrinology 122, 214–218 (1988)

    Article  CAS  Google Scholar 

  18. Welsh, M. et al. Coexpression of the platelet-derived growth factor (PDGF) B chain and the PDGF beta receptor in isolated pancreatic islet cells stimulates DNA synthesis. Proc. Natl Acad. Sci. USA 87, 5807–5811 (1990)

    Article  ADS  CAS  Google Scholar 

  19. Su, I. et al. Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell 121, 425–436 (2005)

    Article  CAS  Google Scholar 

  20. Mendel, D. B. et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327–337 (2003)

    CAS  PubMed  Google Scholar 

  21. Hilberg, F. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68, 4774–4782 (2008)

    Article  CAS  Google Scholar 

  22. Moenning, A. et al. Sustained platelet-derived growth factor receptor α signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase C-γ pathway. Mol. Cell. Biol. 29, 881–891 (2009)

    Article  CAS  Google Scholar 

  23. Duncia, J. V. et al. MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg. Med. Chem. Lett. 8, 2839–2844 (1998)

    Article  CAS  Google Scholar 

  24. Uhrbom, L., Nerio, E. & Holland, E. C. Dissecting tumor maintenance requirements using bioluminescence imaging of cell proliferation in a mouse glioma model. Nature Med. 10, 1257–1260 (2004)

    Article  CAS  Google Scholar 

  25. Furstoss, O., Manes, G. & Roche, S. Cyclin E and cyclin A are likely targets of Src for PDGF-induced DNA synthesis in fibroblasts. FEBS Lett. 526, 82–86 (2002)

    Article  CAS  Google Scholar 

  26. Bracken, A. P. et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335 (2003)

    Article  CAS  Google Scholar 

  27. Moberg, K., Starz, M. A. & Lees, J. A. E2F4 switches from p130 to p107 and pRB in response to cell cycle reentry. Mol. Cell. Biol. 16, 1436–1449 (1996)

    Article  CAS  Google Scholar 

  28. Viatour, P. et al. Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family. Cell Stem Cell 3, 416–428 (2008)

    Article  CAS  Google Scholar 

  29. Brelje, T. C., Parsons, J. A. & Sorenson, R. L. Regulation of islet β-cell proliferation by prolactin in rat islets. Diabetes 43, 263–273 (1994)

    Article  CAS  Google Scholar 

  30. Scherping, S. C., Jr et al. Effect of growth factors on the proliferation of ligament fibroblasts from skeletally mature rabbits. Connect. Tissue Res. 36, 1–8 (1997)

    Article  CAS  Google Scholar 

  31. Pallante, B. A. et al. Bone marrow Oct3/4+ cells differentiate into cardiac myocytes via age-dependent paracrine mechanisms. Circ. Res. 100, e1–e11 (2007)

    Article  CAS  Google Scholar 

  32. LeBras, S., Czernichow, P. & Scharfmann, R. A search for tyrosine kinase receptors expressed in the rat embryonic pancreas. Diabetologia 41, 1474–1481 (1998)

    Article  CAS  Google Scholar 

  33. Fujii, S. et al. MEK–ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene 10.1038/onc.2011.118 (18 April 2011)

  34. Gupta, R. K. et al. Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α. Genes Dev. 21, 756–769 (2007)

    Article  ADS  CAS  Google Scholar 

  35. Miettinen, P. J. et al. Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal β-cell growth. Diabetes 55, 3299–3308 (2006)

    Article  CAS  Google Scholar 

  36. Butler, A. E. et al. Adaptive changes in pancreatic β-cell fractional area and β-cell turnover in human pregnancy. Diabetologia 53, 2167–2176 (2010)

    Article  CAS  Google Scholar 

  37. Rieck, S. & Kaestner, K. H. Expansion of β-cell mass in response to pregnancy. Trends Endocrinol. Metab. 21, 151–158 (2010)

    Article  CAS  Google Scholar 

  38. Ebert, M. et al. Induction of platelet-derived growth factor A and B chains and over-expression of their receptors in human pancreatic cancer. Int. J. Cancer 62, 529–535 (1995)

    Article  CAS  Google Scholar 

  39. Nyblom, H. K. et al. Apoptotic, regenerative, and immune-related signaling in human islets from type 2 diabetes individuals. J. Proteome Res. 8, 5650–5656 (2009)

    Article  CAS  Google Scholar 

  40. Tallquist, M. D. & Soriano, P. Cell autonomous requirement for PDGFRα in populations of cranial and cardiac neural crest cells. Development 130, 507–518 (2003)

    Article  CAS  Google Scholar 

  41. Herrera, P. L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127, 2317–2322 (2000)

    CAS  PubMed  Google Scholar 

  42. Hara, M. et al. Transgenic mice with green fluorescent protein-labeled pancreatic β-cells. Am. J. Physiol. Endocrinol. Metab. 284, E177–E183 (2003)

    Article  CAS  Google Scholar 

  43. Sugiyama, T. et al. Conserved markers of fetal pancreatic epithelium permit prospective isolation of islet progenitor cells by FACS. Proc. Natl Acad. Sci. USA 104, 175–180 (2007)

    Article  ADS  CAS  Google Scholar 

Download references

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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Authors and Affiliations

  1. Department of Developmental Biology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Hainan Chen, Xueying Gu, Yinghua Liu, Jing Wang & Seung K. Kim

  2. Departments of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, 94305, California, USA

    Stacey E. Wirt & Julien Sage

  3. Department of Pediatrics, Division of Immunogenetics, Children’s Hospital of Pittsburgh, University of Pittsburgh, School of Medicine, Pittsburgh, 15213, Pennsylvania, USA

    Rita Bottino

  4. Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany

    Hubert Schorle

  5. Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, 94305, California, USA

    Seung K. Kim

  6. Department of Developmental Biology, Howard Hughes Medical Institute, B300 Beckman Center, 279 Campus Drive, Stanford, 94305, California, USA

    Seung K. Kim

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  1. Hainan Chen
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Contributions

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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The authors declare no competing financial interests.

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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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