Abstract
Adult mammalian hearts respond to injury with scar formation and not with cardiomyocyte proliferation, the cellular basis of regeneration. Although cardiogenic progenitor cells may maintain myocardial turnover, they do not give rise to a robust regenerative response. Here we show that extracellular periostin induced reentry of differentiated mammalian cardiomyocytes into the cell cycle. Periostin stimulated mononucleated cardiomyocytes to go through the full mitotic cell cycle. Periostin activated αV, β1, β3 and β5 integrins located in the cardiomyocyte cell membrane. Activation of phosphatidylinositol-3-OH kinase was required for periostin-induced reentry of cardiomyocytes into the cell cycle and was sufficient for cell-cycle reentry in the absence of periostin. After myocardial infarction, periostin-induced cardiomyocyte cell-cycle reentry and mitosis were associated with improved ventricular remodeling and myocardial function, reduced fibrosis and infarct size, and increased angiogenesis. Thus, periostin and the pathway that it regulates may provide a target for innovative strategies to treat heart failure.
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Acknowledgements
We thank M. Dai and L.-B. Chen (Dana Farber Cancer Institute, Boston, Massachusetts, USA) for recombinant human periostin; members of the Clapham, del Monte, Hajjar, Keating, McGowan, and Pu laboratories for discussions and sharing reagents; S.P. Sardi (Children's Hospital Boston, Boston, Massachusetts, USA) for lentivirus constructs; and R. Breitbart for suggestions and critical review of the manuscript. This study was supported in part by grants from the US National Institutes of Health (R01 HL078691, HL057263, HL071763, HL080498 and HL083156 to R.J.H.; K08 HL069842 to F.d.M.; and K01 HL076659 to D.L.) and the Leducq Transatlantic Network (to R.J.H.).
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B.K. supervised research; B.K., F.d.M., R.J.H., Y.-S.C., D.L., S.A. and M.T.K. designed experiments; B.K., F.d.M., Y.-S.C. and S.A. performed and analyzed experiments; F.d.M., Y.-S.C., and D.L. provided plasmids and adenovirus constructs; B.K. and S.A. wrote the manuscript.
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B.K. and M.T.K. filed a patent application relevant to this work on January 22, 2007 (US Provisional Patent Application Serial No. 60/881,938).
R.J.H. is the scientific founder of Celladon Inc. and Nanocor, two biotechnology companies, which are commercializing AAV gene therapy for heart failure.
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Kühn, B., del Monte, F., Hajjar, R. et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med 13, 962–969 (2007). https://doi.org/10.1038/nm1619
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DOI: https://doi.org/10.1038/nm1619