Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair.
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 alphaV, beta1, beta3 and beta5 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.
Kühn
Bernhard
B
Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. bernhard.kuhn@cardio.chboston.org
del Monte
Federica
F
Hajjar
Roger J
RJ
Chang
Yuh-Shin
YS
Lebeche
Djamel
D
Arab
Shima
S
Keating
Mark T
MT
D000818:Animals; D015815:Cell Adhesion Molecules / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D006984:Hypertrophy / Q000188:drug therapy / Q000473:pathology; D016023:Integrins / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000187:drug effects*
D015815:Cell Adhesion Molecules; D016023:Integrins; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases