FGF10 promotes regional foetal cardiomyocyte proliferation and adult cardiomyocyte cell-cycle re-entry

Cardiomyocyte proliferation gradually declines during embryogenesis resulting in severely limited regenerative capacities in the adult heart. Understanding the developmental processes controlling cardiomyocyte proliferation may thus identify new therapeutic targets to modulate the cell-cycle activit...

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Bibliographic Details
Published in:Cardiovascular research 2014-12, Vol.104 (3), p.432-442
Main Authors: Rochais, Francesca, Sturny, Rachel, Chao, Cho-Ming, Mesbah, Karim, Bennett, Michael, Mohun, Tim J, Bellusci, Saverio, Kelly, Robert G
Format: Article
Language:English
Subjects:
Animals
Cell Cycle
Cell Proliferation
Cells, Cultured
Cellular Biology
Cyclin-Dependent Kinase Inhibitor p27 - metabolism
Fibroblast Growth Factor 10 - physiology
Forkhead Box Protein O3
Forkhead Transcription Factors - metabolism
Heart - embryology
Life Sciences
Mice
Myocytes, Cardiac - physiology
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Summary:Cardiomyocyte proliferation gradually declines during embryogenesis resulting in severely limited regenerative capacities in the adult heart. Understanding the developmental processes controlling cardiomyocyte proliferation may thus identify new therapeutic targets to modulate the cell-cycle activity of cardiomyocytes in the adult heart. This study aims to determine the mechanism by which fibroblast growth factor 10 (FGF10) controls foetal cardiomyocyte proliferation and to test the hypothesis that FGF10 promotes the proliferative capacity of adult cardiomyocytes. Analysis of Fgf10(-/-) hearts and primary cardiomyocyte cultures reveals that altered ventricular morphology is associated with impaired proliferation of right but not left-ventricular myocytes. Decreased FOXO3 phosphorylation associated with up-regulated p27(kip) (1) levels was observed specifically in the right ventricle of Fgf10(-/-) hearts. In addition, cell-type-specific expression analysis revealed that Fgf10 and its receptor, Fgfr2b, are expressed in cardiomyocytes and not cardiac fibroblasts, consistent with a cell-type autonomous role of FGF10 in regulating regional specific myocyte proliferation in the foetal heart. Furthermore, we demonstrate that in vivo overexpression of Fgf10 in adult mice promotes cardiomyocyte but not cardiac fibroblast cell-cycle re-entry. FGF10 regulates regional cardiomyocyte proliferation in the foetal heart through a FOXO3/p27(kip1) pathway. In addition, FGF10 triggers cell-cycle re-entry of adult cardiomyocytes and is thus a potential target for cardiac repair.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvu232