title: FGF10 promotes regional foetal cardiomyocyte proliferation and adult cardiomyocyte cell-cycle re-entry.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Aix-Marseille Université, CNRS UMR 7288, IBDM, Campus de Luminy Case 907, Marseilles Cedex 9 13288, France francesca.rochais@univ-amu.fr.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rochais
authors.affiliation: Aix-Marseille Université, CNRS UMR 7288, IBDM, Campus de Luminy Case 907, Marseilles Cedex 9 13288, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sturny
authors.affiliation: Justus-Liebig-Universitaet Giessen, Excellence Cluster Cardio-Pulmonary System, Giessen, Germany.
authors.forename: Cho-Ming
authors.initials: CM
authors.lastname: Chao
authors.affiliation: Aix-Marseille Université, CNRS UMR 7288, IBDM, Campus de Luminy Case 907, Marseilles Cedex 9 13288, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Mesbah
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Bennett
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Mohun
authors.affiliation: Justus-Liebig-Universitaet Giessen, Excellence Cluster Cardio-Pulmonary System, Giessen, Germany Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlevskaya St 18, Kazan, 420008, Russia.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
authors.affiliation: Aix-Marseille Université, CNRS UMR 7288, IBDM, Campus de Luminy Case 907, Marseilles Cedex 9 13288, France.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kelly
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000502:physiology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology*
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: Cardiac repair; Cardiomyocyte proliferation; Fibroblast growth factor 10; Heart development