Francesca Rochais1, Rachel Sturny2, Cho-Ming Chao3, Karim Mesbah2, Michael Bennett4, Tim J Mohun4, Saverio Bellusci5, Robert G Kelly2. 1. Aix-Marseille Université, CNRS UMR 7288, IBDM, Campus de Luminy Case 907, Marseilles Cedex 9 13288, France francesca.rochais@univ-amu.fr. 2. Aix-Marseille Université, CNRS UMR 7288, IBDM, Campus de Luminy Case 907, Marseilles Cedex 9 13288, France. 3. Justus-Liebig-Universitaet Giessen, Excellence Cluster Cardio-Pulmonary System, Giessen, Germany. 4. MRC National Institute for Medical Research, Mill Hill, London, UK. 5. 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.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Raghav Pandey; Sebastian Velasquez; Shazia Durrani; Min Jiang; Michelle Neiman; Jeffrey S Crocker; Joshua B Benoit; Jack Rubinstein; Arghya Paul; Rafeeq Ph Ahmed Journal: Am J Transl Res Date: 2017-06-15 Impact factor: 4.060