Fabien Hubert1, Sandy M Payan1, Edeline Pelce1,2, Laetitia Bouchard1, Rachel Sturny3, Nicolas Lenfant1, Giovanna Mottola4,5, Frédéric Collart2, Robert G Kelly3, Francesca Rochais1. 1. Aix-Marseille Univ, INSERM, MMG, U 1251, 27 Boulevard Jean Moulin, 13005 Marseille, France. 2. Department of Cardiac Surgery, Timone Hospital, AP-HM, 264 rue Saint-Pierre, 13005 Marseille, France. 3. Aix Marseille Univ, CNRS UMR 7288, IBDM, Campus de Luminy Case 907, CEDEX 9, 13288 Marseille, France. 4. Aix-Marseille Univ, C2VN, INSERM 1263, INRAE 1260, 27 Boulevard Jean Moulin, 13005 Marseille, France. 5. Laboratory of Biochemistry, Timone Hospital, AP-HM, 264 rue Saint-Pierre, 13005 Marseille, France.
Abstract
AIMS: Promoting cardiomyocyte renewal represents a major therapeutic approach for heart regeneration and repair. Our study aims to investigate the relevance of FGF10 as a potential target for heart regeneration. METHODS AND RESULTS: Our results first reveal that Fgf10 levels are up-regulated in the injured ventricle after MI. Adult mice with reduced Fgf10 expression subjected to MI display impaired cardiomyocyte proliferation and enhanced cardiac fibrosis, leading to a worsened cardiac function and remodelling post-MI. In contrast, conditional Fgf10 overexpression post-MI revealed that, by enhancing cardiomyocyte proliferation and preventing scar-promoting myofibroblast activation, FGF10 preserves cardiac remodelling and function. Moreover, FGF10 activates major regenerative pathways including the regulation of Meis1 expression levels, the Hippo signalling pathway and a pro-glycolytic metabolic switch. Finally, we demonstrate that elevated FGF10 levels in failing human hearts correlate with reduced fibrosis and enhanced cardiomyocyte proliferation. CONCLUSIONS: Altogether, our study shows that FGF10 promotes cardiac regeneration and repair through two cellular mechanisms: elevating cardiomyocyte renewal and limiting fibrosis. This study thus identifies FGF10 as a clinically relevant target for heart regeneration and repair in man. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Promoting cardiomyocyte renewal represents a major therapeutic approach for heart regeneration and repair. Our study aims to investigate the relevance of FGF10 as a potential target for heart regeneration. METHODS AND RESULTS: Our results first reveal that Fgf10 levels are up-regulated in the injured ventricle after MI. Adult mice with reduced Fgf10 expression subjected to MI display impaired cardiomyocyte proliferation and enhanced cardiac fibrosis, leading to a worsened cardiac function and remodelling post-MI. In contrast, conditional Fgf10 overexpression post-MI revealed that, by enhancing cardiomyocyte proliferation and preventing scar-promoting myofibroblast activation, FGF10 preserves cardiac remodelling and function. Moreover, FGF10 activates major regenerative pathways including the regulation of Meis1 expression levels, the Hippo signalling pathway and a pro-glycolytic metabolic switch. Finally, we demonstrate that elevated FGF10 levels in failing human hearts correlate with reduced fibrosis and enhanced cardiomyocyte proliferation. CONCLUSIONS: Altogether, our study shows that FGF10 promotes cardiac regeneration and repair through two cellular mechanisms: elevating cardiomyocyte renewal and limiting fibrosis. This study thus identifies FGF10 as a clinically relevant target for heart regeneration and repair in man. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Daryl M Okamura; Elizabeth D Nguyen; Sarah J Collins; Kevin Yoon; Joshua B Gere; Mary C M Weiser-Evans; David R Beier; Mark W Majesky Journal: J Muscle Res Cell Motil Date: 2022-09-21 Impact factor: 3.352