FGF10 promotes cardiac repair through a dual cellular mechanism increasing cardiomyocyte renewal and inhibiting fibrosis
Fabien Hubert, Sandy M. Payan, Edeline Pelcé, Laetitia Bouchard, Rachel Sturny, Nicolas Lenfant, Giovanna Mottola, Frédéric Collart, Robert G. Kelly, Francesca Rochais
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.