FGF10 promotes cardiac repair through a dual cellular mechanism increasing cardiomyocyte renewal and inhibiting fibrosis

Author:

Hubert Fabien1ORCID,Payan Sandy M1,Pelce Edeline12,Bouchard Laetitia1,Sturny Rachel3,Lenfant Nicolas1ORCID,Mottola Giovanna45ORCID,Collart Frédéric2,Kelly Robert G3,Rochais Francesca1ORCID

Affiliation:

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

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.

Funder

Agence Nationale de la Recherche

Fédération Française de Cardiologie 2017, and AFM-Téléthon

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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