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FGF10 promotes cardiac repair through a dual cellular mechanism increasing cardiomyocyte renewal and inhibiting fibrosis
Cardiovascular Research ( IF 10.2 ) Pub Date : 2021-11-05 , DOI: 10.1093/cvr/cvab340
Fabien Hubert 1 , Sandy M Payan 1 , Edeline Pelce 1, 2 , Laetitia Bouchard 1 , Rachel Sturny 3 , Nicolas Lenfant 1 , Giovanna Mottola 4, 5 , Frédéric Collart 2 , Robert G Kelly 3 , Francesca Rochais 1
Affiliation  

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.

中文翻译:

FGF10 通过增加心肌细胞更新和抑制纤维化的双重细胞机制促进心脏修复

目的 促进心肌细胞更新是心脏再生和修复的主要治疗方法。我们的研究旨在调查 FGF10 作为心脏再生潜在靶点的相关性。方法和结果 我们的结果首先表明心肌梗死后受伤心室的 Fgf10 水平上调。经受 MI 的 Fgf10 表达降低的成年小鼠表现出心肌细胞增殖受损和心脏纤维化增强,导致心功能恶化和 MI 后重塑。相比之下,MI 后条件性 Fgf10 过表达表明,通过增强心肌细胞增殖和防止瘢痕促进肌成纤维细胞活化,FGF10 保留了心脏重塑和功能。此外,FGF10 激活主要的再生途径,包括调节 Meis1 表达水平,Hippo 信号通路和促糖酵解代谢开关。最后,我们证明在衰竭的人类心脏中升高的 FGF10 水平与减少的纤维化和增强的心肌细胞增殖相关。结论 总之,我们的研究表明,FGF10 通过两种细胞机制促进心脏再生和修复:提高心肌细胞更新和限制纤维化。因此,这项研究将 FGF10 确定为人类心脏再生和修复的临床相关靶点。提高心肌细胞更新和限制纤维化。因此,这项研究将 FGF10 确定为人类心脏再生和修复的临床相关靶点。提高心肌细胞更新和限制纤维化。因此,这项研究将 FGF10 确定为人类心脏再生和修复的临床相关靶点。
更新日期:2021-11-05
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