Background: Cardiac fibrosis is a key feature of myocardial infarction (MI) and cardiomyopathies, yet no approved therapy directly targets it. Given the heart's continuous exposure to mechanical stress from blood flow, pressure, and contractility, alterations in the mechanical environment during cardiac pathology may activate Piezo1, a mechanosensitive ion channel. While previous studies have highlighted the roles of Piezo1 in cardiomyocytes and endothelial cells, its specific function in cardiac fibroblasts (CFs) remains unclear. In this study, we investigate the fibroblast-specific role of Piezo1 in cardiac fibrosis and dysfunction in the ischemic heart. Methods: Single-cell RNA sequencing (scRNA-seq) data of CFs from control and MI-induced mice was analysed to assess the differential expression of Piezo1. To delineate the specific role of CF- Piezo1 in fibroblast activation and myocardial fibrosis, we generated conditional CF-specific Piezo1 knockout (KO) mice using a tamoxifen-inducible Tcf21 promoter-driven MerCreMer transgene. Following tamoxifen administration, both control and KO mice underwent left anterior descending (LAD) artery ligation, and cardiac function and other heart parameters were evaluated. Results: ScRNA-seq analysis revealed increased Piezo1 expression in CFs from MI-induced mice compared to sham controls. Echocardiographic analysis at 4- and 8-weeks post-MI demonstrated systolic dysfunction in control mice, characterized by reduced ejection fraction and fractional shortening, along with structural remodeling, as indicated by increased left ventricular internal diameter (LVIDs), heart weight-to-tibia length (HW/TL) ratio, and upregulation of hypertrophy marker such as ANP. Notably, these pathological changes were alleviated in CF-Piezo1 KO mice, suggesting a detrimental role for CF-Piezo1. Moreover, fibrotic remodeling, including increased expression of extracellular matrix genes (Col1a1 and Col3a1) and collagen deposition, was observed in control-MI mice but was significantly reduced in KO-MI mice. Interestingly, scRNA-seq analysis of Piezo1-high fibroblasts revealed elevated expression of multiple pro-fibrotic genes such as Col1a1 , Fn1, Postn, Cthrc1, and Tgfb1, further supporting the pro-fibrotic role of CF-Piezo1. Conclusion: Our findings demonstrate that CF-Piezo1 plays a key pro-fibrotic role in MI-induced cardiac injury. Targeting CF-Piezo1 may represent a novel therapeutic strategy for mitigating cardiac fibrosis.
Jaiswal et al. (Fri,) studied this question.