Intercellular chemerin-cmklr1 couples epicardial mechanosensing to fibroblasts in pressure overload

Mechanical sensation has become a recent focus and key pathological driver of cardiac fibrosis. However, the crosstalk between major mechanosensitive cell and fibroblasts remains to be elucidated. In this study, single-cell temporal atlas of mechanosensitive ion channels is depicted in transverse aortic constriction male mouse heart. Piezo1 is the most abundant mechanosensitive ion channel and exhibits the highest expression in epicardial cells. Epicardial-specific Piezo1 knockout mice exhibit decreased fibrosis and cardiac dysfunction. Piezo1 mediates epithelial-mesenchymal transition only contributes to subepicardial fibrosis. Further functional experiments and human samples validation reveal that Piezo1 facilitates intraventricular fibroblast activation via the Chemerin-Cmklr1 paracrine signaling pathway. The activation of cardiac fibroblasts is mediated by Pi3k-Akt1-Pou3f1 pathway. The Cmklr1 inhibitor α-NETA effectively mitigates myocardial fibrosis and dysfunction, holding therapeutical potential. Collectively, this study untangles the global landscape of mechanosensitive channels and the spatiotemporal mechanism of epicardial cells to activate fibroblast via the Chemerin-Cmklr1 paracrine signaling pathway.