A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype

Abstract

Cardiac fibrosis is associated with activation of cardiac fibroblasts (CFs), a pathological, phenotypic transition that is widely believed to be irreversible in the late stages of disease development. Sensing of a stiffened mechanical environment through regulation of integrin-based adhesion plaques and activation of the Piezo1 mechanosensitive ion channel is known to factor into this transition. Here, using integrated in vitro and in silico models, we discovered a mutually reinforcing, mechanical positive feedback loop between integrin β1 and Piezo1 activation that forms a bistable switch. The bistable switch is initiated by perturbations in matrix elastic modulus that amplify to trigger downstream signaling involving Ca2+ and YAP that, recursively, leads fibroblasts to further stiffen their environment. By simultaneously interfering with the newly identified mechanical positive feedback loop and modulating matrix elastic modulus, we reversed markers of phenotypical transition of CF, suggesting new therapeutic targets for fibrotic disease.