Piezo1 Channels Contribute to the Regulation of Human Atrial Fibroblast Mechanical Properties and Matrix Stiffness Sensing

Abstract

The mechanical environment of cardiac cells changes continuously and undergoes major alterations during diseases. Most cardiac diseases, including atrial fibrillation, are accompanied by fibrosis which can impair both electrical and mechanical function of the heart. A key characteristic of fibrotic tissue is excessive accumulation of extracellular matrix, leading to increased tissue stiffness. Cells are known to respond to changes in their mechanical environment, but the molecular mechanisms underlying this ability are incompletely understood. We used cell culture systems and hydrogels with tunable stiffness, combined with advanced biophysical and imaging techniques, to elucidate the roles of the stretch-activated channel Piezo1 in human atrial fibroblast mechano-sensing. Changing the expression level of Piezo1 revealed that this mechano-sensor contributes to the organization of the cytoskeleton, affecting mechanical properties of human embryonic kidney cells and human atrial fibroblasts. Our results suggest that this response is independent of Piezo1-mediated ion conduction at the plasma membrane, and mediated in part by components of the integrin pathway. Further, we show that Piezo1 is instrumental for fibroblast adaptation to changes in matrix stiffness, and that Piezo1-induced cell stiffening is transmitted in a paracrine manner to other cells by a signaling mechanism requiring interleukin-6. Piezo1 may be a new candidate for targeted interference with cardiac fibroblast function.

Channelling the Force to Reprogram the Matrix: Mechanosensitive Ion Channels in Cardiac Fibroblasts

“…Over-expression and siRNA studies revealed that Piezo1 positively affected stiffness of a human atrial fibroblast cell line, including increasing the amount, thickness and organization of the F-actin network. Moreover, Piezo1 overexpressing cells could confer increased stiffness to neighbouring non-transfected cells through a paracrine IL-6 signalling mechanism [228]; similar to that identified in our recent study [134].…”

“…While Piezo1 was directly activated by stretch, mechanical induction of BKCa activity was secondary to calcium influx via Piezo1, suggesting interplay between these channels in human atrial fibroblasts [ 69 ]. Another recent report from the same group described a role for Piezo1 in increasing atrial fibroblast cell stiffness in response to increased ECM stiffness [ 228 ]. Over-expression and siRNA studies revealed that Piezo1 positively affected stiffness of a human atrial fibroblast cell line, including increasing the amount, thickness and organization of the F-actin network.…”

Piezo1 Mechanosensitive Ion Channel Mediates Stretch-Induced Nppb Expression in Adult Rat Cardiac Fibroblasts

“…Of note, the stiffness of fibrotic myocardium is estimated at 20-100 kPa [51][52][53]. It has also been shown previously that Piezo1 reacts to stiffness, in both stem cells [54] and atrial fibroblasts [55].…”

High-Resolution Bioprinting of Recombinant Human Collagen Type III

“…The mechanical properties of the AJP samples were characterised using a Chiaro nanoindenter (Optics11). This system and its sister system, the Piuma, are emerging tools for measuring the mechanical properties of hydrogels and for mechanobiology [ 40 , 41 , 42 ]. Both are comprised of a spherical indenter on a cantilever of known stiffness, the deflection of which is measured by interferometry via a ferrule-topped optical fiber [ 43 ].…”