Abstract P2062: Distinct Stiffness-induced Mechanical Memory Induction And Maintenance In Cardiomyocytes And Cardiac Fibroblasts

Abstract

Recognizing that cells “feel” and respond to their mechanical environment, recent studies demonstrate that many cells exhibit a phenomenon of “mechanical memory” in which features induced by prior mechanical cues persist after the mechanical stimulus has ceased. While there is a general recognition that different cell types exhibit different responses to changes in extracellular matrix stiffening, the phenomenon of mechanical memory within myocardial cell types has received little attention to date. To probe the dynamics of mechanical memory in cardiomyocytes(CMs) and cardiac fibroblasts (CFs), we developed a magnetorheological elastomer (MRE) cell culture substrate with tunable and reversible stiffness spanning the range from normal to diseased myocardium. Employing IPSC-derived CMs, and CFs while measuring canonical responses to matrix stiffening: cell area, myofibroblasts activation, and chromatin condensation parameter reveals distinct temporal dynamics of mechanical memory induction in each cell type where mechanical memory is invoked much earlier in CMs than in CFs. Experiments using specific inhibitors of cytoskeletal components revealed that induction of mechanical memory is actin-dependent in CFs and microtubule-dependent in CMs. Prevention of α-tubulin detyrosination blocks both induction and maintenance of mechanical memory in CMs. Overall, these results emphasize the distinct temporal dynamics of mechanical memory in CMs and CFs with different cytoskeletal mediators responsible for inducing and maintaining the stiffness activated phenotype. Due to its flexibility, this model is broadly applicable to future studies interrogating mechanotransduction and mechanical memory in the heart and might inform strategies for attenuating the impact of load-dependent pathology and excess myocardial stiffness.