Cardiovascular disease continues to be the leading cause of death globally, and adverse extracellular matrix (ECM) remodeling often plays a critical role in reduced heart function during disease. Persistent activation of cardiac fibroblasts (CF) can cause them to increase ECM deposition, leading to myocardial fibrosis. While inflammatory cytokines or increased ECM stiffnesses are necessary to activate CFs, the extent to which intrinsic matrix properties activate CFs is less clear. Pluripotent stem cell-derived cardiac fibroblasts were cultured in low-serum media, serially passaged on a range of ECM stiffness, and then selectively replated on ECM of different stiffness with or without myofibroblast agonists to assess the persistence of ECM-induced activation. As classically seen with primary cells, stem-cell derived CFs cultured on tissue culture plastic for multiple passages and in the presence of myofibroblast agonists become activated myofibroblasts. However, these same CFs on soft substrates become quiescent-like but remain capable of responding to myofibroblast agonists and activating. To assess mechanical “memory” of the prior niche, CFs were cultured on tissue culture plastic and then replated to soft or stiff ECM; when the niche softened, CFs lost a-smooth muscle actin (aSMA) expression but did not when the niche remained stiff. Surprisingly, CFs on softened matrix became the most activated when exposed to myofibroblast agonists or a histone deacetylase inhibitor. These data suggested epigenetic regulation of CF mechanical “memory”, with ATAC-seq showing that softened matrix facilitates CF response to agonists via enhanced accessibility of myofibroblast transcription sites. These results highlight the need for physically relevant in vitro models that account for the epigenetic and mechanical history of CFs.
Bishop et al. (Fri,) studied this question.
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