Assessing the Role of the Extracellular Matrix in Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a congenital heart disease and its pathological features include myocyte hypertrophy, myocyte disarray, interstitial fibrosis, and cardiac dysfunction. Nearly 35-50% of HCM genetic mutations are associated with mutations in the MYH7 gene. These mutations result in stressed myocytes, fibrosis and scar formation, leading to heart failure and sudden cardiac death. Identifying the underlying mechanism for the early-stage HCM disease could provide cues for novel therapeutics to delay or prevent its progression.
Recently we generated a single mutation in the myosin heavy chain 7 gene (MYH7) with a known pathogenic significance (MYH7 c.2167C>T [R723C]), and a dual MYH7/MYH6 converter domain mutation (MYH7 c.2167C>T [R723C]; MYH6 c.2173C>T [R725C]) with unknown significance in human induced pluripotent stem cells (hiPSCs) using a base-editing strategy. Mutant and control hiPSC-derived cardiomyocytes (hiPSC-CMs) were obtained via the direct differentiation of modulating Wnt/-catenin signaling. Through the comparison of mutant and control hiPSC-CMs, our data showed that MYH7/MYH6 dual mutation had dysregulated extracellular matrix (ECM) remodeling, and interrupted cell-ECM adhesion by limiting the formation of focal adhesions. Quantitative analysis of the focal adhesion showed a significant reduction in the colocalized focal adhesion sites with α-actinin in the mutant hiPSC-CMs, suggesting weak attachment. Indeed, our preliminary analysis showed that, when exposed to shear stress, mutant hiPSC-CMs dislodge readily relative to wild-type hiPSC-CMs. Similarly, bulk RNA-seq analysis showed altered cell-ECM pathways in the mutant CMs relative to the isogenic controls.
Based on these data, we propose that strategies to enhance cell-ECM interactions could prevent myocyte disarray, and cardiac dysfunction.