YAP dysregulation triggers hypertrophy by CCN2 secretion and TGFß uptake in human pluripotent stem cell-derived cardiomyocytes
Our research has demonstrated the following: (1) Confirmed that MYH7 mutations D239N, H251N, G256E lead to hypercontractility in hiPSC-derived cardiomyocytes (hiPSC-CMs); (2) Increase in YAP's nuclear localization in both hiPSC-CMs and patient tissue with MYH7 HCM mutations; (3) A correlation between YAP's nuclear localization and enhanced force generation; (4) Nuclear deformation as a mechanism enabling YAP's nuclear entry and activation; (5) Transcriptomic changes resulting from positive and negative modifications in force generation; and (6) A distinctive paracrine hypertrophic signal reliant on cardiomyocyte-cardiac fibroblast crosstalk. Our unique insights to the intricacies of hypertrophic cardiomyopathy phenotypes hold the potential to provide mechanistic clarity, informing potential therapeutic strategies. Overall design: We performed bulk RNA-seq on D60 hiPSC-CMs from four separate conditions: 1) WT hiPSC-CMs, 2) WT hiPSC-CMs + levosimendan (300 nM) to mimic the hypercontractile phenotype, 3) MYH7-R663H hiPSC-CMs, and 4) MYH7-R663H hiPSC-CMs+ verapamil (100 nM) in an effort to reduce hypercontractility and therefore presumably restore a normal transcriptional profile (2 & 3 = high force, 1 & 4 = low force). MYH7-R663H hiPSC-CMs are iPSCs derived cardiomyocytes derived from a cliniically diagnosed Hypertrophic Cardiomyopathy patient sample.