Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) modeling hypertrophic cardiomyopathy
CRISPR/Cas9 editing to introduce the R453C-βMHC-mutation
Cardiomyocyte functionality, including energy depletion, ATP production, αMHC to βMHC switching, and arrhythmiassurrogate
CRISPR/Cas9-engineered hPSC-CMs reveal that energy depletion, arrhythmias, and hypocontractility are key mechanisms and potential therapeutic targets in hypertrophic cardiomyopathy.
Our holistic and comprehensive approach showed that energy depletion affected core cardiomyocyte functionality. The engineered R453C-βMHC-mutation triggered compensatory responses in hPSC-CMs, causing increased ATP production and αMHC to energy-efficient βMHC switching. We showed that pharmacological rescue of arrhythmias was possible, while MHY7: MYH6 and mutant: wild-type MYH7 ratios may be diagnostic, and previously undescribed lncRNAs and gene modifiers are suggestive of new mechanisms.
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Diogo Mosqueira
Ingra Mannhardt
Jamie R. Bhagwan
European Heart Journal
University of Nottingham
Universität Hamburg
Wellcome Sanger Institute
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Mosqueira et al. (Wed,) studied this question.
synapsesocial.com/papers/69bd604c331c354bb52ff524 — DOI: https://doi.org/10.1093/eurheartj/ehy249