Modeling hypertrophic cardiomyopathy caused by mutations in beta-myosin using human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs)




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Alison Schroer, Gina Jung, Kristina Kooiker, Arjun Adhikari, Kathleen Ruppel, Beth Pruitt, James Spudich, Daniel Bernstein

Hypertrophic cardiomyopathy affects 1:500 Americans and is commonly caused by mutations in beta-myosin heavy chain, the main motor protein responsible for contraction of human ventricles. This protein is arranged in hierarchical structures called sarcomeres and myofibrils that allow for coordinated contraction of cardiomyocytes. We have used CRISPR-Cas9 gene editing to insert mutations (P710R and D239N) into hiPSCs that we subsequently differentiate into cardiomyocytes. We used micropatterning techniques to promote cell and myofibril alignment and contractile function. Transmission electron microscopy has confirmed microstructural changes in the sarcomeres and myofibrils of cells containing these mutations, and traction force microscopy has revealed differences in force generation at the single cell level. We have also measured altered signaling through MAPK pathways that may regulate hypertrophy. These cellular level experiments provide an important complement to molecular studies of these mutations, and we are developing models that will allow us to predict how changes in force and kinetics might translate across scales and contribute to cellular and tissue remodeling.

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