hiPSC-derived engineered heart tissue to study the impact of novel hypertrophic cardiomyopathy-associated MYBPC3 variants

hiPSC technology coupled with genome editing technology (CRISPR) offers an unprecedented opportunity to study patient-specific disease in a dish. Indeed, hiPSC-directed differentiation has emerged as an exciting paradigm to model human genetic disorders and to implement the discovery of novel therapies because of their capacity to generate tissue models which can be used for understanding patient-specific disease mechanisms. However, one of the most important hurdles in modeling cardiac disorders with hiPSC-derived cardiomyocytes is their immaturity, both structurally and functionally. Engineered heart tissues (EHT) are 3D structure that facilitates the self-organization of cardiomyocytes into more mature structures. With this project, we propose to take advantage of the human EHT model to determine the functional impact of recently identified MYBPC3 mutations on human cardiomyocyte function. Using newly CRISPR-generated hiPSC lines and following targeted cardiac differentiation, EHTs will be made to perform functional studies. We anticipate that our project will provide novel insights to better define the impact of novel MYBPC3 mutations on cardiac function.