Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function

Summary

Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the electrophysiology, bioenergetics, and contractile force generation of hPSC-CMs. In this optimized condition, hiPSC-CMs with mutations in MYBPC3, a gene encoding myosin-binding protein C, which, when mutated, causes HCM, showed significantly lower contractile force generation than controls. This was recapitulated by direct knockdown of MYBPC3 in control hPSC-CMs, supporting a mechanism of haploinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM.

Graphical Abstract

Highlights

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  T3 ⁺IGF-1 ⁺ dexamethasone improves the electrophysiology of hPSC cardiomyocytes

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  These factors synergistically enhance bioenergetics and contractile force generation

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  Cardiomyocytes with HCM-causing mutations have a contractile defect

Abstract

Birket et al. identify a combination of factors that cooperatively improve the function of human pluripotent stem cell (hiPSC)-derived cardiomyocytes. Optimizing the system facilitated the identification of a contraction force defect in a model of hypertrophic cardiomyopathy (HCM), a disease affecting ∼1:500 of the population.