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

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Genetics

Background:

• Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are crucial for cardiac disease and toxicity modeling.
• Maximizing hPSC-CMs baseline function is essential for accurate in vitro disease modeling.

Purpose of the Study:

• To identify factors that enhance hPSC-CMs function for robust contractility measurements.
• To establish a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM) using MYBPC3 mutations.

Main Methods:

• Screening for factors including thyroid hormone, IGF-1, and dexamethasone to optimize hPSC-CMs function.
• Utilizing hiPSC-CMs with MYBPC3 mutations to model HCM.
• Assessing electrophysiology, bioenergetics, and contractile force generation.
• Performing direct knockdown of MYBPC3 in control hPSC-CMs.

Main Results:

• A combination of thyroid hormone, IGF-1, and dexamethasone significantly improved hPSC-CMs electrophysiology, bioenergetics, and contractility.
• hiPSC-CMs with MYBPC3 mutations exhibited significantly reduced contractile force compared to controls.
• MYBPC3 knockdown in control hPSC-CMs recapitulated the reduced contractility, supporting haploinsufficiency.

Conclusions:

• Optimized culture conditions enhance hPSC-CMs function for disease modeling.
• The in vitro hiPSC-CMs model effectively recapitulates HCM phenotypes linked to MYBPC3 mutations.
• This model provides a platform for investigating HCM mechanisms and developing therapeutic interventions.