Implementation of human-induced pluripotent stem cell-derived cardiomyocyte to model excitation-contraction coupling in health and disease

Abstract

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) have the potential to be an important tool for cardiovascular disease modeling, pre-clinical cardiotoxicity evaluation, and drug discovery. However, detailed studies of their excitation-contraction (EC) coupling are limited by the lack of appropriate methodology. Here, I set out to investigate the EC coupling of normal and diseased hiPSC-CMs and compare the results to that of adult ventricular CMs (i.e., rabbit and mouse) under identical experimental conditions. I found that hiPSC-CMs display relatively mature EC coupling properties (i.e., electrophysiology, Ca handling and contractility). To assess their contractile properties I have developed a novel culture method that enables robust contractile measurements of single hiPSC-CMs. I discovered that hiPSC-CMs display contractile properties comparable to that of adult rabbit CMs, including comparable contraction kinetics. Moreover, EC coupling properties were comparable across hiPSC-CM lines generated at different institutions and post recovery from cryopreservation. Using disease specific hiPSC-CMs I revealed that HCM MYH7 R633H hiPSC-CMs display contractile abnormalities, and I provided evidence supporting an enhanced myofilament Ca sensitivity mechanism. Furthermore, I demonstrated hiPSC-CMs display a robust response to pharmacological stimuli including the myofilament Ca sensitizer EMD57033. These findings will aid functional studies of disease specific hiPSC-CMs as well as the effects of novel and known pharmacological agents.