Independent compartmentalization of functional, metabolic, and transcriptional maturation of hiPSC-derived cardiomyocytes
K. Ashley Fetterman, Malorie Blancard, Davi M Lyra-Leite, Carlos G. Vanoye, Hananeh Fonoudi, Mariam Jouni, Jean-Marc L DeKeyser, Brian Lenny, Yadav Sapkota, Alfred L George, Paul W. Burridge
Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) recapitulate numerous disease and drug response phenotypes, but cell immaturity may limit their accuracy and fidelity as a model system. Cell culture medium modification is a common method for enhancing maturation, yet prior studies have used complex media with little understanding of individual component contribution, which may compromise long-term hiPSC-CM viability. Here, we developed high-throughput methods to measure hiPSC-CM maturation, determined factors that enhanced viability, and then systematically assessed the contribution of individual maturation medium components. We developed a medium that is compatible with extended culture. We discovered that hiPSC-CM maturation can be sub-specified into electrophysiological/EC coupling, metabolism, and gene expression and that induction of these attributes is largely independent. In this work, we establish a defined baseline for future studies of cardiomyocyte maturation. Furthermore, we provide a selection of medium formulae, optimized for distinct applications and priorities, that promote measurable attributes of maturation.