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Abstract The immaturity of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a major limitation for their use in drug screening to identify pro-arrhythmogenic or cardiotoxic molecules, thus hindering their potential role in guiding personalised drug selection for patients. Here, we demonstrate an approach that combines lipid-enriched maturation medium, nanopatterning of culture surfaces and electrostimulation to generate iPSC-CMs with an advanced electrophysiological, structural and metabolic phenotype. Through a systematic, stepwise parallel testing of the three stimuli, electrostimulation emerged as the pivotal factor to enhance mitochondrial development and to improve the electrophysiological properties of iPSC-CMs. The combined approach brought a substantial modification in their current composition by increasing I Na , I to , I K1 and I Kr but decreasing I Ca−L , resulting in a significant change in their sensitivity to cardioactive drugs. Transcriptome analysis revealed that activation of HMCES and TFAM targets played a role in mitochondrial development, whereas the downregulation of MAPK/PI3K signalling pathways and SRF targets were associated with polyploidy of iPSC-CMs. Taken together, our study provides mechanistic insights into the maturation of iPSC-CMs with a more adult-like drug response.
Guan et al. (Wed,) studied this question.