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Advanced physiological maturation of iPSC-derived human cardiomyocytes using an algorithm-directed optimization of defined media components

Callaghan, N. I.; Durland, L. J.; Chen, W.; Kuzmanov, U.; Miranda, M. Z.; Mirzaei, Z.; Ireland, R. G.; Wang, E. Y.; Wagner, K.; Kim, M. M.; Audet, J.; Santerre, P.; Gramolini, A. O.; Billia, F.; Radisic, M.; Ellis, J.; Mital, S.; Backx, P. H.; Simmons, C. A.

2022-10-13 bioengineering
10.1101/2022.10.10.507929 bioRxiv
Show abstract

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold tremendous promise for in vitro modeling to assess native myocardial function and disease mechanisms as well as testing drug safety and efficacy. However, current iPSC- CMs are functionally immature, resembling in vivo CMs of fetal or neonatal developmental states. The use of targeted culture media and organoid formats have been identified as potential high-yield contributors to improve CM maturation. This study presents a novel iPSC-CM maturation medium formulation, designed using a differential evolutionary approach targeting metabolic functionality for iterative optimization. Relative to gold-standard reference formulations, our medium significantly matured morphology, Ca2+ handling, electrophysiology, and metabolism, which was further validated by multiomic screening, for cells in either pure or co-cultured microtissue formats. Together, these findings not only provide a reliable workflow for highly functional iPSC-CMs for downstream use, but also demonstrate the power of high-dimensional optimization processes in evoking advanced biological function in vitro.

Published in Nature Communications (predicted rank #5) · training set

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