Molecular rewiring of human induced pluripotent stem cell-derived cardiomyocytes during metabolic maturation

The maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is of critical importance in the field of cardiovascular regenerative medicine. However, studies have largely focused on individual factors that promote maturation, leaving the molecular mechanisms underlying maturation unexplored. Here, we investigated how hormonal and metabolic maturation inducing factors (MIF) reprogram CMs to a more mature state through molecular mechanisms. Using a multiomics approach to assess the effects of MIFs in hiPSC-CMs maturation, we found extensive rewiring of the transcriptional network, epigenome status, and proteomics profile that are consistent with metabolic profiles of mature hiPSC-CMs. Furthermore, we monitored mTORC1 activity during MIF-treatment and observed that maturation stimuli suppress mTORC1 signalling throughout the maturation timeline. Lastly, we examined how MIF-treated hiPSC-CMs respond to Doxorubicin treatment and found changes in chromatin organization affecting genes related to extracellular matrix and contractile machinery, suggesting gene regulation mechanisms potentially contributing to DOX-induced cardiotoxicity.