Donor Sex Modulates hiPSC-Derived Cardiomyocyte Metabolic and Functional Response to Fatty Acids

Abstract

Human induced pluripotent stem cells (hiPSCs) are a powerful platform for modeling cardiovascular disease (CVD) and developing regenerative therapies, yet progress is limited by variability among hiPSC-derived cardiomyocytes (hiPSC-CMs) and their incomplete metabolic maturation. To address this, maturation schemes supplementing the fatty acids (FAs) palmitate (PA) and oleate (OA) have been shown to promote a more aerobic phenotype, though outcomes vary due to intrinsic hiPSC-CM heterogeneity. While donor-related factors such as age and somatic origin have been studied, the influence of sex remains largely unexplored despite its role in adult cardiac metabolism. Here, we investigate allosome-driven contributions to hiPSC-CM metabolic and functional diversity. Using three male and three female hiPSC lines, we evaluate whether sex modulates hiPSC-CM responses to PA or OA. Our results reveal modest sex differences at baseline, but pronounced divergence following FA treatment in contractility, aerobic metabolism, and transcriptomic profiles. These findings inform the development of maturation strategies by highlighting sex-specific regulation of hiPSC-CM metabolism and function.