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Donor sex modulates hiPSC-derived cardiomyocyte metabolic and functional response to fatty acids
Anna K McClain1, Cody Callahan1, Saivee S Shelke1
1Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, United States.
Insights
Sex influences human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) maturation. Female and male hiPSC-CMs respond differently to fatty acid supplementation, impacting their metabolism and function.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Metabolic Disease
Background:
- Human induced pluripotent stem cells (hiPSCs) are vital for cardiovascular disease (CVD) modeling and regenerative therapies.
- Variability and incomplete metabolic maturation of hiPSC-derived cardiomyocytes (hiPSC-CMs) limit their clinical translation.
- Fatty acid (FA) supplementation (palmitate/oleate) promotes aerobic phenotypes, but outcomes are affected by hiPSC-CM heterogeneity.
Purpose of the Study:
- To investigate the impact of sex on hiPSC-CM metabolic and functional diversity.
- To determine if sex influences hiPSC-CM responses to fatty acid (FA) supplementation.
Main Methods:
- Utilized three male and three female hiPSC lines.
- Evaluated hiPSC-CMs for sex-specific responses to palmitate (PA) and oleate (OA) treatments.
- Assessed contractility, aerobic metabolism, and transcriptomic profiles.
Main Results:
- Observed modest sex differences in hiPSC-CMs at baseline.
- Detected significant divergence in contractility, aerobic metabolism, and transcriptomic profiles after FA treatment between sexes.
- Demonstrated that sex modulates hiPSC-CM response to FA supplementation.
Conclusions:
- Sex plays a crucial role in hiPSC-CM metabolic and functional characteristics.
- Findings highlight sex-specific regulation of hiPSC-CM metabolism and function.
- Informs the development of sex-specific maturation strategies for hiPSC-CMs.
Background:
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enable cardiovascular disease modeling and regenerative research but exhibit substantial heterogeneity and incomplete metabolic maturation. Palmitate (PA) and oleate (OA) can promote aerobic maturation, although responses vary. Despite sex differences in adult cardiac metabolism, sex effects in hiPSC-CMs remain poorly defined.
Methods:
We assessed sex-dependent metabolic and functional responses in hiPSC-CMs from three male and three female lines treated with PA or OA. Contractile function, aerobic metabolism, and transcriptomic profiles were evaluated.
Results:
Sex differences were modest at baseline but pronounced after FA treatment. Male- and female-derived hiPSC-CMs responded differently to PA and OA across contractile, metabolic, and transcriptional measures, indicating that FA identity and sex jointly shape hiPSC-CM phenotypes.
Conclusions:
Sex contributes to hiPSC-CM heterogeneity and modulates responses to FA-based maturation. Incorporating sex-specific metabolic and functional regulation may improve the consistency and physiological relevance of hiPSC-CM maturation strategies.
