Pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) enable the in vitro study of human heart biology but they remain functionally and structurally immature. In vivo heart development involves a metabolic switch from glycolysis to fatty acid oxidation (FAO) that coincides with increased Peroxisome-Proliferator-Associated-Receptor (PPAR) signaling activity.
Here we show that PPAR signaling activation in hPSC-CMs enhances metabolic and structural maturation in an isoform-specific manner. PPARdelta activation improves myofibril organization and increases binucleation, with no effect on contractility. PPARdelta activation further upregulates the gene regulatory network involved in FAO, increases mitochondrial content and FAO flux in hPSC-CMs. Transient lactate treatment also induces transcriptional maturation, and shows a similar metabolic response upon PPARd activation.
In summary, we identify a role for PPARdelta signaling in recapitulating the metabolic switch to FAO in hPSC-CMs, with no effect on contractility, thus uncoupling a metabolic prerequisite from contractile maturation during early heart development.
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| GROUP | CONDITION |
|---|---|
| PPARδ modulation | |
| Other isoforms | |
| Early timepoints | |
| Other 7d timepoints | |
| Engineered Heart Tissues | |
| Lactate Selection | |
| AMPK Activation | |
| High [LCFA] | |
| Embryoid Bodies |
Pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) enable the in vitro study of human heart biology but they remain functionally and structurally immature. In vivo heart development involves a metabolic switch from glycolysis to fatty acid oxidation (FAO) that coincides with increased Peroxisome-Proliferator-Associated-Receptor (PPAR) signaling activity.
Here we show that PPAR signaling activation in hPSC-CMs enhances metabolic and structural maturation in an isoform-specific manner. PPARdelta activation improves myofibril organization and increases binucleation, with no effect on contractility. PPARdelta activation further upregulates the gene regulatory network involved in FAO, increases mitochondrial content and FAO flux in hPSC-CMs. Transient lactate treatment also induces transcriptional maturation, and shows a similar metabolic response upon PPARd activation.
In summary, we identify a role for PPARdelta signaling in recapitulating the metabolic switch to FAO in hPSC-CMs, with no effect on contractility, thus uncoupling a metabolic prerequisite from contractile maturation during early heart development.