Protein PPARd Can Induce Rapid Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes
In a new study, researchers from the Icahn School of Medicine at Mount Sinai have developed a reproducible and scalable method to advance the maturation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and hPSC-CMs produced by human stem cell lines in the laboratory support myocardial contraction, which will improve methods for disease modeling, regenerative therapy, and drug testing. The findings were published in Cell Stem Cell, entitled "PPARdelta activation induces metabolic and contractile maturation of human pluripotent cell-derived cardiomyocytes".
These authors investigated multiple metabolic modifications of hPSC-CMs. They also determined the role of a metabolic switch from glycolysis to fatty acid oxidation in hPSC-CMs generated in the laboratory by protein induction called peroxisome proliferator activated receptor delta (PPARd). This metabolic switch is a critical part of the heart maturation process.
Dr. Nicole C. Dubois, corresponding author of the paper and researcher at the Icahn School of Medicine at Mount Sinai, said, “This new study will create exciting opportunities to further assess human cardiac biology by combining multidisciplinary approaches to developmental biology, transcriptomics, contractility measurement, and drug testing. Our findings provide a new avenue for generating mature hPSC-CMs for disease modeling and regenerative therapy. We are one step closer to understanding how our knowledge of human development can be used to improve access to mature human cell types.”
In this new study, these authors activated different signaling pathways in vitro to reproduce the metabolic changes that would arise during heart development in an organism. They found that PPARd induced a metabolic switch from glycolysis to fatty acid oxidation in a laboratory setting, which affected whether cardiomyocytes utilized glucose or fatty acids for energy production. Although peroxisome proliferator-activated receptor alpha (PPARa) signaling is most active in cardiac myocytes, these authors noted that PPARd signaling plays a separate and important role in effectively activating gene regulatory networks, increasing the number and distribution of organelles involved in energy production, and enhancing fatty acid oxidation processes. Activation of signaling regulated by PPARd can further enhance cardiomyocyte size and distribution and improve cardiomyocyte contractility, which are hallmarks of cardiac maturation.
These authors also explored the effect of lactate exposure, in which cardiomyocytes were able to survive on lactate in the absence of glucose. This has often been used to enrich hPSC-CMs. They found that this approach can induce an independent mechanism of cardiac maturation, which can enhance oxidative metabolism when combined with PPARd, allowing both carbohydrates and fatty acids to be efficiently energized. This new study allows a detailed analysis of the long-term effects of experimental protocols commonly used in the myocardial field.
In addition, these authors produced a comprehensive, publicly accessible dataset detailing the transcriptome changes they observed. This dataset allows scientists studying PPAR-regulated signaling or lactate selection to rapidly evaluate targets for future use in research or drug testing.