Perturbation of Epigenetic and Environmental Factors
Open Access DepositedImpact on Human Cardiomyocyte Electromechanics and Metabolism
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Human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) combined with all-optical imaging and actuation provide a powerful, scalable framework for gaining patient-specific insights into cardiac electromechanics and metabolism. The recent development of pharmacological epigenetic modulators, histone deacetylase (HDAC) inhibitors, raises the question
environmental exposure to plastic nanoparticles and stressors. Lastly, we demonstrated a strategy for controlling cardiac electromechanics through contact-free application of static magnetic fields. Exposure to low-strength (< 50mT) magnetic fields alone had no impact on hiPSC-CM behavior. However, our results are the first to establish that low-strength magnetic fields, when combined with the addition of magnetic nanoparticles, can selectively speed up or slow down cardiac wave conduction, instantaneously and in a direction-specific manner. With further development, the approach has potential applications for anti-arrhythmic control of cardiac waves. This project highlights hiPSC-CM as a “new approach methodology” (NAM) for human cardiac epigenetics. We show that the hiPSC-CM transcriptomic profile, their scalability, and their compatibility with sophisticated high-throughput all-optical platforms enable mechanistic and translational studies for the accelerated development of new therapies.
are hiPSC-CMs also a suitable tool for studying cardiac epigenetics? Because HDAC regulation in the human heart can be pro-arrhythmic or anti-arrhythmic, the effects of HDAC modulators on cardiac ion channels are of great interest. We sought to establish the utility of hiPSC-CM for probing such connections between HDAC perturbation and cardiac electromechanical and metabolic responses. First, we constructed computational models of transcriptomic regulation to investigate whether in vitro hiPSC-CM syncytia are capable of recapitulating in vivo epigenetic relationships. RNA sequencing data from the adult human left ventricle (from the GTEx database) were compared to data from our hiPSC-CM, in which systematic perturbations of each HDAC gene were applied. We found strikingly similar patterns of baseline expression and of regulation for HDAC genes, cardiac transcription factor genes, and key cardiac ion channel genes. Second, hiPSC-CM were leveraged for a functional follow-up, robustly capturing the effects of HDAC perturbation on functional outcomes, specifically electrophysiological behavior and metabolic responses. This framework was further applied to explore the interplay with other forms of perturbation
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