Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity,posing a serious threat to pharmaceutical industries and patients’lives.However,mitochondrial toxicity testing is not incorporated into routine cardiac safety screening procedures.To accurately model native human cardiomyocytes,we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes(h PCMs)to a nucleoside analog,remdesivir(RDV).Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in h PCMs.Accordingly,action potential duration was elongated in h PCMs,reflecting clinical incidences of RDV-induced QT prolongation.In a screen for mitochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced cardiotoxicity.Our study demonstrates the utility of h PCMs in the detection of clinically relevant cardiac toxicities,and offers a framework for h PCM-based high-throughput screening of cardioprotective agents.

Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes

With defined culture protocol, human embryonic stem cells （hESCs） are able to generate cardiomyocytes in vitro, therefore providing a great model for human heart development, and holding great potential for car- diac disease therapies. In this study, we successfully generated a highly pure population of human cardio- myocytes （hCMs） （〉95% cTnT＋） from hESC line, which enabled us to identify and characterize an hCM-specific signature, at both the gene expression and DNA meth- ylation levels. Gene functional association network and gene-disease network analyses of these hCM-enriched genes provide new insights into the mechanisms of hCM transcriptional regulation, and stand as an informative and rich resource for investigating cardiac gene func- tions and disease mechanisms. Moreover, we show that cardiac-structural genes and cardiac-transcription fac- tors have distinct epigenetic mechanisms to regulate their gene expression, providing a better understandingof how the epigenetic machinery coordinates to regulate gene expression in different cell types.