Altering Cardiac Cell Fate for Heart Repair

Abstract Direct cardiac reprogramming holds great promise as a novel therapy for heart failure, a common and morbid disease that is usually caused by irreversible loss of massive functional cardiomyocytes. By leveraging the knowledge in developmental and stem cell biology gained during my PhD and postdoc training, in 2012 I demonstrated that in a murine acute myocardial infarction model, delivery of three transcription factors, Gata4, Mef2c and Tbx5 (GMT) converted cardiac fibroblasts (CFs) into functional induced cardiomyocytes (iCMs) that integrated electrically and mechanically with surrounding myocardium, resulting in functional improvement and scar size reduction. These findings suggest that iCM reprogramming is an effective means of regenerating heart tissue in vivo for human patients with heart disease. However, because relatively little was known about the factors that allow CFs to be reprogrammed, the applicability of cardiac reprogramming was limited to the context in which it had been attempted at that time. Since my independence, my own laboratory has established robust murine and human iCM reprogramming systems. By using these systems, we obtained novel insights into the transcriptional, post-transcriptional and epigenetic regulation of both murine iCM (supported by R01HL128331 as ESI) and human iCM reprogramming (supported by R01HL144551), and concomitantly improved the quality and yield of iCMs. This R35 EIA application is an extension to these two currently funded NHLBI R01 grants to further unravel the molecular mechanisms underlying iCM conversion, to test in vivo iCM reprogramming in non- acutely injured hearts and to exploit the latest single cell multi-omics and mathematical modeling for optimized and individualized reprogramming. Successful completion of this proposal will help to move direct cardiac reprogramming closer to its clinical application, provide new insights into molecular mechanisms underlying cardiac cell fate determination, and open new opportunities for the field to leverage the models and platforms we will develop here to study other cardiovascular physiological and pathological processes.