In Vivo Cardiac Reprogramming Contributes to Zebrafish Heart Regeneration

Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardiomyocytes to divide and replace ventricular myocardium lost from ischemia-induced infarct(1,2). As a result, there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium(3). Past studies have shown that lower vertebrate and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles(4–6); however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration(3). Here, we have developed in the zebrafish a combination of fluorescent reporter transgenes, genetic fate-mapping strategies, and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-ventricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. Importantly, we observed that Notch signaling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signaling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration.