Regulatory Mechanisms of Myocardial Reprogramming in Zebrafish

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Cardiomyocytes experience a wide range of physiologic and pathologic stimuli, which can influence their cellular state. Although cardiomyocyte hypertrophy and hyperplasia are well known adaptive cardiac cellular responses, some cardiomyocytes also retain the capacity to reprogram (i.e. cardiac plasticity) in order to alter their differentiation state and identity to adapt to stress. For instance, cardiomyocyte de-differentiation is a component of the maladaptive response during heart failure; a portion of the right ventricle in Ebstein's anomaly, which is exposed to altered hemodynamic forces, becomes “atrialized”; and both cardiomyocyte de- differentiation and trans-differentiation regulate cardiac regeneration under certain conditions. Thus, this cardiac “adaptive cellular reprogramming” can act in not only pathologic but also beneficial circumstances. However, despite the importance of cardiac reprogramming in regulating adaptive responses to stimuli, our understanding of the intrinsic processes that control cardiomyocyte plasticity and the external cues that activate cardiac reprogramming to modify cardiomyocyte differentiation states and cell identities remains yet to be fully elucidated. Thus, the overall goals of these proposed studies are to illuminate the underlying mechanisms that 1) control cardiomyocyte plasticity, 2) activate cardiomyocyte reprogramming in plastic cardiomyocytes and 3) regulate the reprogramming of these cardiomyocytes. The results of these cardiac reprogramming studies will not only illuminate how cardiomyocytes may adaptively (or maladaptively) reprogram in response to cellular stress in vivo but also provide further insight into how to direct mammalian cells from various cell sources (i.e. fibroblasts, pluripotent stem cells, cardiac progenitor cells) into functional ventricular and atrial cardiomyocytes for human cardiac disease modeling and therapeutic screening in cell culture systems as well as for human cardiac regenerative therapies.