Developmental and regenerative biology of cardiomyocytes.

Current progress and challenges in understanding the molecular and cellular mechanisms of cardiomyocyte embryonic development and regeneration are reviewed in our present work. Three major topics are critically discussed: how do cardiomyocytes form in the embryo? What is the adult origin of the cells that regenerate cardiomyocytes in animal models with adult heart regeneration capabilities? Can the promise of therapeutic cardiomyocyte regeneration be realized in humans? In the first topic, we highlight current advances in understanding the developmental biology of cardiomyocytes, with emphasis on the regulative capabilities of the early embryo during specification and allocation of the cardiomyoblasts that produce the primordial heart. We place further emphasis on trabecular cardiomyocyte development from late cardiomyoblasts, neural crest cells and primordial cardiomyocytes, and their critical role in the clonal growth of the compact/septal and cortical cardiomyocyte layers in the mammalian embryo and adult zebrafish, respectively. In the second topic, we focus on the re-activation of the cortical or trabecular compaction programs as hallmarks of cardiomyocyte regenerative cells during adult zebrafish and neonatal mouse heart regeneration, respectively, and underscore the metabolic remodeling that commonly drives cardiomyocyte regeneration in these organisms. Finally, we discuss the status of preclinical and clinical-stage therapeutics for cardiomyocyte regeneration, with particular emphasis on gene therapy, as well as adult and pluripotent stem cell-based cellular cardiomyoplasty approaches. In summary, our article provides a bird's-eye view of current knowledge and potential pitfalls in the field of developmental biology-guided regenerative medicine strategies for the treatment of heart diseases.