Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration

Abstract With the high morbidity and mortality rates, cardiovascular diseases have become one of the most concerning diseases worldwide. The heart of adult mammals can hardly regenerate naturally after injury because adult cardiomyocytes have already exited the cell cycle, which subseqently triggers cardiac remodeling and heart failure. Although a series of pharmacological treatments and surgical methods have been utilized to improve heart functions, they cannot replenish the massive loss of beating cardiomyocytes after injury. Here, we summarize the latest research progress in cardiac regeneration and heart repair through altering cardiomyocyte fate plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions. First, residual cardiomyocytes in damaged hearts re-enter the cell cycle to acquire the proliferative capacity by the modifications of cell cycle-related genes or regulation of growth-related signals. Additionally, non-cardiomyocytes such as cardiac fibroblasts, were shown to be reprogrammed into cardiomyocytes and thus favor the repair of damaged hearts. Moreover, pluripotent stem cells have been shown to transform into cardiomyocytes to promote heart healing after myocardial infarction (MI). Furthermore, in vitro and in vivo studies demonstrated that environmental oxygen, energy metabolism, extracellular factors, nerves, non-coding RNAs, etc. play the key regulatory functions in cardiac regeneration. These findings provide the theoretical basis of targeting cellular fate plasticity to induce cardiomyocyte proliferation or formation, and also provide the clues for stimulating heart repair after injury.