Cell-free strategies for cardiomyocyte proliferation and heart repair

Heart regeneration, or the replacement or restoration of damaged myocardium, remains one of the most challenging areas in regenerative medicine, primarily due to the limited regenerative capacity of the adult human heart. Unlike the embryonic heart, which exhibits robust cardiomyocyte proliferation, postnatal cardiac muscle cells permanently exit the cell cycle, resulting in minimal regenerative potential following injury such as myocardial infarction. This limitation contributes significantly to the progression of heart failure, a leading cause of morbidity and mortality worldwide. Recent breakthroughs in understanding the molecular and cellular mechanisms that govern cardiomyocyte proliferation have revealed that targeting signaling pathways (e.g., Hippo-YAP), cell cycle regulators, epigenetic modulators, and extracellular components may be a promising strategy for stimulating heart repair. Despite these advances, cardiac regeneration still faces significant obstacles in replacing damaged tissue and ensuring the regenerated muscle functions effectively within the complex heart system. This review aims to provide a comprehensive analysis of emerging regulatory mechanisms involved in cardiomyocyte proliferation and myocardial regeneration. It critically evaluates current strategies for promoting heart regeneration, with particular emphasis on the most promising molecular pathways and therapeutic approaches with translational potential. Ongoing research, as summarized in this review, continues to expand the potential of regenerative medicine to repair heart damage, offering hope for more effective treatments for heart disease.