Abstract
The substantial loss of cardiomyocytes resulting from myocardial infarction leads to pathological remodeling of the heart and the onset of heart failure. Promoting heart regeneration is therefore a critical therapeutic goal for repairing damaged cardiac tissue. Over the past two decades, the utilization of cardiac stem cells for heart regeneration has emerged as a focal point of research. However, the related mechanisms and efficacy remain constrained by poor integration and survival. Concurrently, genetic lineage tracing has definitively shown that the adult mammalian heart lacks significant endogenous stem cells. It is now widely accepted that heart regeneration primarily arises from the proliferation of pre-existing adult cardiomyocytes. This review systematically summarizes the physiological and microenvironmental changes during the developmental process of cardiomyocytes, elucidates the intrinsic and extrinsic molecular biological mechanisms that regulate cardiomyocyte proliferation, and discusses exogenous cell transplantation therapy, potentially endogenous pharmacological and genetic approaches, as well as promising bioengineering and cross-disciplinary methods. By synthesizing these multifaceted advances, this review aims to clarify important issues that require further elucidation in this field, thereby advancing the depth of research on heart regeneration and its clinical translational applications.