My research focuses on alternative approaches to elicit cardiomyocyte-centric protective interventions for myocardial injuries. Cardiomyocytes are the unit of cardiac contractility and constitute about two-thirds of the total cardiac volume, therefore, play a significant role in maintaining the cardiac microenvironment. In the past decade, studies have demonstrated the pivotal role of paracrine signaling as a primary mechanism underlying various cellular and molecular-based interventions to repair cardiac injury. In fact, such approaches essentially rejuvenate the cardiac extracellular microenvironment to regulate signaling pathways across cell types and improve wound healing. However, the role of cardiomyocyte-mediated paracrine signaling to non-myocytes in defining the overall physiological, and pathological response in the heart after injury has yet to be determined. We have previously reported that the activation of the cell cycle in adult cardiomyocytes through external interventions induces the cardiac rejuvenation-associated pathway and reprograms paracrine signaling from cardiomyocytes; which improves angiogenesis, cell survival, and immune response to restrict wound expansion. This signifies the importance of specific intercellular communication in cardiac health, disease, and therapeutic development. Therefore, our central premise is that paracrine signaling-mediated intercellular communication in the heart plays a critical role in restoring heart function and cardiac injury repair.