Abstract
The epicardium plays a pivotal role in heart development, regeneration, and disease response through its contributions to multiple cardiac lineages and its dynamic paracrine signaling. Recent advances in lineage tracing, single-cell technologies, and, particularly, human pluripotent stem cell (hPSC)-derived cardiac organoid models have illuminated the cellular heterogeneity, developmental plasticity, and intercellular crosstalk of epicardial cells with other cardiac cell types. These models have revealed conserved and divergent mechanisms of epicardial function across species, offering new insights into epicardial-myocardial-endothelial-immune interactions and the regulation of cardiac repair. This review highlights recent key findings from developmental and regenerative studies, integrating them with emerging data from human cardiac organoids to provide an updated framework for understanding epicardial biology and its therapeutic potential.