Single nuclei multiomic analyses identify human cardiac lymphatic endothelial cells associated with coronary arteries in the epicardium

Cardiac lymphatic vessels play important roles in fluid homeostasis, inflammation, disease, and regeneration of the heart. The developing cardiac lymphatics in human fetal hearts are closely associated with coronary arteries, similar to those in zebrafish hearts. We identified a population of cardiac lymphatic endothelial cells that reside in the epicardium. Single nuclei multiomic analysis of the human fetal heart revealed the plasticity and heterogeneity of the cardiac endothelium. Furthermore, we found that VEGFC is highly expressed in arterial endothelial cells, providing a molecular basis for the arterial association of cardiac lymphatic development. Using a cell-type-specific integrative analysis, we identified a novel population of cardiac lymphatic endothelial cells marked by the PROX1, the lymphangiocrine RELN, and enriched in binding motifs of ETV transcriptional factors. We report the first in vivo molecular characterization of human cardiac lymphatics and provide a valuable resource to understand fetal heart development.