Organ-specific transcriptional programs regulate cellular plasticity in lymphatic endothelial cells.

Lymphatic vessels play essential roles in maintaining fluid homeostasis and responding to inflammatory and tissue environmental changes. During these biological processes, lymphatic endothelial cells (LECs) lining lymphatic vessels adapt to external stimuli in various organs and alter their characteristics. While organ-specific molecular and functional heterogeneity has been well-characterized in blood vascular endothelial cells, the extent and functional significance of such heterogeneity in LECs remain poorly understood. In this study, we established LECs derived from the heart and lung tissues of Prox1-GFP mice for comparative analyses. Both cell types retained lymphatic endothelial marker expression and exhibited tube-forming capacity in two- and three-dimensional culture systems, indicating the preservation of functional LEC phenotypes. Transcriptomic analysis revealed that LEC gene expression profiles were primarily segregated according to the organ of origin, indicating that LECs possess stable organ-specific transcriptional states. Notably, cardiac-derived LECs displayed enrichment of proliferation-related pathways, including MYC signaling, as well as inflammatory pathways such as TNF-α-NFκB and IL2-STAT5 signaling, indicating a transcriptional state primed for enhanced responsiveness to external stimuli. Furthermore, cardiac-derived LECs exhibited increased susceptibility to TGF-β-induced endothelial-to-mesenchymal transition (EndoMT) compared with pulmonary-derived LECs, reflecting enhanced cellular plasticity. These findings demonstrate that organ-specific transcriptional states regulate stimulus responsiveness, thereby defining cellular plasticity in LECs.