Mural Lymphatic Endothelial Cells at CNS Borders: Endothelial Heterogeneity, Functional Specialization, and Cross-Species Perspectives

Recent advances in developmental biology and single-cell transcriptomics have revealed remarkable endothelial heterogeneity within the central nervous system, leading to the identification of specialized endothelial populations at brain border regions. Among these, mural lymphatic endothelial cells, also termed brain lymphatic endothelial cells in zebrafish, have emerged as a unique non-lumenized endothelial population with distinctive developmental and functional characteristics. In this review, we critically evaluate current evidence regarding the nomenclature, developmental origin, molecular identity, functional specialization, cross-species relationships, and disease relevance of mural lymphatic endothelial cell-related populations. Current studies demonstrate that zebrafish mural lymphatic endothelial cells depend on Vegfc–Vegfr3 signaling, express multiple lymphatic-associated markers, and exhibit exceptionally strong scavenger and endocytic activity while remaining closely associated with cerebral blood vessels rather than forming conventional lymphatic vessels. Recent transcriptomic analyses further identify these cells as a transcriptionally distinct endothelial population enriched in uptake, endocytosis, and intracellular trafficking pathways. We also distinguish established evidence from unresolved questions concerning developmental lineage, functional heterogeneity, and evolutionary relationships among related cell populations described in vertebrates. Collectively, current evidence supports mural lymphatic endothelial cells as a specialized endothelial population at central nervous system borders and highlights their importance for understanding endothelial heterogeneity, neurovascular homeostasis, and future studies of neurological and cerebrovascular diseases.