Vascular endothelial cells as signaling niches for epithelial stem cells in the skin.

In many non-skin tissues, vascular endothelial cells (VECs) are increasingly recognized as integral components of stem cell niches engaged in bidirectional molecular crosstalk, regulating stem cell behavior through angiocrine signaling. In the skin, however, the nature and physiological relevance of VEC cues influencing epithelial stem cells remain poorly defined. While many cell types, including fibroblast, immune cells, nerves, and adipocytes are known to crosstalk to the epithelial stem cells in skin contributing to their niche, recent studies began to implicate VECs as a putative niche component. Indeed, skin epithelial stem cells can actively influence local vasculature via stage- and spatially restricted secretion of vascular remodeling factors. Conversely, genetic perturbations that enhance secretion of quiescence-inducing signals from the blood vessel VECs alter hair follicle stem cell proliferation and disrupt tissue homeostasis. Although these findings demonstrate that VECs can in principle modulate epithelial stem cell states, the specific signals and physiological contexts where VECs instruct skin stem cells remain largely unknown. Beyond homeostasis, VEC-stem cell interactions may in theory contribute to skin responses to environmental and pathological stresses, including ultraviolet irradiation, psoriasis, and cancer. Here we aim to raise awareness that, as observed in many non-skin tissues and tumors, skin VECs may likewise function not only as delivery conduits but also as putative signaling niches that shape epithelial stem cell states across diverse contexts. This review highlights an underexplored layer of vascular-epithelial crosstalk with potential relevance for skin homeostasis and disease, revealing a need for deeper mechanistic investigation in this research area.