SKIN VASCULATURE AND HAIR FOLLICLE CROSS-TALKING REGULATES STEM CELL ACTIVATION AND SKIN HOMEOSTASIS
Stem cells are vital for maintaining and regenerating tissues, and they are influenced by both internal factors and external signals from their niche. However, the molecular signals involved in the communication between stem cells and their niche, particularly in the hair follicle stem cell (HFSC) field, are not well understood. Recent findings have provided more insights into this crosstalk, and this dissertation focuses on the signaling between HFSCs and their vascular niche specifically.The first part of the study characterized the changes in the vascular niche during different stages of the hair cycle under homeostasis. The skin vasculature was found to form a horizontal plexus under the hair germ (HPuHG) and then disperse upon anagen onset. To investigate the two-way signaling between HFSCs and their vascular niche, we induced (1) Runx1 knockout in the epithelium using K14-CreERT2 driver (Runx1 KO) and (2) Alk1 knockout in the endothelium using Cdh5-CreERT2 driver (pan-endothelial Alk1EndoKO), both in adult mice to investigate changes in the other compartment. Both knockout mice exhibited delayed HFSC activation and accumulation of the HPuHG. Further investigation revealed that Alk1 represses BMP4 expression in the endothelial cells, which is supported by both BMP4-LacZ reporter allele and genomic evidence from scRNA-seq data of sorted endothelial cells and bulk RNA-seq data of sorted HFSCs in Alk1EndoKO mice. The rescue experiment using Alk1;BMP4dKO mice showed a partial rescue of the HFSC activation delay seen in Alk1EndoKO mice. The study also revealed that blood vessels, but not lymphatics, can inhibit HFSC activation through signaling by genetically perturbing the Alk1-BMP4 pathway in all endothelial cells or solely in lymphatic endothelial cells. Overall, these results suggested that blood vessels have a more significant impact and function as signaling niches for adult HFSCs, expanding the functional repertoire of endothelial cells in the skin. In addition to the stem cell-niche communication, this work also identified a novel K19+/VE-Cadherin+ perineurial population, revealing the heterogeneity of the VE-Cadherin+ lineage.