Progenitor-derived endothelin controls dermal sheath contraction for hair follicle regression

Progenitor cell death and dermal papilla relocation during the regression phase of the hair growth cycle are essential for stem cell activation and follicle regeneration. This drastic follicle remodeling is coordinated by dermal sheath (DS) smooth muscle contraction, but how DS-generated forces are regulated is unknown. Here, we identify endothelin signaling - a potent vasoconstriction-regulating pathway - as the key activating mechanism of DS contraction. Pharmacological blocking or genetic ablation of both endothelin receptors, ETA and ETB, impedes DS contraction and halts follicle regression. Progenitors at the epithelial strand bottleneck are the main source of endothelin ligand ET-1, which is required for follicle regression. ET signaling in DS cells and downstream contraction is dynamically regulated by cytoplasmic Ca2+ levels via cell membrane and sarcoplasmic reticulum calcium channels. Together, these findings illuminate an epithelial-mesenchymal-interaction paradigm in which progenitors - before undergoing programmed cell death - control the contraction of the surrounding sheath smooth muscle to orchestrate homeostatic tissue regression and follicle reorganization. Overall design: Bulk RNA seq was performed on FACS sorted Dermal sheath (DS), Dermal Papilla (DP) and Dermal fibroblasts (2 biological replicates x 3 populations) from P16 (Early catagen) mice back skins using Illumina HiSeq 2000 platform at the Genome Technology Center at NYU.