Corticosterone inhibits Gas6 to govern hair follicle stem cell quiescence

Chronic, sustained exposure to stressors can profoundly impact tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here, we report the adrenal gland-derived stress hormone corticosterone (the rodent equivalent of cortisol) regulates hair follicle stem cell (HFSC) quiescence and hair growth in mice. Without systemic corticosterone, HFSCs enter substantially more rounds of the regeneration cycle throughout life. Conversely, under chronic stress, elevated corticosterone levels prolong HFSC quiescence and keep hair follicles in an extended resting phase. Mechanistically, corticosterone acts on dermal papilla (DP) to suppress the expression of a secreted factor, Growth Arrest Specific 6 (Gas6). Restoring Gas6 expression overcomes stress-induced inhibition of HFSC activation and hair growth. Our work identifies corticosterone as a systemic inhibitor of HFSC activity via its impact on the niche, and demonstrates that removal of such inhibition drives HFSCs into frequent regeneration cycles with no observable defects long-term. Cell type: FACS purified dermal papilla cells (DP) from the mouse skin; Conditions: Sham (Control) vs ADX (adrenalectomized mice); GR KO (Pdgfra-CreER; GRfl/fl) vs control; 2 replicate for each condition. FACS purified hair follicle stem cells (HFSC) from the mouse skin; Conditions: Sham vs ADX vs ADX+CORT (corticosterone); GR KO vs control; 2 replicate for each condition.