Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence

Sekyu Choi1,2, Bing Zhang1,2,14, Sai Ma1,3,9, Meryem Gonzalez-Celeiro1,2, Daniel Stein1,2, Xin Jin4, Seung Tea Kim1,2, Yuan-Lin Kang1,2, Antoine Besnard2,5,6,15, Amelie Rezza7,8,16, Laura Grisanti7,8, Jason Buenrostro1,2,9, Michael Rendl7,8,10, Matthias Nahrendorf11,12,13, Amar Sahay2,5,6,9, Ya-Chieh Hsu1,2* 1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. 2Harvard Stem Cell Institute, Cambridge, MA, USA. 3Department of Biology and Koch Institute, MIT, Cambridge, MA, USA. 4Society of Fellows, Harvard University, Cambridge MA, USA. 5Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. 6Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 7Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 8Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 9Broad Institute of Harvard and MIT, Cambridge, MA, USA. 10Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 11Center for Systems Biology and Department of Radiology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA, USA. 12Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 13Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany. *Correspondence to: Ya-Chieh Hsu 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 driv