Person:

Buenrostro, Jason

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.

Empirical and anecdotal evidence have associated stress with accelerated hair greying (formation of unpigmented hairs)1,2, but the scientific evidence linking the two is scant. Here, we report that acute stress leads to hair greying through fast depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics3,4, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of immune attack or adrenal stress hormones. Rather, hair greying results from activation of the sympathetic nerves that innervate the MeSC niche. Upon stress, sympathetic nerve activation leads to burst release of the neurotransmitter norepinephrine, which drives quiescent MeSCs into rapid proliferation, followed by differentiation, migration, and permanent depletion from the niche. Transient suppression of MeSC proliferation prevents stress-induced hair greying. Our studies demonstrate that acute stress-induced neuronal activity can drive rapid and permanent loss of somatic stem cells, and illustrate an example in which somatic stem cell maintenance is directly influenced by the overall physiological state of the organism.

microRNAs (miRNA) play an important role in immune system development and function, often participating in regulatory networks with the transcription factors that drive their expression. However, many of these relationships remain obscured because regulatory elements controlling miRNA expression in different immune cells remain largely uncharacterized. To address this, we analyzed miRNA expression and open chromatin regions (OCR) from >60 immune cell populations. This enabled us to establish maps of miRNA promoter and enhancer usage across the immune system. Unique miRNA signatures within different populations were associated with local chromatin accessibility changes, revealing putative regulatory elements for differentially expressed miRNAs. These maps suggest many miRNAs utilize multiple promoters to increase abundance, and also identified dominant and divergent miRNA regulatory elements between lineages and during immune cell development, as well as between closely clustered miRNAs. This study provides insight into the miRNA regulatory network of the immune system and is a resource for further discovery.