Chronic Stress Inhibits Hair Growth by Prolonging Follicle Stem Cells’ “Resting Phase”

Sustained stress exposure inhibits hair growth, wrote authors of a study published in Nature. In rodent models, increased systemic levels of stress hormone corticosterone were found to prolong the “resting phase” of hair follicle stem cells (HSFCs), thus preventing hair turnover.

Conversely, following adrenalectomy to prevent secretion of stress hormones, HSFCs underwent more frequent regeneration throughout the life course. These results outline the cellular and molecular mechanisms by which chronic stress may inhibit hair growth and provide a framework for future studies.

While the relationship between stress exposure and tissue homeostasis is well-documented, the mechanisms underlying this association are poorly understood. To better determine the impact of chronic stress on hair growth, investigators manipulated the secretion of corticosterone — the rodent equivalent of human hormone cortisone — in mouse models.

To assess hair growth in the absence of systemic stress hormones, the investigators performed adrenalectomy (ADX) in C57BL/6 mice to remove both adrenal glands, the source of corticosterone. ADX mice and control mice were then shaved and monitored for hair coat recovery over a period of several months.

In separate trials, investigators tested the impact of increased corticosterone levels in 2 sets of mice: (1) mice supplied supplementary corticosterone via drinking water; and (2) mice exposed to stress triggers, such as cage tilts or sudden light-dark changes. In all trials, blood corticosterone levels were quantified using enzyme-linked immunosorbent assay (ELISA); hair cycle phases were determined visually and confirmed histologically. Fluorescence-activated cell sorting (FASC) of dorsal skin samples was used to identify the cells through which corticosterone acts to regulate HFSC quiescence.

The surgical removal of both adrenal glands was found to activate HFSCs and enhance their proliferation. In ADX mice, hair follicles were longer at the same stage of anagen compared with control mice.

Over approximately 16 months post-adrenalectomy, ADX mice underwent an average of 10 synchronized hair cycles. By comparison, sham mice only completed 3 hair cycles in the same time period, within which phase entry was inconsistent. Over time, the telogen phases became progressively longer in sham mice, and entry into anagen “sporadic and asynchronized.” In ADX mice, however, telogen phases consistently lasted just 2 weeks, and entry into anagen afterwards was consistent. Percent regrowth was significantly greater in ADX vs sham mice at 66 and 74 days after shaving (both P <.0001).

By contrast, exposure to systemic corticosterone was observed to profoundly inhibit hair growth. Corticosterone-fed mice experienced prolongation of the telogen phase compared with controls. When corticosterone was removed from the drinking water, however, mice were able to enter the anagen phase, suggesting that the effects of stress on hair growth are reversible.

In mice exposed to external stressors without corticosterone supplementation, results were similar. Stressed mice displayed extended telogen phases, though this effect was also reversible following adrenalectomy.

Per FACS analyses, corticosterone was found to act on the dermal papillae to regulate HFSC quiescence. Specifically, corticosterone was observed to inhibit the expression of Gas6, a gene which encodes the secreted factor growth arrest specific 6. Inhibition of Gas6 expression forces HFSCs to remain in prolonged quiescence, thus explaining poor hair growth in mice with high corticosterone levels.

By contrast, Gas6 was found to be significantly upregulated in the dermal papillae of ADX mice. Further, intradermal injection of Gas6 was found to induce anagen at injection sites. Gas6 overexpression was also found to counteract stress-induced inhibition of hair growth; mice injected with Gas6 then exposed to corticosterone feeding or stress triggers were able to maintain HFSC activation.  

Per these results, long-term stress substantially impacts hair growth via inhibition of Gas6 expression in the dermal papillae. Reversal of this effect was achieved by the reduction of stress or the overexpression of Gas6, providing potential insight into the process of hair regeneration. While rodent models provide only a preliminary look into human mechanisms, these data describe the processes which underlie hair growth and regeneration under stressful conditions.

“Our findings not only reveal important regulators of HFSC quiescence and activation at both local and systemic levels, but also identify the cellular and molecular mechanisms by which chronic stress influences the hair cycle,” the investigators wrote. “Moreover, we demonstrate that the tissue-regeneration capacity of HFSCs remains robust even after significantly increased rounds of anagen entry throughout life.”

Disclosure: A patent application covering the methods and compositions for controlling hair growth has been filed by the President and Fellows of Harvard College, listing Y.-C.H. and S.C. as inventors. Please see the original document for more information.

Reference

Choi S, Zhang B, Ma S, et al. Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence. Nature. 592,428–432 (2021). doi:10.1038/s41586-021-03417-2