Environmental signal, “stress”, in mice helps explain why hair can turn prematurely grey

Stress has been associated with a variety of changes in many tissues, including premature hair-greying. However, whether external stressors are the causal factors, and whether stress-related changes occur at the level of somatic stem cells — remain poorly understood. Hair follicle cycles comprise growth (anagen), degeneration (catagen) and resting phase (telogen) [see diagram, Fig. 1 of attached editorial]. The bulge and hair-germ region of the follicle contains two populations of stem cells: hair follicle stem cells (HFSCs; which are derived from epithelium), and melanocyte stem cells (MeSCs, derived from neural crest). This topic is perfect for these GEITP pages and the gene-environment interactions theme. “Stress” is the environmental signal, and genes in specific genetic pathways can respond to stress, creating the “response” of premature hair-greying.

HFSCs and MeSCs are normally quiescent — except during early anagen, when they are concurrently activated to regenerate a pigmented hair. Activation of HFSCs produces a new hair follicle; activation of MeSCs generates differentiated melanocytes that migrate downwards. At the hair bulb, differentiated melanocytes synthesize melanin to color the newly regenerated hair from the root. At catagen, mature melanocytes are destroyed — leaving only MeSCs that will initiate new rounds of melanogenesis in future cycles. This predictable behavior of MeSCs and melanocytes, and the visible nature of hair color, makes the melanocyte lineage an accessible model to investigate how stress influences tissue regeneration.

To examine whether psychological or physical stressors enhance hair-greying, authors [see attached article] used three approaches to imitate stress in C57BL/6J mice (having a black coat color): restraint stress, chronic unpredictable stress (this would be similar to grant-writing scientists, always wondering if their next proposal will get funded), and nociception-induced stress [achieved by way of injecting resiniferatoxin (RTX), an analog of capsaicin]. Authors found that all three procedures lead to increased numbers of unpigmented white hairs over time. Restraint stress and chronic unpredictable stress led to noticeable hair-greying after 3 to 5 rounds of hair cycles; nociception-induced stress produced the most pronounced and rapid effect — many new hairs that formed in the next hair cycle following RTX injection became unpigmented.

To reiterate, authors [see attached article] used a combination of adrenalectomy, denervation, chemogenetics, cell ablation, and knockout of the adrenergic receptor — specifically in MeCSs. Authors discovered that stress-induced loss of MeSCs is independent of immune attack, or adrenal stress hormones; instead, hair-greying results from activation of the sympathetic nerves that innervate the MeSC niche. Under conditions of stress, activation of these sympathetic nerves leads to sudden release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent MeSCs to proliferate rapidly — which is followed by their differentiation, migration and then permanent depletion from their niche. Transient suppression of MeSC proliferation prevented stress-induced hair-greying. This study demonstrates that neuronal activity — induced by acute stress — can result in a rapid and permanent loss of HFSCs. These data provide an example in which maintenance of somatic stem cells is directly influenced by the overall physiological state of the animal. And you can rest assured that there exist genetic differences in response to stress (i.e. some people’s hair will grey easily, whereas other people’s hair might require a great deal more stress). 😉


Nature 30 Jan 2020; 577: 676-681 & editorial pp 623-624

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