FEATURE
Signalling from the sympathetic nervous system of mice when
subjected to stress leads to the depletion of a stem-cell population in their
hair follicles. This discovery sheds light on why stress turns hair prematurely
grey.
Shayla A.
Clerk and Christopher D. Deppmann
It has been said that Marie Antoinette’s hair went completely
white on the night before her beheading. This story might be apocryphal, but
rapid greying of the hair is now widely referred to as Marie Antoinette
syndrome. It is often assumed to be caused by stress — a phenomenon perhaps
best exemplified by photographs of heads of state before and after they held
office. However, the relative contributions of ageing, genetic factors and
stress to greying are not known — in part owing to a lack of mechanistic
understanding of the process. Writing in Nature, Zhang et al. identify the
mechanism governing premature greying in mice that have experienced stress.
The average human scalp has 100,000 hair follicles, and a wide
range of hair colours can be found across the human population. Hair colour is
determined by cells called melanocytes, which produce different combinations of
light-absorbing melanin pigments. Melanocytes are derived from melanocyte stem
cells (MeSCs), which are located in a part of the hair follicle called the
bulge. The normal hair cycle is divided into three stages: hair-follicle
regeneration (anagen), degeneration (catagen) and rest (telogen). Melanocyte
production begins early in the anagen phase (Fig. 1a). As people age, the pool
of MeSCs is gradually depleted — and so pigmented hair becomes ‘salt and
pepper’ coloured, and then turns to grey and finally to white after a complete
loss of pigment in all hair follicles.
Melanocyte stem cells and stress. Melanocyte stem cells
(MeSCs) are located in the bulge of the hair follicle, which is innervated by
neurons of the sympathetic nervous system that release the neurotransmitter
molecule noradrenaline. The follicle cycles through three phases: regeneration
(anagen), degeneration (catagen) and rest (telogen). a, Under normal
conditions, MeSCs migrate away from the bulge (red arrows) and differentiate
into melanocytes during anagen.
Melanocytes synthesize pigments that add colour
to the regenerating hair. During catagen and telogen, they begin to die and
migrate out of the niche (not shown). However, plentiful MeSCs remain to
replace the melanocytes in the next anagen phase. b, Zhang et al. show that
stressful stimuli activate the sympathetic nervous system, increasing
noradrenaline release in hair follicles.
Noradrenaline causes complete
conversion of MeSCs into melanocytes, which migrate out of the niche in catagen
and telogen. The hair follicle is depleted of MeSCs that would have
differentiated to replace these melanocytes. Without any pigment cells to
colour the hair in the next anagen phase, it begins to look grey or white.
Aside from ageing, there are several factors that bring about
premature greying, including dietary deficiencies, disorders such as alopecia
areata or vitiligo, and stress. Zhang et al. set out to test the role of stress
in the greying process in mice. They exposed the animals to three different
stressors — pain, restraint and a model of psychological stress — during
different phases of hair growth. Each stressor caused depletion of MeSCs from
the bulge region, eventually leading to the development of patches of white
hair.
Prevailing theories posit that stress-induced greying involves
hormones (such as corticosterone) or autoimmune reactions. Zhang and colleagues
examined these potential mechanisms, first by preventing corticosterone
signalling and next by stressing animals that had compromised immune systems.
In both cases, greying occurred after stress, indicating that neither
corticosterone nor autoimmune reactions cause MeSC depletion. However, the
authors found that MeSCs express β2-adrenergic receptors, which respond to
noradrenaline — a neurotransmitter molecule involved in the ‘fight or flight’
response to stress. Loss of this receptor specifically in MeSCs completely
blocked stress-induced greying.
Adrenal glands are the main source of circulating
noradrenaline. But, surprisingly, the researchers discovered that removing
these glands did not prevent greying in response to stress in the mice.
Another source of noradrenaline is the sympathetic nervous
system (SNS), which is highly active in response to stress, and which drives
the fight-or-flight response. Zhang and colleagues showed that bulge regions
are highly innervated by sympathetic neurons, and that ablating the SNS using a
neurotoxin molecule, or blocking the release of noradrenaline from sympathetic
neurons, prevented stress-induced greying. Next, the authors generated mice in
which sympathetic neurons could be acutely activated, and found that
overactivation of the SNS in these mice caused greying in the absence of
stress. Together, these results indicate that noradrenaline released from
active sympathetic neurons triggers MeSC depletion. Interestingly, Zhang et al.
found that the propensity of an area to turn grey correlates with its level of
sympathetic innervation.
Exactly how does sympathetic activity cause depletion of MeSCs
from hair follicles? Normally, these stem cells are maintained in a dormant
state until hair regrowth is required. However, when the researchers tracked
MeSCs labelled with a fluorescent protein, they discovered that MeSC
proliferation and differentiation increase markedly under extreme stress or
exposure to a high level of noradrenaline. This results in mass migration of
melanocytes away from the bulge, and leaves no remaining stem cells. To further
confirm this result, the researchers suppressed MeSC proliferation
pharmacologically and genetically. When proliferation was dampened, the effects
of stress on MeSC proliferation, differentiation and migration were blocked.
Zhang and colleagues’ work raises several questions. For
instance, is the mechanism underlying MeSC depletion in response to stress the
same as that which causes greying during ageing? Future experiments modulating
SNS activity over a longer period would determine whether age-related greying
can be slowed or hastened. Perhaps, in the absence of sympathetic signals, MeSCs
have the capacity for unlimited replenishment, pointing to a way to delay
age-related greying.
Are other pools of stem cells similarly susceptible to
stem-cell depletion in response to stress, if they or the cells that make up
their niche express β2-adrenergic receptors? In support of this idea,
haematopoietic stem and progenitor cells (HSPCs), which give rise to blood and
immune lineages, reside in a bone-marrow niche that contains stromal cells, and
stimulation of those cells by the SNS causes HSPCs to leave their niche.
Perhaps, like MeSCs, stress depletes HSPCs — which could partially explain why
immune function is impaired in response to chronic stress. Whether this type of
relationship extends beyond MeSCs and HSPCs is an open question.
It is fascinating to consider what possible evolutionary
advantage might be conferred by stress-induced greying. Because grey hair is
most often linked to age, it could be associated with experience, leadership
and trust. For example, adult male silverback mountain gorillas (Gorilla
beringei beringei), which get grey hair on their backs after reaching full
maturity, can go on to lead a gorilla troop. Perhaps an animal that has endured
enough stress to ‘earn’ grey hair has a higher place in the social order than
would ordinarily be conferred by that individual’s age.
Connecting the dots between stress, fight or flight, stem-cell
depletion and premature greying opens up several avenues for future research.
Beyond developing anti-greying therapies, Zhang and colleagues’ work promises
to usher in a better understanding of how stress influences other stem-cell
pools and their niches.
(Courtesy: Nature)
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