How stress stops hair growth (in mice)

When faced with incredible stress, people sometimes shed hair by the handful, but scientists don't know exactly why that is. Now, a new study in mice offers a clue: Stress hormones may put hair growth on pause.   

Follicles, the specialized organs that sprout hairs, cycle through "growth" and "rest" stages, where the follicle first actively produces new hair and then falls dormant. In mice, chronically high levels of the stress hormone corticosterone — similar to the human hormone cortisol — keep follicles in the rest stage for longer than usual, according to the new study, published March 31 in the journal Nature. This response prevents hair follicles from entering the growth stage, during which stem cells in the follicle produce new hair.

Specifically, corticosterone halts hair growth by plugging into a receptor on cells that sit beneath the base of each follicle and release chemicals to regulate the hair cycle. Once plugged in, corticosterone blocks production of a protein called GAS6; without GAS6, the hair follicle stem cells can't activate to start growing hair. 

Related: 5 ways your cells deal with stress 

"So instead of regulating stem cells directly, chronic stress affects the expression of stem cell activating signals," senior author Ya-Chieh Hsu, an associate professor of stem cell and regenerative biology at Harvard University, told Live Science in an email. 

This chain reaction may play out slightly differently in human hair follicles, but the mechanism may be very similar, because rodent corticosterone and human cortisol belong to the same family of hormones and interact with the same kind of receptors, she said. "In humans, hairs in the resting phase can shed off more easily than the hairs in [the growth phase]," which might explain how stress leads to hair loss, Hsu noted.  

"If the finding can be translated in humans, they have to show that cortisol can push growing hair follicles into the rest phase," said Rui Yi, a professor in the departments of pathology and dermatology at the Northwestern University Feinberg School of Medicine in Chicago, who was not involved in the study. 

If the mechanism pinpointed in mice also applies to people, "in principle," treatments could potentially be developed to prevent stress-induced hair loss, Yi told Live Science. But before jumping into new treatments, scientists will need to sort out any differences between the mouse model and humans, he said. 

As for mice, "scientifically, it's a really complete story;" the authors traced each link in the chain reaction that resulted in hair growth changes, Yi said.

In the study, Hsu and her colleagues first stalled all stress hormone production in a group of mice by removing the animals' adrenal glands — an endocrine organ that produces stress hormones. These mice's hair follicles entered the growth stage about three times as often as unmodified control mice. In addition, their rest phase significantly shortened, lasting less than 20 days, compared with the usual 60 to 100 days in normal mice.   

The study authors found that, if they fed the modified mice corticosterone, their hair follicle cycle fell back in step with that of normal mice. This hinted that the hormone somehow suppressed their exuberant hair growth. The authors tested this idea in normal mice by exposing them to mild stressors on-and-off for nine weeks and found that, as the stressed animals' corticosterone levels rose, their normal hair growth became stunted.

Seeing this link between hormone levels and hair growth, the authors zoomed in on the hair follicle itself, to see whether corticosterone directly interacts with the stem cells inside. The hormone plugs into the so-called "glucocorticoid receptor," so the authors selectively deleted that receptor in different cells involved in hair growth and then applied corticosterone to the mice. 

Removing the receptor from hair-follicle stem cells made no difference; the hormone still stunted hair growth. However, when the team deleted the receptor from nearby dermal papilla cells, hair growth proceeded as usual, without an extended rest phase. So whatever causes the hair growth to pause, it must work at the dermal papilla, the authors thought.

The team subsequently found that normal dermal papilla cells stop producing GAS6 when exposed to corticosterone. They also found that GAS6 usually plugs into hair-follicle stem cells and switches them on, jump-starting hair growth. But without the protein, hair follicles remain at rest. Likewise, injecting GAS6 directly into a mouse's skin can trigger hair growth, even if the animal is stressed and has elevated corticosterone levels, the team found.

It's possible, in theory, that GAS6 or a highly similar protein could also trigger hair growth in stressed-out humans, Yi said. But several big questions must be answered first.

For one, although corticosterone and cortisol are chemically similar, we don't know that they play the exact same role in rodent and human hair cycles, Yi said. Additionally, the rodent and human hair cycles unfold on very different timelines. As mice reach maturity, the rest stage of their hair follicles grows longer and longer, he said. And by the time a mouse is about 1.5 years old, the majority of its hair follicles remain at rest most of the time, meaning its hair stops growing.

"You never see any mice go to the barber shop," Yi said.

In comparison, about 90% of adult human hair follicles can be in the growth stage at any given time, Yi wrote in an independent commentary on the study, also published March 31 in Nature. Given that the mouse study only showed how stress hormones can prolong the rest state and prevent growth from starting, it will be interesting to see whether cortisol can not only prolong the rest state in humans, but also force actively growing hair back into the rest state, Yi said.

And finally, while hair usually sheds during the rest state, it's unknown exactly why the dormant hair becomes unmoored from the scalp, Yi said. So, in addition to preventing hair growth, perhaps stress somehow loosens the hair from its place, he said. But that's another mechanism to explore.

While many questions remain to be answered, the mouse study does hint at potential solutions for stress-induced hair loss that could someday be explored in people. "I can imagine manipulations related to the GAS6 pathways might have potential, if the findings are confirmed in humans in the future," Hsu said. The mouse study represents a "first critical step" toward developing those treatments, she said.

Originally published on Live Science.