When people get stressed, they often suffer hair loss. This condition, known as telogen effluvium, results from hair follicles going dormant. But the molecular cause of this switch is unknown.

To solve that mystery, Harvard University stem cell biologist Ya-Chieh Hsu and her colleagues turned to mice. They first confirmed the effects of stress by subjecting mice to unpredictable discomforts such as tilting their cages or flashing the room lights, and indeed saw that the animals grew less hair than unstressed animals did. The researchers then conducted a series of experiments to dig deeper into the physiological consequences of stress and found long-range signaling from the endocrine glands above the kidneys to cells in the skin. The group published its results March 31 in Nature.

“This is the first paper that identifies the [mechanistic] link between stress hormones and the hair growth,” says Rui...

Hsu says she has long been interested in how stress affects skin and hair. Last year, for example, her group found that stress can cause hair to go gray by triggering signals in the sympathetic nervous system that reduce the numbers of melanocyte stem cells that give hair its color. Next, her group set out to understand how stress might cause hair loss.

Previous work has shown that removing the adrenal glands from animals such as rats and rabbits boosts hair growth. In this latest study, Hsu’s group found the same to be true in mice, observing that animals who’d had their glands removed grew more hair on their backs than did mice with their glands intact. Specifically, the hair follicles, which normally toggle back and forth between a rest phase known as telogen and a growth phase known as anagen, had shorter telogen phases and longer anagen phases in mice lacking adrenal glands.

Hsu notes that the group was surprised that removing mice’s adrenal glands caused the mice’s hair follicle stem cells to enter a near-constant growth phase even as the animals aged. “These results suggested that even the baseline level of stress hormone that’s normally circulating in the body is an important regulator of the resting phase,” she tells The Scientist in an email.

Corticosterone suppresses the production of GAS6 by dermal papilla cells (green), preventing the activation of hair follicle stem cells. The U-shape structures above the dermal papilla cells, with their glucocorticoid receptors stained magenta, are two stem cells.

Looking at the animals’ circulating hormones, the team deduced that corticosterone, an analog to humans’ cortisol, was likely playing a role—mice lacking adrenal glands had almost undetectable levels of the molecule. Feeding unstressed mice corticosterone reduced their hair growth.

When Hsu and her colleagues suppressed the expression of the gene encoding the glucocorticoid receptor that binds corticosterone on hair follicle stem cells, they saw no change in hair growth, suggesting the stem cells were not responding directly to changes in corticosterone levels. The researchers then tried depleting the receptor on fibroblasts in and around the hair follicle and identified support cells called dermal papilla cells as translating the corticosterone signal into hair growth regulation. Specifically, corticosterone prevents these cells from releasing a protein called GAS6 that activates stem cells to grow hair. Mice treated to overexpress Gas6 had active stem cells and noticeable hair growth, even under stressful conditions that caused reduced fur growth in control mice.

“In the last few years, this laboratory has tackled some of the most fascinating phenomena about hair follicles that have long been appreciated but not understood in molecular terms,” Elaine Fuchs, a stem cell biologist at the Rockefeller University who was not involved in the study, writes in an email. “They show that remarkably, cortisone, produced in response to chronic stress by the adrenal glands and circulated through the bloodstream, profoundly impacts the dermal papilla, a specialized population of mesenchymal cells that are needed to stimulate hair growth.”

“It’s a very nice study,” says Yi. “It’s very complete in terms of going from the organ and finding there’s a hormone molecule, and then finding which cell type [is] responding to this, and then the molecular mechanism.”

How the results will translate to humans remains to be seen, and there are some key differences between mouse and human hair growth that need to be considered, Yi says. While a human hair can stay in the growth phase for years, then rest for a few weeks or months and start growing again, mouse hairs grow for only a couple of weeks before resting for longer and longer periods of time as it cycles through rest and growth.

“That’s why we almost always go to [the] barber shop; we actually can appreciate our hair growth over time. . . . You never see anyone say, ‘we trim mouse hair,’” Yi notes. Another contrast with humans is that, while mouse hairs grow less, “they’re not falling off either.”

The question thus remains: What happens in humans suffering from telogen effluvium, in which hair not only stops growing, but loses anchorage and falls out? To be able to closely observe fur growth, Hsu and her colleagues shaved their mice, making it hard to tell whether hairs from follicles that stay in extended rest phases actually fall out, but Hsu says she suspects this would happen eventually.

There is “still a long way to go,” she writes, but says that she and her colleagues “are excited about the potential of Gas6 in promoting hair follicle stem cell activity and [about] exploring its relevance and impact in human skin. The President and Fellows of Harvard College has filed for a patent covering the methods and compositions for controlling hair growth, listing Hsu and her coauthor, Sekyu Choi of Harvard, as inventors.

S. Choi et al., “Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence,” Nature, doi:10.1038/s41586-021-03417-2, 2021.

Clarification (April 9): This story has been updated to note that the authors have a patent application pending. The Scientist regrets the oversight. 

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