Researchers identify mechanism for regenerating hair follicle stem cells

Researchers at Harvard University have identified the biological mechanism of how chronic stress impairs hair follicle stem cells, confirming long-standing observations that stress could lead to hair loss.

In a study on mice published in the journal Nature, researchers found that a major stress hormone causes hair follicle stem cells to remain in a prolonged resting phase, without regenerating the hair follicle and hair. Researchers have identified the specific cell type and molecule responsible for transmitting the stress signal to stem cells, and have shown that this pathway can potentially be targeted to restore hair growth.

“My lab is interested in understanding how stress affects stem cell biology and tissue biology, stimulated in part by the fact that everyone has a story to share about what happens to their skin and hair when stressed. . I realized that as a stem of the skin cell biologist, I could not provide a satisfactory answer as to whether stress indeed has an impact – and more importantly, if so, what are the mechanisms, ”said Ya-Chieh Hsu, Ph.D., Alvin and Esta Star associate professor of Stem Cell and Regenerative Biology at Harvard and lead author of the study. “The skin provides a treatable and accessible system to study this important problem in depth, and in this work we found that stress actually delays stem cell activation and fundamentally alters the frequency with which hair follicle stem cells regenerate tissues.

The hair follicle is one of the few tissues in mammals that can undergo cycles of regeneration throughout life and has become a paradigm that informs much of our fundamental understanding of mammalian stem cell biology. The hair follicle goes naturally between growth and rest, a process fueled by stem cells from the hair follicle. During the growth phase, the hair follicle stem cells are activated to regenerate the hair follicle and hair, and the hair grows longer every day. During the resting phase, the stem cells are at rest and the hair can fall out more easily. Hair loss can occur if the hairs fall out and the stem cells remain at rest without regenerating new tissue.

The researchers studied a mouse model of chronic stress and found that hair follicle stem cells remained in the resting phase for a very long time without regenerating tissue. A major stress hormone produced by the adrenal glands, corticosterone, was upregulated by chronic stress; supplying corticosterone to mice was able to mimic the effect of stress on stem cells. The equivalent hormone in humans is cortisol, which is also upregulated under stress and is often referred to as a “stress hormone”.

“This result suggests that high stress hormones indeed have a negative effect on hair follicle stem cells,” Hsu said. “But the real surprise came when we eliminated the source of the stress hormones.”

Under normal conditions, the regeneration of hair follicles slows down over time – the resting phase lengthens as animals get older. But when the researchers eliminated the stress hormones, the resting phase of the stem cells became extremely short, and the mice constantly entered the growth phase to regenerate hair follicles throughout their lives, even when they were old. .

“So even the basal level of the stress hormone that normally circulates in the body is an important regulator of the resting phase. Stress essentially elevates this pre-existing “adrenal gland-hair follicle axis”, making it even more difficult for the hair follicle stem cells to work. enter the growth phase to regenerate new hair follicles, ”Hsu said.

After establishing the link between the stress hormone and the activity of hair follicle stem cells, the researchers investigated the biological mechanism underlying this connection.

“We first asked if the stress hormone directly regulates stem cells and checked by suppressing the corticosterone receptor, but that turned out to be wrong. Instead, we found that the stress hormone actually acts on a group of dermal cells under the hair follicle, known as the skin papilla, ”said Sekyu Choi, Ph.D., the author. principal of the study.

The skin papilla is known to be essential for activating hair follicle stem cells, but none of the previously identified factors secreted by the skin papilla changed when stress hormone levels were altered. On the contrary, the stress hormone prevented cells in the dermal papilla from secreting Gas6, a molecule that researchers have shown can activate hair follicle stem cells.

“Under normal and stressful conditions, the addition of Gas6 was enough to activate the stem cells in the hair follicles that were in the resting phase and to promote hair growth,” Choi said. “In the future, the Gas6 pathway could be exploited for its potential to activate stem cells to promote hair growth. It will also be very interesting to explore whether other stress-related tissue changes are linked to the impact of the stress hormone on the regulation of Gas6.

These initial findings in mice require further study before they can be safely applied to humans. Harvard’s Technology Development Office has protected the intellectual property relating to this work and is exploring collaborative possibilities for its future development and eventual commercialization.

Last year, Hsu’s group discovered how stress affects another type of stem cells located in the hair follicle, melanocytic stem cells which regenerate hair pigment. Researchers have found that stress activates the sympathetic nervous system and depletes melanocyte stem cells, leading to premature graying of hair. Now, with the new study, the two results together demonstrate that although stress has adverse effects on hair follicle stem cells and melanocyte stem cells, the mechanisms are different. Stress depletes melanocytic stem cells directly via signals derived from the nerves, while stress prevents hair follicle stem cells from making new hair indirectly via the impact of an adrenal-derived stress hormone on the niche. Because the hair follicle stem cells are not depleted, it might be possible to reactivate the stem cells under stress with mechanisms such as the Gas6 pathway.

Beyond the potential application of the Gas6 pathway in promoting hair growth, the study results also have broader implications for stem cell biology.

“When we look for factors that control stem cell behaviors, we normally look locally in the skin. While there are important local factors, our results suggest that the main switch for hair follicle stem cell activity is actually far into the adrenal gland and it works by changing the threshold required for stem cell activation. Hsu said. “You can have systemic control over the behavior of stem cells located in a different organ that plays a really important role, and we’re learning more and more examples of these ‘organ interactions’. Tissue biology is interconnected with bodily physiology. We still have a lot to learn in this area, but our findings constantly remind us that in order to understand skin stem cells, we often have to think beyond the skin. ”