The skin contains two main types of adult stem cells: epidermal stem cells and hair follicle stem cells. Normally, each type has a clear role – one maintains the skin while the other supports hair growth. However, research from Rockefeller University has revealed that hair follicle stem cells (HFSCs) are surprisingly adaptable. When the skin is injured, these cells can switch from growing hair to helping repair the wound.

So what tells them when it’s time to make that switch?

A Stress Signal That Changes Cell Behavior

The same Rockefeller research team has now identified the key signal behind this transformation. Hair follicle stem cells respond to what’s called an integrated stress response (ISR) – a cellular alert system that helps them conserve energy and focus on survival tasks.

In the skin, this stress response is tied to the amino acid serine, a non-essential nutrient found in common foods like meat, grains, and milk. In their study published in Cell Metabolism, the scientists showed that when serine levels fall, the ISR activates and hair production slows down. If the skin is also wounded, the ISR ramps up even further, stopping hair growth entirely so that cells can concentrate on repairing damaged tissue. This shift in priorities helps the skin heal faster.

“Serine deprivation triggers a highly sensitive cellular ‘dial’ that fine tunes the cell’s fate – towards skin and away from hair,” explains first author Jesse Novak, an MD-PhD student at Weill Cornell’s Tri-Institutional MD-PhD Program and former doctoral student in the Rockefeller lab of Elaine Fuchs. “Our findings suggest that we might be able to speed up the healing of skin wounds by manipulating serine levels through diet or medications.”

Adult tissues depend on stem cells to maintain balance – replacing cells that die and repairing tissue when it’s damaged. Yet, scientists still know little about how these cells manage their energy and nutrients during different tasks. Novak and his team wanted to understand the metabolic factors that keep stem cells functioning normally and what changes when they must shift gears to heal a wound.

“Most skin wounds that we get are from abrasions, which destroy the upper part of the skin,” says Novak. “That area is home to a pool of stem cells that normally takes charge in wound repair. But when these cells are destroyed, it forces hair follicle stem cells to take the lead in repair,” Novak says. “Knowing that, we thought that tracking these skin cells through wound healing presented a very good model for testing if and how metabolites are regulating this process overall.”

Serine’s Role Beyond Hair and Skin

Earlier research from the Fuchs lab showed that precancerous skin stem cells can become dependent on circulating serine and that limiting serine in the diet helps stop these cells from turning cancerous. Those findings highlighted serine’s powerful influence on cell behavior and even inspired studies testing serine-free diets as cancer treatments.

However, it remained unclear how reducing serine might affect healthy tissue. To explore this, Novak focused on serine’s role in normal stem cell activity and how its absence might reshape regeneration.

The researchers tested how hair follicle stem cells respond to metabolic stress. They either deprived mice of dietary serine or used genetic methods to block the cells from producing their own. In both cases, the results showed that serine communicates directly with the ISR – a system that monitors when tissue conditions go off balance.

When serine levels were low, hair growth slowed because it requires significant energy. When wounds occurred, the ISR activated even more strongly, prioritizing healing over hair regeneration. In other words, when stress increases, the skin’s repair mechanisms take priority.

“No one likes to lose hair, but when it comes down to survival in stressful times, repairing the epidermis takes precedence,” says Fuchs. “A missing patch of hair isn’t a threat to an animal, but an unhealed wound is.”

Can Extra Serine Boost Hair Growth?

Once the team confirmed that low serine levels affect stem cell behavior, they wondered about the reverse – could increasing serine levels enhance hair growth? The answer appears to be no. The body maintains tight control over serine levels, and even when mice were given six times more dietary serine than usual, levels only increased by about 50%.

“However, we did see that if we prevented a stem cell from making its own serine and replenished its losses through a high-serine diet, we were able to partially rescue hair regeneration,” Novak adds.

Next, the researchers plan to investigate whether wound healing can be improved by lowering serine intake or by using medications that influence serine levels or the ISR pathway. They also aim to test other amino acids to see if any have similar effects.

“Overall, the ability of stem cells to make cell fate decisions based upon the levels of stress they experience is likely to have broad implications for how tissues optimize their regenerative capacities in times where resources are scarce,” says Fuchs.