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 shown that hair follicle stem cells (HFSCs) are surprisingly adaptable. When the skin is injured, these cells can switch from hair growth to wound healing. So what tells them when it’s time for this switch?
A Stress Signal that Changes Cell Behavior
The same Rockefeller University research team has now identified the key signal behind this transformation. Hair follicle stem cells respond to a so-called integrated stress response (ISR) – a cellular alarm system that helps them conserve energy and focus on survival tasks. In the skin, this stress response is linked to the amino acid serine, a non-essential nutrient found in common foods such as meat, grains and milk. In their study published in Cell Metabolism, the scientists showed that when serine levels drop, the ISR is activated and hair production slows down. If the skin is also injured, the ISR is further strengthened so that hair growth comes to a complete standstill and the cells can concentrate on repairing the damaged tissue. This shift in priorities helps the skin to heal faster.
“Serine deficiency triggers a highly sensitive cellular ‘regulator’ that fine-tunes the cell’s fate – toward skin and away from hair,” explains first author Jesse Novak, MD-PhD student at Weill Cornell Medical College’s Tri-Institutional MD-PhD program and former graduate student in the Rockefeller lab of Elaine Fuchs. “Our results suggest that we could accelerate the healing of skin wounds by influencing serine levels through diet or medication.”
Adult tissue relies on stem cells to maintain balance – replacing dead cells and repairing damaged tissue. Yet scientists still know little about how these cells manage their energy and nutrients in various tasks. Novak and his team wanted to understand the metabolic factors that keep stem cells functioning normally and what changes when they need to switch to heal a wound.
“Most of the skin wounds we suffer are abrasions that destroy the upper part of the skin,” says Novak. “This area contains a pool of stem cells that are normally responsible for wound healing. However, if these cells are destroyed, the hair follicle stem cells have to take over the repair,” explains Novak. “With this knowledge, we came to the conclusion that tracking these skin cells during wound healing is a very good model to test whether and how metabolites regulate this process overall.”
The Role of Serine Beyond Hair and Skin
Previous research from the Fuchs lab showed that precancerous skin stem cells can become dependent on circulating serine, and that a low-serine diet helps prevent these cells from degenerating. These findings underscored the strong influence of serine on cell behavior and even inspired studies testing serine-free diets as a cancer treatment. However, it remained unclear how a reduction in serine levels could affect healthy tissue. To investigate this, Novak focused on the role of serine in normal stem cell activity and how its absence might alter regeneration.
The researchers investigated how hair follicle stem cells respond to metabolic stress. They either deprived mice of serine from their diet or used genetic methods to block the cells’ endogenous serine production. In both cases, the results showed that serine communicates directly with the ISR – a system that monitors when the tissue is out of balance. When serine levels were low, hair growth slowed down as it requires a lot of energy. When injured, the ISR was activated even more, prioritizing healing over hair regeneration. In other words: When stress increases, the skin’s repair mechanisms take precedence. “Nobody likes to lose hair, but when it comes to survival in stressful times, epidermal repair takes priority,” says Fuchs. “A missing patch of hair is not a threat to an animal, but an unhealed wound is.”
Can Additional Serine Promote Hair Growth?
After the team confirmed that low serine levels affect stem cell behavior, they wondered if the reverse is also true: can increased serine levels promote hair growth? The answer seems to be “no”. The body tightly controls serine levels, and even when mice were given six times more serine than usual in their diet, levels only increased by about 50%. However, the researchers found that by preventing the stem cells from producing their own serine and compensating for their losses with a serine-rich diet, they were able to partially restore hair regeneration.
Next, they want to investigate whether wound healing can be improved by reducing serine uptake or by using drugs that affect serine levels or the ISR signaling pathway. They also want to test other amino acids to see if they have similar effects. Overall, the ability of stem cells to make their cellular determination based on the level of stress they are exposed to is likely to have far-reaching implications for how tissues optimize their regenerative capacity in times of scarce resources.