When skin is injured, the survival instinct of stem cells kicks in. New research shows that a simple amino acid, serine, helps push stem cells away from hair growth and instead promotes wound healing, opening the door to new treatments for chronic wounds.
Hair follicle stem cells (HFSC) are constantly self-renewing cells responsible for two important body functions: maintaining the hair growth cycle through hair follicle regeneration, and regenerating skin tissue to aid in wound healing.
A new study led by The Rockefeller University in New York explored how the non-essential amino acid serine affects the behavior of HFSCs and found that when serine levels are low, the cells prioritize wound healing over hair growth.
“Serine deficiency triggers a highly sensitive cellular ‘dial’ that fine-tunes cell fate—toward the skin, away from the hair,” said the study’s lead author Jesse Novak, a current MD student in the Tri-Hospital Program at Weill Cornell Medical College and a former doctoral student in the Laboratory of Mammalian Cell Biology and Development at The Rockefeller University. "Our results suggest that we may be able to control serine levels through diet or medication to speed up skin wound healing."
stages of hair growth cycle
Serine is a non-essential amino acid that the body can synthesize on its own but is also found in foods such as meat, poultry, fish, soybeans, nuts and dairy products. Serine is a building block of proteins and is involved in cell proliferation and various metabolic pathways.
The researchers found that in mice fed a diet low in serine and glycine, another amino acid, HFSC slowed hair growth and accelerated wound repair, specifically the process of re-epithelialization, or repairing the skin barrier. Although serine is classified as a nonessential amino acid, HFSCs would struggle to survive if they were unable to synthesize and absorb serine from external (i.e., dietary) sources.
The researchers discovered that the integrated stress response (ISR) is an internal cell program that triggers a shift in HFSC function in response to stress, such as injury or serine deficiency. When serine is deficient, the ISR in HFSCs is activated, prompting these cells to become more like epidermal stem cells, helping to rebuild the skin rather than performing their typical hair-growing functions.
"Most of the skin wounds we encounter come from abrasions, which destroy the top half of the skin," Novak said. "That area is home to a pool of stem cells that are normally responsible for wound repair. But when these cells are destroyed, it forces the hair follicle stem cells to take over the lead role in repair. Knowing this, we thought that tracking these skin cells during wound healing could provide a very good model for testing whether and how metabolites regulate the entire process."
The ISR can be thought of as a volume adjuster. If stress levels are high, such as an injury or when serine levels are low, ISR shifts the function of HFSCs away from hair production and toward skin repair. The researchers found that enhancing ISR activity in mice with a drug that mimics the effects of serine deficiency improved wound healing at the expense of hair regeneration. Conversely, inhibiting activity by blocking ISR sensing proteins reversed these skin-related effects, confirming the central role of the ISR in this process. In human skin models, similar ISR signatures were found at the edges of healing wounds, suggesting that the mechanism is evolutionarily conserved, meaning that it remains unchanged over time across species.
"No one likes losing their hair, but when it comes to surviving stress, repairing the epidermis is critical," said Dr. Elaine Fox, director of the Mammalian Cell and Biology and Development Laboratory at The Rockefeller University and corresponding author of the study. "A missing patch of hair is not a threat to the animal, but an unhealed wound is."
Hair follicles in early stages of regeneration The Rockefeller University/Fox Laboratory
Researchers tested whether high doses of serine could enhance hair regrowth. Unfortunately, for those suffering from hair loss, the results are less than dramatic. When mice were fed six times the normal dose of serine, their serine levels increased by only 50%. It turns out that the body has tight control over this amino acid.
"We did find, however, that if we prevent the stem cells from producing their own serine and replace their losses with a high-serine diet, we can partially rescue hair regrowth," Novak said.
The researchers' findings have clear practical implications, especially when it comes to wound healing. Targeting the ISR through diet or drugs may speed healing of burns or chronic wounds in patients with diabetes. Additionally, understanding the role of the ISR may provide ways to protect hair regrowth, especially in stress-related or injury-induced hair loss. However, because cancer cells also exploit ISR-like stress response pathways, careful control of any future therapies will be critical.
The researchers will continue to explore serine's potential to accelerate wound healing and plan to test other amino acids to see if they have similar properties.
"Overall, the ability of stem cells to determine cell fate based on the level of stress they experience may have broad implications for how tissues organize their ability to regenerate when resources are scarce," Fox said.
The research was published in the journal Cell Metabolism.