Scientists have discovered a cellular "switch" that could revolutionize skin healing: a drop in the amino acid serine signals hair follicle stem cells (HFSCs) to halt hair growth and mobilize for wound repair. Published in Cell Metabolism, this groundbreaking research from Rockefeller University reveals how stress-triggered nutrient cues can guide stem cell behavior, opening potential avenues to accelerate tissue regeneration through dietary or pharmacological strategies.
The skin is home to two main types of adult stem cells-epidermal and hair follicle stem cells—each traditionally carrying specialized roles in maintaining the skin or growing hair. However, these cells display remarkable adaptability when the skin is injured. The new study shows that falling serine levels activate the integrated stress response (ISR), a molecular alarm that prompts HFSCs to “switch gears,” slowing energy-intensive hair production and committing resources to urgent tissue repair. This dynamic response not only increases survival but also speeds skin healing after superficial wounds.
The Rockefeller team conducted experiments in mice, manipulating dietary serine or genetically blocking its synthesis in HFSCs. When serine became scarce—either from the diet or molecular blocks—ISR signaling increased, hair regeneration slowed dramatically, and HFSCs pivoted to wound healing. Conversely, supplementing dietary serine could partially rescue hair growth in genetically impaired mice, though serine levels remained tightly regulated by the body.
Further investigations revealed that while depriving stem cells of serine curbs their proliferation for hair growth, it is essential in directing them to sites of injury for rapid skin repair. Notably, wounds typically destroy the upper pool of stem cells in the skin, forcing HFSCs from deeper in the follicle to take over tissue regeneration duties—a flexibility crucial for healing.
Lead author Jesse Novak asserts that these findings illuminate how adult stem cells make fate decisions based on environmental stress and resource availability, hinting at novel ways to harness metabolism for therapeutic healing. Their work suggests a future where dietary management or ISR-modulating drugs could optimize tissue regeneration, with broad applications in wound care and recovery from injury.
REFERENCE: Jesse S.S. Novak, Lisa Polak, Sanjeethan C. Baksh, Douglas W. Barrows, Marina Schernthanner, Benjamin T. Jackson, Elizabeth A.N. Thompson, Anita Gola, M. Deniz Abdusselamoglu, Alain R. Bonny, Kevin A.U. Gonzales, Julia S. Brunner, Anna E. Bridgeman, Katie S. Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H. Amalia Pasolli, Thomas S. Carroll, Lydia W.S. Finley, Elaine Fuchs. The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury. Cell Metabolism, 2025; 37 (8): 1715 DOI: 10.1016/j.cmet.2025.05.010
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