Serine Metabolism Leverages the Integrated Stress Response to Direct Stem Cell Fate During Tissue Regeneration

<p>Epidermal stem cells constantly rejuvenate the skin's barrier, which excludes harmful microbes and prevents dehydration. While hair follicle stem cells (HFSCs) normally regenerate hair, they must also reconstruct and thereafter maintain the overlying epidermis upon a barrier breach, such as a wound. How these fate choices are balanced to restore physiologic function to damaged tissue remains poorly understood. Here, I uncover the non-essential amino acid serine as a surprising regulator in this process. Utilizing dietary intervention and HFSC-specific loss-of-function studies, I demonstrate that under serine-depleted conditions HFSCs delay hair growth. Upon injury, serine-restricted HFSCs skew their fate towards epidermal re-epithelialization while concomitantly limiting hair growth. Combining temporal single-cell RNA sequencing, loss-of-function genetics, and pharmacological intervention, I show that serine deficiency augments an injury-activated integrated stress response (ISR). Moreover, this response accelerates re-epithelization and rapidly restores the skin's barrier at the wound edge. Altogether, my findings demonstrate that stem cells use serine metabolism and the ISR as regulators of tissue regeneration, offering potential for dietary and pharmacological intervention to accelerate wound healing.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year dc:date.available

2025

Author dc:creator

• Novak, Jesse Stephen Swyer

Contributors dc:contributor

• Elaine Fuchs

• serine metabolism
• hair follicle stem cells
• wound healing
• integrated stress response
• epidermal regeneration
• stem cell fate
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/821

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1825