Summary:
Epidermal stem cells constantly rejuvenate the skinâs barrier, which excludes harmful microbes and prevents dehydration. In routine wounds, underlying hair follicle stem cells (HFSCs), normally dedicated to hair regeneration, must also reconstruct and thereafter maintain the overlying epidermis. How these fate choices are balanced to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover the non-essential amino acid serine as a surprising rheostat in this process. Utilizing diet and HFSC-specific loss-of-function studies, we show that under serine-depleted conditions, HFSCs delay hair growth, and upon injury skew their fate towards epidermal re-epithelialization while concomitantly limiting hair growth. Combining temporal single-cell RNA sequencing, genetics and pharmacological intervention, we show that serine deficiency augments an injury-activated integrated stress response (ISR), boosting re-epithelization and rapidly restoring the skinâs barrier at the wound edge. Our findings integrate injury, the ISR, metabolism, tissue fate-selection and repair, offering potential for dietary and pharmacologic intervention to accelerate wound healing.
