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Serine metabolism leverages the integrated stress response to direct stem cell fate during tissue regeneration [RNA-seq]

ABSTRACT: Epidermal stem cells constantly rejuvenate the skin’s 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 skin’s 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE270324 | GEO | 2024/06/20

REPOSITORIES: GEO

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Project description:Cell fates are defined by specific transcriptional program. Previously, we developed a unique stem cell regeneration mouse model, in which transcriptional program for ectoderm organs such as tooth and skin is switched. Genomic deletion of one subunit of Mediator complex, Med1, resulted in defective enamel regeneration, in which dental stem cells were inhibited from undergoing transcriptional program for dental fate. In stead, they exerted skin program for both hair and epidermis, and post-natally regenerate ectopic hairs in the incisors. Here, we report that Med1 also modulates epidermal and hair cell fates in the skin. Med1 ablation further enhanced epidermal and sebocyte fates, and accelerated injury induced epidermal regeneration. However, it blunted hair fate resulting in hair loss in the skin. Ablation of Med1 increased the number of isthmus stem cells and epidermal stem cells, which regenerate epidermis during cutaneous wound healing process. Med1 deficiency also constitutively activated these stem cells and increased their proliferation. Microarray profiling indicated that Med1 deletion causes activation of β-catenin and suppression of TGFβ signaling. Med1 deficiency induced the expression of β-catenin target genes to control cell fate and proliferation. It also decreased TGFβ expression in interfollicular epidermis. Med1 deficiency increased the proliferation and migration of epidermal cells, and induced nuclear translocation of β-catenin, and decreased TGFβ1 expression in vitro. Our finding together with previous observations demonstrated that Med1 governs ectoderm cell fate in both tooth and skin. Med1 ablation blunts hair fate but induces epidermal and sebocyte cell fates to accelerated injury induced epidermal regeneration in the skin. Accelerated regeneration is derived from constitutive activation of epidermal stem cells accompanied with increased proliferation and migration of their progeny by balancing of β-catenin induced growth promoting and TGFβ mediated growth inhibitory activities in the skin.