Dissecting the role of serine metabolism in stem cell fate and tissue regeneration

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Project Summary/Abstract Tissue stem cells stem cells of the epidermis protect us from external insults, grow hair, and repair wounds. Extensive characterization of epidermal stem cells (IFE-SCs) and hair follicle stem cells (HFSCs) has uncovered how their transcriptional and signaling pathways regulate regeneration. Far less is known about how stem cells incorporate metabolic inputs, which can profoundly affect the balance between proliferation and differentiation. When regeneration is slowed in wound repair, it can be detrimental and lead to hyperproliferative states associated with inflammation and malignancy. Therefore, a knowledge of how metabolism impacts the regenerative capabilities of stem cells will fill a critical knowledge gap and an unmet and pressing need for new ways to promote tissue regeneration and wound repair. Furthermore, it may provide novel avenues to curb inflammation and metastatic cutaneous squamous cell carcinomas (SCCs). Serine is an attractive candidate for therapeutic intervention, as we know that SCC cells become addicted to serine uptake to avoid serine biosynthesis and production of the metabolite a-ketoglutarate (aKG). To be able to clinically translate these findings, we must understand how serine impacts normal HFSCs and their two regenerative processes: 1) HF regeneration, which involves lineage specification, and 2) wound healing, where HFSCs re-epithelialize epidermis and undergo a fate switch to the IFE-SC lineage. These two processes entail different stem cell fate decisions and demonstrate different responses to histone modifications. Given the importance of aKG in regulating histone modifications and its accumulation upon exogenous restriction of serine, I hypothesize that serine metabolism controls stem cell fate decisions in both wound healing and hair regeneration via aKG-dependent histone demethylase enzymes (KDMs). My preliminary data demonstrated a striking acceleration in wound repair upon dietary serine/glycine restriction, which results in increased de novo serine biosynthesis. I also observed a marked reduction in the histone mark H3K27me3, implicating activation of aKG-dependent KDMs. Thus, in Aim 1, I will first test whether dietary serine and glycine restriction controls HF regeneration. In Aim 2, I will test whether the effects of serine and glycine restriction on HF regeneration and wound repair are HFSC-autonomous. In Aim 3, I will test whether dietary ser/gly restriction alters the histone modification and chromatin accessibility landscape and dissect the underlying mechanism behind it. I expect these studies to 1) provide the first direct evidence of whether serine metabolism controls endogenous stem cells during tissue regeneration, 2) inform novel therapies to promote wound repair, and 3) enable dietary or metabolic interventions in the prevention and treatment of SCC in ways that do not harm normal regenerative processes.