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

项目总结/摘要 组织干细胞表皮的干细胞保护我们免受外界的伤害，生长头发，修复伤口。 表皮干细胞（IFE-SC）和毛囊干细胞（HFSC）的广泛表征揭示了 它们的转录和信号通路如何调节再生。我们对干细胞 将代谢输入，这可以深刻地影响增殖和分化之间的平衡。 当伤口修复中再生减慢时，它可能是有害的，并导致过度增殖状态 与炎症和恶性肿瘤有关。因此，了解新陈代谢如何影响 干细胞的再生能力将填补一个关键的知识空白，以及对新的 促进组织再生和伤口修复的方法。此外，它可能提供新的途径，以遏制 炎症和转移性皮肤鳞状细胞癌（SCC）。 丝氨酸是治疗干预的有吸引力的候选者，因为我们知道SCC细胞对丝氨酸上瘾。 丝氨酸摄取以避免丝氨酸生物合成和代谢物α-酮戊二酸（aKG）的产生。能够 为了将这些发现应用于临床，我们必须了解丝氨酸是如何影响正常的HFSC及其两个细胞的， 再生过程：1）HF再生，其涉及谱系特化，和2）伤口愈合，其中 HFSC使表皮再上皮化并经历向IFE-SC谱系的命运转换。这两个过程需要 不同的干细胞命运决定，并表现出对组蛋白修饰的不同反应。鉴于 aKG在调节组蛋白修饰及其在丝氨酸的外源性限制下的积累中的重要性， 我假设丝氨酸代谢控制着伤口愈合和毛发中干细胞的命运决定 通过aKG依赖性组蛋白脱甲基酶（KDM）再生。 我的初步数据表明，在饮食丝氨酸/甘氨酸后， 限制，其导致增加的从头丝氨酸生物合成。我还观察到， 组蛋白标记H3 K27 me 3，暗示aKG依赖性KDM的激活。因此，在目标1中，我将首先测试 饮食丝氨酸和甘氨酸限制控制HF再生。在目标2中，我将测试丝氨酸的作用是否 甘氨酸对HF再生和创伤修复的限制是HFSC自主的。在目标3中，我将测试 饮食ser/gly限制改变了组蛋白修饰和染色质可及性景观， 我希望这些研究能够1）提供第一个直接证据，证明丝氨酸是否 代谢控制组织再生过程中的内源性干细胞，2）告知新的疗法，以促进 伤口修复，以及3）使饮食或代谢干预在预防和治疗SCC的方式 不会损害正常的再生过程。

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.