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

剖析丝氨酸代谢在干细胞命运和组织再生中的作用

• 批准号: 10389594
• 负责人: Jesse Stephen Swyer Novak
• 金额: $ 5.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389594
• 关键词: ATAC-seq; Ablation; Acceleration; Affect; Anabolism; Apoptosis; Cell Lineage; Cells; ChIP-seq; Chromatin; Clinical; Data; Diet; Disease; EZH2 gene; Environment; Enzymes; Epidermis; Epithelial; Equilibrium; Genetic; Genetic Transcription; Genus Mentha; Glycine; Goals; Hair; Hair Removal; Hair follicle structure; Histones; Immune; Immunofluorescence Microscopy; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methyltransferase; Monitor; Morbidity - disease rate; Mus; Natural regeneration; Phase; Phenocopy; Phenotype; Prevention; Process; Production; Role; Serine; Signal Pathway; Skin; Specific qualifier value; Squamous cell carcinoma; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Translating; Work; alpha ketoglutarate; base; cell behavior; cell type; chromatin modification; deprivation; dietary; epidermal stem cell; epidermis cell; fitness; hair regeneration; healing; histone demethylase; histone modification; improved; knock-down; loss of function; mortality; novel; novel therapeutics; overexpression; regenerative; response; skin barrier; skin squamous cell carcinoma; stem cell fate; stem cells; therapeutic candidate; tissue regeneration; tissue stem cells; transcriptome sequencing; uptake; wound; wound healing

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.

项目摘要/摘要 组织干细胞表皮干细胞保护我们免受外界侮辱，生长毛发，修复伤口。 表皮干细胞和毛囊干细胞的广泛特征已被发现 它们的转录和信号通路是如何调控再生的。关于干细胞是如何 包括代谢投入，这可以深刻地影响增殖和分化之间的平衡。 在伤口修复中，当再生速度减慢时，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缺口和对新的、未得到满足的迫切需求 促进组织再生和伤口修复的方法。此外，它可能会提供新的途径来遏制 炎症和转移性皮肤鳞癌(SCCs)。 丝氨酸是治疗干预的一个有吸引力的候选者，因为我们知道，SCC细胞会对 摄取丝氨酸以避免丝氨酸的生物合成和代谢物α-酮戊二酸(AKG)的产生。为了能够 为了在临床上解释这些发现，我们必须了解丝氨酸是如何影响正常的hfscs及其两种细胞的。 再生过程：1)HF再生，涉及血统规范；2)伤口愈合，其中 HfSCs使表皮重新上皮化，并经历了向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。给定 AKG在调节组蛋白修饰及其在外源丝氨酸限制下堆积的重要性， 我假设丝氨酸代谢控制着伤口愈合和头发中干细胞的命运。 通过依赖AKG的组蛋白去甲基酶(KDM)进行再生。 我的初步数据显示，饮食中的丝氨酸/甘氨酸显著加速了伤口的修复 限制，导致从头合成丝氨酸增加。我还观察到明显减少了 组蛋白标记H3K27me3，暗示AKG依赖的KDM激活。因此，在目标1中，我将首先测试 饮食中丝氨酸和甘氨酸的限制控制了HF的再生。在目标2中，我将测试丝氨酸对 甘氨酸对HF再生和伤口修复的限制是HFSC自主的。在目标3中，我将测试 限制饮食丝氨酸/甘氨酸改变组蛋白修饰和染色质可及性格局并剖析 它背后的潜在机制。我希望这些研究能提供第一个直接证据，证明丝氨酸 新陈代谢控制组织再生过程中的内源性干细胞，2)提供新的治疗方法以促进 伤口修复，以及3)使饮食或代谢干预在预防和治疗鳞状细胞癌的方式 不会损害正常的再生过程。