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: 10523521
• 负责人: Jesse Stephen Swyer Novak
• 金额: $ 5.27万
• 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/10523521
• 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; Epithelium; Equilibrium; Genetic; Genetic Transcription; Genus Mentha; Glycine; Goals; Hair; Hair Removal; Hair follicle structure; Histones; Immune; Immunofluorescence Microscopy; Inflammation; Inflammatory; Intervention; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methyltransferase; Monitor; Morbidity - disease rate; Mus; Natural regeneration; Phase; Phenocopy; Phenotype; Prevention; Process; Production; Proliferating; Role; Serine; Signal Pathway; Skin; Specific qualifier value; Squamous cell carcinoma; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Translating; Work; alpha ketoglutarate; 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; ATAC-seq; Ablation; Acceleration; Affect; Anabolism; Apoptosis; Cell Lineage; Cells; ChIP-seq; Chromatin; Clinical; Data; Diet; Disease; EZH2 gene; Environment; Enzymes; Epidermis; Epithelium; Equilibrium; Genetic; Genetic Transcription; Genus Mentha; Glycine; Goals; Hair; Hair Removal; Hair follicle structure; Histones; Immune; Immunofluorescence Microscopy; Inflammation; Inflammatory; Intervention; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methyltransferase; Monitor; Morbidity - disease rate; Mus; Natural regeneration; Phase; Phenocopy; Phenotype; Prevention; Process; Production; Proliferating; Role; Serine; Signal Pathway; Skin; Specific qualifier value; Squamous cell carcinoma; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Translating; Work; alpha ketoglutarate; 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 表皮的组织干细胞干细胞可保护我们免受外部侮辱，长发和修复伤口的伤害。 表皮干细胞（IFE-SCS）和毛囊干细胞（HFSC）的广泛表征已发现 它们的转录和信号通路如何调节再生。关于干细胞的了解少得多 结合了代谢输入，这可以深刻影响增殖与分化之间的平衡。 当伤口修复减慢后再生时，它可能有害并导致过度增强状态 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关键的知识差距，并且对新的需求未满足和迫切需求 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来遏制 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细胞会上瘾 丝氨酸摄取以避免丝氨酸生物合成和代谢物A-酮戊二酸（AKG）的产生。能够 要在临床上翻译这些发现，我们必须了解丝氨酸如何影响正常的HFSC及其两个 再生过程：1）HF再生，涉及谱系规范，2）伤口愈合，其中 HFSC重新上皮化表皮，并将命运开关转换为IFE-SC谱系。这两个过程需要 不同的干细胞命运决策，表现出对组蛋白修饰的不同反应。鉴于 AKG在调节组蛋白修饰中的重要性及其对丝氨酸外源限制的积累， 我假设丝氨酸代谢控制了伤口愈合和头发中的干细胞命运决定 通过AKG依赖性组蛋白脱甲基酶（KDMS）再生。 我的初步数据表明，饮食丝氨酸/甘氨酸时的伤口修复中有惊人的加速度 限制，从而导致从头丝氨酸生物合成增加。我还观察到了明显的减少 组蛋白标记H3K27me3，暗示了依赖AKG的KDM的激活。因此，在AIM 1中，我将首先测试是否 饮食丝氨酸和甘氨酸限制控制HF再生。在AIM 2中，我将测试丝氨酸的影响 甘氨酸对HF再生和伤口修复的限制是HFSC自主的。在AIM 3中，我将测试是否 饮食中的饮食饮食限制改变了组蛋白的修饰和染色质可及性景观，并剖析 其背后的基本机制。我希望这些研究对1）提供了第一个直接证据，表明丝网是否是否 代谢控制组织再生期间内源性干细胞，2）告知新疗法以促进 伤口修复，3）以预防和治疗SCC的饮食或代谢干预措施 不会损害正常的再生过程。