The Metabolic Regulation of Hematopoietic Stem Cell Function

造血干细胞功能的代谢调节

• 批准号: 10343751
• 负责人: SEAN J MORRISON
• 金额: $ 36.45万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343751
• 关键词: Address; Affect; Alleles; American; Aplastic Anemia; Ascorbic Acid; Bone Marrow; Cancer Patient; Cardiovascular Diseases; Cells; Cellular Metabolic Process; Clonal Expansion; Clonal Hematopoietic Stem Cell; Cytosine; DNA; DNMT3a; DNMT3a mutation; Data; Development; Diet; Elderly; Frequencies; Genes; Health; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Maps; Mediating; Metabolic; Metabolism; Methods; Molecular; Mus; Myelopoiesis; Natural regeneration; Outcome; Oxidases; Patients; Phenocopy; Physiological; Plasma; Population; Public Health; RNA; Regulation; Solid; Stress; Testing; Time; Variant; ascorbate; dietary; epigenome; gulonolactone; hematopoietic stem cell self-renewal; hematopoietic transplantation; in vivo; leukemia; leukemogenesis; loss of function mutation; metabolic abnormality assessment; metabolomics; response; stem cell function; stem cells; tissue regeneration; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT A fundamental question is whether physiological variations in metabolite levels in vivo influence stem cell function or tissue regeneration. Our understanding of somatic stem cell metabolism remains limited due to the technical challenges associated with studying metabolism in rare cells in vivo. To address this issue we optimized the sensitivity of metabolomics methods to enable the analysis of rare cell populations. We used this approach to compare metabolite levels between hematopoietic stem cells (HSCs) and a wide range of restricted hematopoietic progenitors isolated from mouse bone marrow. We found that each hematopoietic stem and progenitor cell population has a distinct metabolic signature. Human and mouse HSCs are distinguished from most other hematopoietic cells by unusually high levels of ascorbate (vitamin C). Ascorbate depletion in mice, to a level observed in 5% of Americans, increases HSC frequency and function, partly by reducing the activity of Tet2, a cytosine demethylase that suppresses leukemia development. Ascorbate depletion, like Tet2 deletion, cooperates with Flt3ITD to promote myelopoiesis and leukemogenesis. Ascorbate acts cell-autonomously to negatively regulate HSC function and myelopoiesis mainly through Tet2-dependent mechanisms. These observations are likely relevant to public health as plasma ascorbate levels vary widely among Americans, largely due to dietary differences. At any one time, 13% of Americans are considered ascorbate deficient. In Aim 1, we propose to test whether ascorbate levels influence steady-state hematopoiesis or regeneration after hematopoietic stresses. In Aim 2, we propose to test whether ascorbate depletion promotes clonal hematopoiesis under steady state conditions or in response to hematopoietic stresses. Clonal hematopoiesis of indeterminate potential has recently been shown to be common in healthy older people as well as in patients with aplastic anemia, solid cancers, and patients who have received hematopoietic transplants. The presence of clonal hematopoiesis is associated with adverse health outcomes including cardiovascular disease. Clonal hematopoiesis is usually caused by the loss of one allele of Tet2 or by loss-of-function mutations in Dnmt3a. We hypothesize that ascorbate depletion can promote the development and progression of clonal hematopoiesis by reducing Tet2 function. In Aim 3 we will assess the molecular mechanisms by which ascorbate depletion and Tet2 deficiency regulate HSC function and myelopoiesis. We expect these studies to expand our understanding of how metabolism regulates the HSC epigenome, HSC function, normal hematopoiesis, and clonal hematopoiesis.

项目摘要/摘要 一个基本问题是体内代谢物水平的生理变化是否影响干细胞功能 或组织再生。由于技术 与研究体内稀有细胞中的代谢相关的挑战。为了解决这个问题，我们优化了 代谢组学方法的敏感性使得能够分析稀有细胞群体。我们使用了这种方法 比较造血干细胞（HSC）和广泛限制的代谢物水平 从小鼠骨髓分离出来的造血祖细胞。我们发现每个造血茎和 祖细胞群具有独特的代谢特征。人类和鼠标HSC与 大多数其他造血细胞通过异常高的抗坏血酸（维生素C）。小鼠的抗坏血酸耗尽， 在5％的美国人中观察到的水平增加了HSC的频率和功能，部分是通过降低的活性 TET2，一种抑制白血病发育的胞嘧啶脱甲基酶。抗坏血酸的耗竭，例如TET2删除， 与FLT3ITD合作以促进骨髓病和白血病。抗坏血酸人对细胞自动起作用 负面调节HSC功能和脊髓脉的作用主要通过TET2依赖性机制。这些 观察结果可能与公共卫生有关，因为美国人之间的血浆抗坏血酸水平差异很大， 很大程度上是由于饮食差异。在任何时候，有13％的美国人被认为是抗坏血酸的。目标 1，我们建议测试抗坏血酸水平是否影响稳态造血或再生 造血应激。在AIM 2中，我们提议测试抗坏血酸是否促进克隆 在稳态条件下或对造血应激的反应下造血。克隆造血 最近已显示不确定的潜力在健康的老年人和患者中很常见 具有性贫血，固体癌和接受造血移植的患者。存在 克隆造血与包括心血管疾病在内的不良健康结果有关。克隆 造血通常是由一个TET2等位基因丢失或DNMT3A中功能丧失突变引起的。我们 假设抗坏血酸可以通过 降低TET2功能。在AIM 3中，我们将评估抗坏血酸消耗和的分子机制 TET2缺乏调节HSC功能和骨髓病。我们希望这些研究能够扩大我们的理解 如何调节HSC表观基因组，HSC功能，正常造血和克隆 造血。