Metabolic regulation of stem cell niche development and function

干细胞生态位发育和功能的代谢调节

• 批准号: 10581643
• 负责人: CHENG-KUI QU
• 金额: $ 50.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581643
• 关键词: Address; Adipocytes; Adult; Anatomy; Animals; B-Lymphocytes; Bioenergetics; Birth; Blood; Blood Cells; Bone Marrow; Bone Marrow Involvement; Cell Cycle Arrest; Cell Lineage; Cell surface; Cells; Cellular Metabolic Process; Chemotactic Factors; Data; Defect; Development; Embryonic Development; Failure; Fatty Acids; Fermentation; Fetal Liver; Glucose; Glycolysis; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homing; Human; Impairment; Investigation; Knock-out; Knockout Mice; Knowledge; Limb Bud; Liver; Lymphoid; Maintenance; Marrow; Mediating; Mesenchymal; Metabolic; Metabolic stress; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; Myelogenous; NIH Program Announcements; Osteoblasts; Oxidative Phosphorylation; PTPRC gene; Peptides; Perinatal; Phosphatidylinositol Phosphates; Phosphoric Monoester Hydrolases; Play; Population; Process; Proteins; Pyruvate; Regimen; Regulation; Research; Role; Signaling Molecule; Stem cell transplant; Stress; Stromal Cells; Supporting Cell; Testing; cell regeneration; cell type; chemokine; chemotherapy; cytokine; extracellular; hematopoietic stem cell niche; improved; information gathering; migration; mitochondrial metabolism; nestin protein; osteoprogenitor cell; oxidation; perinatal development; preconditioning; precursor cell; progenitor; programs; reconstruction; response; stem cell biology; stem cell niche; stem cells; transplantation therapy

Project Summary Hematopoietic stem cells (HSCs) and progenitors are tightly regulated by both cell intrinsic mechanisms and the microenvironment (also known as niches) created by specialized bone marrow (BM) stromal cells. However, how stem cell or progenitor niches are developed, maintained, and remodeled in response to stress is poorly characterized. Lack of such fundamental knowledge hinders our ability to understand certain hematological diseases directly or indirectly involving the BM microenvironment. HSCs, the precursor cells that give rise to all blood lineages, are maintained in discrete anatomical microenvironments during embryonic development, and they ultimately migrate from the fetal liver to the BM (“homing”) at the perinatal stage. Yet our understanding of the mechanisms regulating this process remains limited. We previously demonstrated a crucial cell-intrinsic role of PTPMT1, a mitochondria-based Pten-like phosphatidylinositol phosphate phosphatase, in hematopoietic cell development − Knockout of PTPMT1 from the hematopoietic system resulted in hematopoietic failure due to the bioenergetic/metabolic stress, cell cycle arrest, and differentiation block of HSCs. Using the PTPMT1 knockout model, we recently examined the role of coordinated cellular metabolism in the stem cell microenvironment by generating and characterizing PTPMT1fl/fl/Prx1-Cre+ mice, in which PTPMT1 was deleted from BM stromal cells (and limb bud progenitor-derived other mesenchymal cells). Surprisingly, deletion of PTPMT1 from BM stromal cells resulted in profound hematopoietic defects: 1). Nearly eighty percent of PTPMT1fl/fl/Prx1-Cre+ mice died within 3 weeks of birth. The migration/homing of HSCs (wild-type) from the fetal liver to the BM was impaired in these animals – HSCs in the BM of knockout mice decreased by ~5-fold compared to those in control mice 2 weeks after birth, while there were ~13 times more hematopoietic foci (CD45+) in the liver of knockout mice. 2). B lymphocyte development was blocked in the pro-B stage in PTPMT1fl/fl/Prx1-Cre+ mice. These striking observations led us to hypothesize that PTPMT1-mediated metabolism plays an important role in establishing or maintaining supportive stem cell niches in the BM. The objective of the current proposal is to further determine the underlying cellular and molecular mechanisms. By studying this particular mitochondrial protein, we aim to decipher the metabolic regulation of HSC niche development/maintenance/remodeling. We plan to test our hypothesis by pursuing the following three aims. 1). To identify the niche cells in which PTPMT1 depletion- induced bioenergetic/metabolic stress causes HSC homing defects during perinatal development. 2). To determine the functional relevance of PTPMT1-mediated metabolism in HSC niche cells to steady-state and stress hematopoiesis in adults. 3). To identify the bioactive molecules that account for the effects of PTPMT1- depletion from the niche on HSCs, and the mechanisms by which PTPMT1 deficiency reprograms cellular metabolism.

项目摘要 造血干细胞（HSC）和祖细胞受细胞内在机制和 由专门的骨髓（BM）基质细胞产生的微环境（也称为壁ni）。然而， 干细胞或祖细胞的开发，维持和响应压力的去除方式很差 特征。缺乏这种基本知识阻碍了我们理解某些血液学的能力 疾病直接或间接涉及BM微环境。 HSC，产生所有的前体细胞 血统在胚胎发育过程中保持在离散的解剖微环境中，并保持 他们最终在围产期阶段从胎儿肝脏迁移到BM（“归”）。但是我们对 调查此过程的机制仍然有限。我们以前证明了至关重要的细胞中性作用 PTPMT1（一种基于线粒体的PTEN样磷脂酰肌醇磷酸磷酸酶）在造血细胞中的 造血系统中PTPMT1的开发 - 导致造血衰竭 生物能量/代谢应激，细胞周期停滞和HSC的分化块。使用PTPMT1淘汰赛 模型，我们最近研究了协调的细胞代谢在干细胞微环境中的作用 生成和表征PTPMT1FL/FL/PRX1-CRE+小鼠，其中PTPMT1从BM基质细胞中删除 （和肢体芽祖细胞衍生的其他间充质细胞）。令人惊讶的是，从BM Stromal中删除PTPMT1 细胞导致深远的造血缺陷：1）。 PTPMT1FL/FL/PRX1-CRE+小鼠的近80％死亡 出生后的3周内。 HSC（野生型）从胎儿肝脏的迁移/归巢在BM中受到损害 这些动物 - 敲除小鼠BM中的HSC降低了约5倍，与对照小鼠2相比 出生后几周，敲除小鼠的肝脏中造血灶（CD45+）的含量增加了约13倍。 2）。 B淋巴细胞发育在PTPMT1FL/FL/PRX1-CRE+小鼠的pro-B阶段被阻塞。这些惊人的 观察结果使我们假设PTPMT1介导的新陈代谢在建立或 维持BM中的支持性干细胞壁ni。当前建议的目的是进一步确定 潜在的细胞和分子机制。通过研究这种特殊的线粒体蛋白，我们的目标是 破译HSC利基生态发展/维护/重塑的代谢调节。我们计划测试我们的 通过追求以下三个目标来假设。 1）。确定ptpmt1部署的利基细胞 - 诱导的生物能量/代谢应激会导致围产期发育过程中HSC归巢缺陷。 2）。到 确定ptpmt1介导的HSC细胞中PTPMT1介导的代谢与稳态和 成人压力造血。 3）。识别解释PTPMT1-影响的生物活性分子 利基在HSC上的耗竭以及PTPMT1缺乏重新编程的机制 代谢。