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

基本信息

批准号：
10416234
负责人：
CHENG-KUI QU
金额：
$ 50.86万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10416234
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 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 Time base cell regeneration cell type chemokine chemotherapy cytokine extracellular hematopoietic stem cell niche improved migration mitochondrial metabolism nestin protein osteoprogenitor cell oxidation perinatal development preconditioning precursor cell progenitor reconstruction response stem cell biology stem cell niche stem cells transplantation therapy

项目摘要

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.

项目概要造血干细胞 (HSC) 和祖细胞受到细胞内在机制和造血干细胞的严格调控。由专门的骨髓 (BM) 基质细胞创建的微环境（也称为生态位）。干细胞或祖细胞生态位如何开发、维持和重塑以应对压力尚不清楚缺乏这样的基础知识会阻碍我们理解某些血液学的能力。直接涉及疾病或间接涉及骨髓微环境，造血干细胞是产生所有疾病的前体细胞。血统，在胚胎发育过程中维持在离散的解剖微环境中，并且它们最终在围产期从胎儿肝脏迁移到BM（“归巢”）。我们之前证明了调节这一过程的机制仍然有限。 PTPMT1（一种基于线粒体的 Pten 样磷脂酰肌醇磷酸酶）在造血细胞中的表达发育 − 从造血系统中敲除 PTPMT1 导致造血功能衰竭使用 PTPMT1 敲除实现 HSC 的生物能量/代谢应激、细胞周期停滞和分化阻断。模型中，我们最近通过以下方法研究了协调细胞代谢在干细胞微环境中的作用生成并表征 PTPMT1fl/fl/Prx1-Cre+ 小鼠，其中 PTPMT1 从 BM 基质细胞中删除（以及肢芽祖细胞衍生的其他间充质细胞）。令人惊讶的是，PTPMT1 从 BM 基质中缺失。细胞导致严重的造血缺陷：近百分之八十的 PTPMT1fl/fl/Prx1-Cre+ 小鼠死亡。出生后 3 周内，HSC（野生型）从胎儿肝脏到 BM 的迁移/归巢受到损害。这些动物 – 与对照小鼠相比，基因敲除小鼠的 BM 中的 HSC 减少了约 5 倍 2 出生后几周，基因敲除小鼠肝脏中的造血灶 (CD45+) 增加了约 13 倍2)。 PTPMT1fl/fl/Prx1-Cre+ 小鼠的 B 细胞淋巴发育被阻断。观察结果使我们认为 PTPMT1 介导的代谢在建立或维持骨髓中的支持性干细胞生态位当前提案的目标是进一步确定。通过研究这种特殊的线粒体蛋白，我们的目标是了解潜在的细胞和分子机制。破译 HSC 生态位发育/维护/重塑的代谢调节我们计划测试我们的。假设通过追求以下三个目标1）。诱导的生物能量/代谢应激导致围产期发育期间 HSC 归巢缺陷 2)。确定 HSC 微环境细胞中 PTPMT1 介导的代谢与稳态和稳态的功能相关性成人应激造血3)。 HSC 上的生态位耗尽，以及 PTPMT1 缺陷重新编程细胞的机制代谢。