权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结