Contribution of macrophages in the HSC niche

巨噬细胞在 HSC 生态位中的贡献

基本信息

  • 批准号:
    10213515
  • 负责人:
  • 金额:
    $ 56.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY: Previous studies from our laboratory have suggested that CD169+ macrophages of the bone marrow (BM) contribute to the hematopoietic stem cell (HSC) niche activity by regulating CXCL12 synthesis in stromal cells and their retention in the BM. Preliminary results reveal two novel functions of macrophages in directly regulating the HSC function. First, we provide evidence that macrophages are critical for HSC regeneration after genotoxic challenge via the regulation of iron availability mediated by signals from the gut microbiota. Second, we have found that BM macrophages can transfer to HSCs/progenitors key retention signals that confer residence in BM. Indeed, HSCs that have received the transfer from macrophages are retained in the BM, whereas only those that have not are mobilized from the BM microenvironment following G-CSF administration. These results raise important new questions as to whether the various functions of macrophages in regulating HSCs, RBC production, or clearance are achieved by the same cells or whether the BM macrophages have specialized functions. In this proposal, we will explore the hypothesis that macrophage can directly contribute to niche activities by regulating HSCs’ ability to regenerate and to egress from the BM. In Specific Aim 1, we will investigate how macrophages interact with the microbiota to promote HSC regeneration. We will use genetic models to manipulate iron delivery pathways in HSCs and macrophages to dissect the mechanism by which iron is supplied to HSCs/progenitors during hematopoietic regeneration. We will also evaluate how BM macrophages can sense signals from the microbiota. In Specific Aim 2, we will investigate the mechanisms by which macrophages assign bone marrow residence. We will assess the role of connexins in the cell-cell communication using CRISPR/Cas9-mediated targeting and determine the role of trogocytosis as transfer mechanism. In Specific Aim 3, we will further define the bone marrow-resident macrophage population. We will evaluate the spatial relationship of these macrophages with vascular structures, HSCs and erythroblasts using immunofluorescence imaging. We will investigate the origin (embryonic or hematopoietic) of BM- resident macrophages using genetic tracing methods. These studies will shed light into the critical functions of an under-appreciated component of the HSC niche and uncover new therapeutic approaches for blood disorders.
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项目成果

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Ulrich Steidl其他文献

Ulrich Steidl的其他文献

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{{ truncateString('Ulrich Steidl', 18)}}的其他基金

Molecular and Cellular Regulation of Pre-Leukemic Stem Cells and their Therapeutic Targeting
白血病前期干细胞的分子和细胞调控及其治疗靶向
  • 批准号:
    10478927
  • 财政年份:
    2021
  • 资助金额:
    $ 56.04万
  • 项目类别:
Contribution of macrophages in the HSC niche
巨噬细胞在 HSC 生态位中的贡献
  • 批准号:
    10571821
  • 财政年份:
    2021
  • 资助金额:
    $ 56.04万
  • 项目类别:
Contribution of macrophages in the HSC niche
巨噬细胞在 HSC 生态位中的贡献
  • 批准号:
    10374928
  • 财政年份:
    2021
  • 资助金额:
    $ 56.04万
  • 项目类别:
Molecular and Cellular Regulation of Pre-Leukemic Stem Cells and their Therapeutic Targeting
白血病前期干细胞的分子和细胞调控及其治疗靶向
  • 批准号:
    10299704
  • 财政年份:
    2021
  • 资助金额:
    $ 56.04万
  • 项目类别:
STAT3 inhibition as a therapeutic strategy against MDS stem cells
STAT3 抑制作为针对 MDS 干细胞的治疗策略
  • 批准号:
    10443583
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
STAT3 inhibition as a therapeutic strategy against MDS stem cells
STAT3 抑制作为针对 MDS 干细胞的治疗策略
  • 批准号:
    10206262
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Therapeutic targeting of MDS stem cells
MDS 干细胞的治疗靶向
  • 批准号:
    10199003
  • 财政年份:
    2018
  • 资助金额:
    $ 56.04万
  • 项目类别:
Therapeutic targeting of MDS stem cells
MDS 干细胞的治疗靶向
  • 批准号:
    9982095
  • 财政年份:
    2018
  • 资助金额:
    $ 56.04万
  • 项目类别:
Therapeutic targeting of MDS stem cells
MDS 干细胞的治疗靶向
  • 批准号:
    9767250
  • 财政年份:
    2018
  • 资助金额:
    $ 56.04万
  • 项目类别:
Mechanisms of Formation and Progression of Preleukemic Stem Cells
白血病前期干细胞的形成和进展机制
  • 批准号:
    9890782
  • 财政年份:
    2017
  • 资助金额:
    $ 56.04万
  • 项目类别:
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