Inflammatory modulation of CXCL12 expressing niche cells in bone marrow

骨髓中表达 CXCL12 的微环境细胞的炎症调节

基本信息

批准号：
9072497
负责人：
Leslie Eric Silberstein
金额：
$ 53.24万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9072497
关键词：
3-Dimensional Actins Acute Adjuvant Affect Apoptosis Area Blood Cells Blood Circulation Bone Marrow Bone Marrow Transplantation CXCL12 gene Cell Count Cell Cycle Cells Cellularity Cytoplasmic Structures Data Defect Disease Dose Effector Cell Experimental Designs Extracellular Matrix Filament Functional disorder Grant Growth Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Homeostasis Hour Image Imaging Techniques Immune Infection Inflammation Inflammatory Injection of therapeutic agent Laser Scanning Cytometry Lead Ligands Link Lipopolysaccharides Measures Mediating Mesenchymal Microscopy Molecular Morphology Mus Natural regeneration Pancytopenia Patients Population Radiation therapy Role Signal Transduction Sorting - Cell Movement Staining method Stains Stem cells Stress Stromal Cells Surface TLR4 gene TNF gene TNFRSF1A gene TNFRSF1B gene Testing Thick Three-dimensional analysis Tissues Toll-like receptors Transfusion Transplantation Tubulin Tumor Necrosis Factor Receptor Vascular blood supply Yeasts blood product bone marrow failure syndrome chemotherapy cohort cytokine expectation in vivo inflammatory modulation intravital microscopy macrophage novel novel strategies novel therapeutic intervention receptor reconstitution research study stem time interval trafficking transcriptional coactivator p75

项目摘要

PROJECT SUMMARY Acute inflammatory signals associated with infection lead to HSC proliferation thus generating large numbers of immune effector cells. However, more severe and prolonged inflammation has been linked to bone marrow failure states, e.g. complications following bone marrow transplantation. Infectious as well as non-infectious inflammatory signals affect HSC homeostasis. Such effects can be mediated directly on HSC or indirectly via niche cells. CXCL12-expressing niche cells represent an important niche cell population forming distinct niches that support hematopoietic stem and/or progenitor cells. Utilizing complementary novel imaging approaches for 2D and 3D analysis of the bone marrow cavity, we show that inflammatory stress following administration of TNF-α and/or lipopolysaccharide (LPS) rapidly reduces the number of CXCL12 expressing niche cells and causes defects in niche cell cytoplasmic structure within 1-4 hours. We propose that understanding how inflammatory signals modulate HSCP niche cells may implicate a pathogenic role of niche cells in disorders of dysfunctional hematopoiesis associated with inflammation in the peri-transplant setting. In Aim 1 we will delineate the consequences of inflammation on CXCL12-niche cell number and/or growth factor expression in specific CXCL12 expressing niche cell populations. The analyses will be done at various time intervals following administration of TNF-α, LPS. In aim 2, the dynamic alterations in CXCL12 expressing niche cell cytoplasmic structure will be visualized and quantified at different time intervals by three complementary imaging techniques. The dynamic structural changes will be correlated with hematopoietic cellularity in BM and egress into the circulation. In aim 3, we will examine whether LPS and TNF-α mediate their effect on hematopoiesis directly or indirectly (e.g. by acting first on hematopoietic cells such as macrophages). To this end, 4 separate reconstituted chimeric mice in which the hematopoietic compartment/bone marrow microenvironment is either WT or deficient in TNFR/TLR4, will be generated. We propose that understanding the dynamic relationship between stromal cells and HSPC following inflammatory stress may lead to new therapeutic approaches for hematopoietic regeneration in bone marrow dysfunction states in the peri- transplant setting, which require significant blood product support.

项目概要与感染相关的急性炎症信号导致 HSC 增殖，从而产生大量然而，更严重和更持久的炎症与骨髓有关。失败状态，例如骨髓移植后的并发症。炎症信号影响 HSC 稳态，这种作用可以直接介导到 HSC 上，也可以通过间接介导。表达 CXCL12 的生态位细胞代表形成独特生态位的重要生态位细胞群。利用互补的新型成像方法支持造血干细胞和/或祖细胞。骨髓腔的 2D 和 3D 分析表明，给药后的炎症应激 TNF-α 和/或脂多糖 (LPS) 迅速减少表达 CXCL12 的微环境细胞的数量，我们建议了解如何在 1-4 小时内导致生态位细胞的细胞质结构缺陷。炎症信号调节 HSCP 微环境细胞可能暗示微环境细胞在疾病中的致病作用在目标 1 中，我们将讨论与移植周围炎症相关的造血功能障碍。描述炎症对 CXCL12 生态位细胞数量和/或生长因子表达的影响特定的 CXCL12 表达生态位细胞群将在不同的时间间隔进行。施用 TNF-α、LPS 后目标 2，表达 CXCL12 的微环境细胞的动态变化。细胞质结构将通过三个互补的在不同时间间隔进行可视化和量化动态结构变化将与 BM 和造血细胞构成相关。在目标 3 中，我们将检查 LPS 和 TNF-α 是否介导其对血液循环的影响。直接或间接造血（例如通过首先作用于造血细胞，例如巨噬细胞）。最后，4只独立的重组嵌合小鼠，其中造血室/骨髓微环境是 WT 或 TNFR/TLR4 缺陷，我们建议理解。炎症应激后基质细胞和 HSPC 之间的动态关系可能会导致新的围周期骨髓功能障碍状态下造血再生的治疗方法移植环境，需要大量的血液制品支持。