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The Role of Erythroblastic Islands in Anemia of Inflammation

成红细胞岛在炎症性贫血中的作用

基本信息

批准号：
10596568
负责人：
Lionel Blanc
金额：
$ 61.99万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10596568
关键词：
Acute Adhesives Adult Affect Anemia Anemia due to Chronic Disorder Animal Model Autoimmune Diseases Biological Assay Bone Marrow Cell Nucleus Cells Cellular Structures Characteristics Chronic Communicable Diseases Complication Coupled DNA Data Defect Discipline of Nursing Disease Dysmyelopoietic Syndromes Erythroblasts Erythrocytes Erythroid Erythropoiesis Fetal Liver Fetal Spleen Flow Cytometry Fostering Genes Genetic Goals Granulopoiesis Growth Factor Hematology Hematopoiesis Hematopoietic Hemoglobin Heterogeneity Homeostasis Human ITGAM gene In Situ In Vitro Inflammation Inflammatory Iron Island Knockout Mice Knowledge Label Macrophage Malignant - descriptor Mammals Mediator Methods Microscopy Modeling Morbidity - disease rate Mus P-Selectin Pathologic Patients Persons Phenotype Population Population Heterogeneity Process Production Proliferating Quality of life Recovery Reporting Role Sedimentation process Stress Structure Surface TFRC gene Testing Thalassemia Therapeutic Intervention Toxic effect density differential expression follow-up granulocyte hematopoietic tissue immune activation improved in vivo insight mortality mouse model neutrophil new therapeutic target novel pharmacologic physiologic model prevent reconstitution single-cell RNA sequencing spectrograph

项目摘要

Project Summary/Abstract Terminal erythropoiesis in mammals occurs within the erythroblastic islands (EBIs), niches where erythroblasts differentiate in close interaction with a central (nursing) macrophage. Although EBIs were described in 1958 by Marcel Bessis as the first hematopoietic niche, there are still many questions to be answered to improve our understanding of their structure and function. Anemia of inflammation (AoI) occurs in patients with chronic or acute immune activation (due to an infectious, malignant, or autoimmune disease) and affects the quality of life of millions of people worldwide. The overall goal of this application is to understand the structure and function of the EBI as the erythropoietic niche in normal, baseline erythropoiesis and how this is modified in conditions leading to anemia of inflammation. Our preliminary data show that F4/80, VCAM1, and CD169 are expressed heterogeneously by the central macrophages within the EBIs. In marked contrast, CD11b is low or negative on the EBI macrophage, while it is abundantly present on other cells within the islands. The CD11b+ cells within EBIs are granulocyte precursors in contact to the central macrophage (Mφ). Moreover, EBIs in the bone marrow of mice with AoI have increased number of CD11b+ cells and their central macrophages, evaluated after isolation of EBIs with gradient density sedimentation, have increased expression of P-selectin, an adhesive molecule that attracts neutrophils. We hypothesize that the central EBI Mφ provides a niche for both erythropoiesis and granulopoiesis at homeostatic (baseline) hematopoiesis through intercellular interactions, while it preferentially supports erythropoiesis in stress erythropoiesis conditions. In contrast, under conditions of inflammation, changes of the central EBI Mφs like increased P-selectin expression, favor granulopoiesis versus erythropoiesis, leading to AoI. Here, we propose to (1) define the spectrum of the central EBI macrophage identity in mouse and human BM at baseline conditions, and in mouse fetal liver and spleen as models of physiological and pathological stress erythropoiesis, (2) determine structural and functional interactions of the EBI Mφs with the granulocyte precursors co-existing within EBIs at baseline conditions, and (3) evaluate the mechanisms by which the EBI Mφs and granulocyte precursors in AoI suppress erythropoiesis and test if P-selectin blockage improves AoI in animal models. These studies will expand our knowledge on the fundamental questions regarding the identity of EBI Mφs and their role in hematopoiesis and illuminate novel therapeutic targets and strategies to manage patients with AoI, a common complication increasing morbidity in millions of patients with malignant, infectious, or autoimmune diseases, worldwide.

项目总结/文摘