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Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature

不同巨噬细胞在发育中的肺血管系统中的多种稳态作用

基本信息

批准号：
10583456
负责人：
Cristina Maria Alvira
金额：
$ 62.08万
依托单位：
STANFORD UNIVERSITY
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：
2021-03-05 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583456
关键词：
Acute Adult Air Sacs Alveolar Alveolar Macrophages Alveolus Anastomosis - action Area Basement membrane Birth Blood Vessels Bronchopulmonary Dysplasia Cell Communication Cells Chronic Complex Complication Coronary artery Cues Data Data Set Development Disease Distal Embryo Endothelial Cells Epithelial Cells Exhibits Gases Gene Expression Genes Genetic Transcription Growth Heart Heterogeneity Hyperoxia Image Immune Immunity Impairment In Situ In Situ Hybridization In Vitro Infant Injury Knockout Mice Life Ligands Location Lung Lung diseases Macrophage Mediating Molecular Myofibroblast Natural Immunity Natural regeneration Neuropeptides Organ Pathway interactions Pattern Phenotype Physiological Play Population Premature Birth Process Pulmonary Circulation Recovery Resolution Retina Role Serine Proteinase Inhibitors Signal Pathway Signal Transduction Smooth Muscle Myocytes Spatial Distribution Stromal Cell-Derived Factor 1 Surface Testing Tissues Transgenic Organisms Translating Vascular Permeabilities Vascular Smooth Muscle Vascular remodeling Vascularization angiogenesis arteriole blood vessel development chemokine conditional knockout genetic signature hindbrain in vivo lung development mouse model novel strategies postnatal postnatal development pulmonary function rapid growth receptor recruit repaired single-cell RNA sequencing therapeutic development transcriptomics

项目摘要

Alveolarization, the final stage of lung development occurring primarily postnatally, markedly increases gas exchange surface area. Rapid growth of the pulmonary vasculature by angiogenesis during early alveolarization drives distal lung growth, and disrupted angiogenesis impairs alveolarization. In other organs, specialized macrophages support angiogenesis by promoting blood vessel formation, providing survival and migratory cues to EC, and facilitating vascular anastomoses. However, the role of macrophages in the developing pulmonary vasculature remains entirely unknown. We recently embarked on a project employing single cell RNA-sequencing to define macrophage diversity during late embryonic and early postnatal lung development. Macrophages are extremely heterogenous with diverse phenotypes that are lineage- and tissue- specific, and highly influenced by the microenvironment. Preliminary data in this proposal demonstrate a tremendous increase in macrophage diversity after birth. Specialized, highly proliferative macrophages present before birth are replaced after birth by a complex and dynamic mixture of diverse macrophage subtypes exhibiting unique gene signatures, developmental gradients in gene expression, and specific locations within the lung suggesting distinct functions in tissue remodeling, angiogenesis, and immunity. Interestingly, a subset of embryonic macrophages was found to completely encircle small arterioles and express numerous genes that regulate lung branching, angiogenesis, and EC phenotype. After birth, these cells transitioned to an intermediate subset present only during the first few weeks of postnatal life that expressed additional tissue remodeling genes. Taken together, our data suggest the hypothesis that distinct macrophage populations support alveolarization by regulating pulmonary vascular development through the expression of factors that influence vascular growth and remodeling, which will be tested through three specific aims. Aim 1 will combine multiplexed in situ hybridization, lineage tracing, studies in primary EC and macrophages, and advanced imaging in transgenic and knock-out mice to define the role of specific macrophage subsets in modulating EC phenotype and regulating lung parenchymal and vascular growth. Aim 2 will utilize multiplexed in situ hybridization, conditional knock out mouse models, and ligand-receptor profiling of single cell datasets from pulmonary EC and macrophages to probe pathways mediating macrophage-EC communication. Finally, Aim 3 will determine if chronic hyperoxia alters diversity and phenotype of the lung macrophages during acute injury and after recovery, and specifically impairs developmental and homeostatic functions of lung macrophages. The successful completion of these studies will provide a multifaceted view of the diverse functions of lung macrophages during embryonic and early postnatal development at single cell resolution, and identify new pathways that could be directly translated into novel strategies to modulate vascular growth and regeneration in diseases marked by impaired pulmonary angiogenesis.

肺泡化，肺发育的最后阶段，主要发生在出生后，显著增加