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Pericytes differentiate into smooth muscle cells through HIF2a/SDF1 activation

周细胞通过 HIF2a/SDF1 激活分化为平滑肌细胞

基本信息

批准号：
10549842
负责人：
Ke Yuan
金额：
$ 44.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549842
关键词：
AMD3100 Animal Model Bioinformatics Biology Blood Vessels Blood capillaries CSPG4 gene CXCR4 Receptors CXCR4 gene Cell Culture Techniques Cell Differentiation process Cell Hypoxia Cell Lineage Cell Proliferation Cells Cellular Assay Cessation of life Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Disease Disease Progression Dissociation Distal Endothelium Exhibits Functional disorder Genes Genetic Transcription Homeostasis Human Hypoxia Impairment Knock-out Label Lead Lesion Life Lung Lung Transplantation Maps Medical Mesenchymal Molecular Morphology Mus Muscle Pathogenesis Pathogenicity Pathologic Patients Pericytes Pharmaceutical Preparations Phenotype Plasma Play Population Production Proliferating Property Pulmonary vessels Reporting Role Severities Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Source Stains Stress Stromal Cell-Derived Factor 1 Testing Time Tissues Transgenic Mice Vascular remodeling Vasodilation antagonist arteriole cell type clinically relevant directed differentiation improved outcome insight lung pressure maladaptive behavior mouse model novel novel therapeutic intervention overexpression premature prevent progenitor pulmonary arterial hypertension pulmonary vascular remodeling response right ventricular failure single-cell RNA sequencing stem cell differentiation therapeutic target transcriptome sequencing transdifferentiation

项目摘要

ABSTRACT Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated lung pressures, right heart failure, and premature death. Current therapies fail to prevent disease progression due to their inability to suppress and/or reverse pulmonary arterial smooth muscle cells (PASMCs) driven muscularization of distal microvessels. The origin of these highly proliferative PASMCs remains incompletely understood, but may be closely related to the maladaptive behavior of contiguous pericyte (PC) populations. In addition to providing mural support to capillaries, PCs can differentiate into other cell types in response to stress. We recently reported that human PAH lung PCs share lineage markers and functional properties with PASMCs, such as morphology and contractility. We thus hypothesize that PASMCs in PAH vascular lesions originate from capillary PCs. Fate-mapping of PCs in chronic hypoxia mice revealed that PCs dissociate from capillaries and relocate to precapillary arterioles, where they co-express markers of mature SMCs and contribute to muscularization. Through single cell and bulk RNA-seq analysis, we discovered that the HIF2A/SDF1 signaling pathway is a master regulator of differentiation of PCs into SMC and a major modifier of PC dysfunction in PAH. We propose to: 1) demonstrate that HIF2a/SDF1 activation causes PC dissociation from pulmonary capillaries, 2) define the molecular mechanism by which HIF2a/SDF1 signaling drives PC differentiation into PASMC-like in human and mice, and 3) determine whether manipulation of HIF2a/SDF1 in PCs can alter the severity of vascular remodeling in animal models of PH. This project will provide novel insight into pericyte pathobiology and establish HIF2a/SDF1 as a potential therapeutic target in PAH, for which the first drugs to reverse muscularization and improve outcomes in PAH may be found.

摘要