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

• 批准号: 10322180
• 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
• 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/10322180
• 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; Medical; Mesenchymal; Molecular; Morphology; Mus; Muscle; Pathogenesis; Pathogenicity; Pathologic; Patients; Pericytes; Pharmaceutical Preparations; Phenotype; Plasma; Play; Population; Production; 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

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 肺动脉高压(PAH)是一种以肺压力升高为特征的危及生命的疾病， 右心衰竭和过早死亡。目前的治疗方法由于无能为力而未能阻止疾病的进展 抑制和/或逆转PASMC驱动的远端肌化 微血管。这些高度增殖的PASMC的起源尚不完全清楚，但可能是 与连续周细胞(PC)群体的不适应行为密切相关。除了提供 对毛细血管的壁上支持，PC可以分化为其他类型的细胞以响应压力。我们最近报道了 人类PAH肺PC与PASMC具有相同的谱系标志和功能特性，如形态 和可伸缩性。因此，我们假设PAH血管病变中的PASMC起源于毛细血管PC。 慢性低氧小鼠PC的命运图谱显示，PC从毛细血管中解离并重新定位到 毛细血管前小动脉，在那里它们共同表达成熟的SMC的标志物，并有助于肌化。 通过单细胞和整体rna-seq分析，我们发现hif2a/sdf1信号通路是一条 PC分化为SMC的主要调节因子和PAH中PC功能障碍的主要调节剂。我们 建议：1)证明HIF2A/SDF1激活导致PC从肺毛细血管解离；2) 明确HIF2A/SDF1信号通路促使PC分化为PASMC样蛋白的分子机制 人和小鼠，以及3)在PC中操作HIF2A/SDF1是否可以改变血管的严重程度 高血压动物模型的重塑。该项目将为周细胞病理生物学提供新的见解，并建立 HIF2A/SDF1作为治疗PAH的潜在靶点，其第一批逆转肌化和 可能会发现改善PAH的结果。