Pulmonary Vascular Regeneration via Venous Endothelial Progenitors

通过静脉内皮祖细胞进行肺血管再生

• 批准号: 10753505
• 负责人: Joanna Wong
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753505
• 关键词: 2019-nCoV; Ablation; Acute Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Alveolus; Area; Automobile Driving; Blood Vessels; Blood capillaries; Brain; Cell Proliferation; Cell Separation; Cell secretion; Chemotaxis; Clone Cells; Data; Development; Dichloromethylene Diphosphonate; Edema; Endothelial Cells; Endothelium; Epithelium; Exhibits; Frequencies; Future; Gases; Goals; Height; Human; Immune; Immune response; Impairment; Individual; Infiltration; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Intravenous; Label; Ligands; Liposomes; Liquid substance; Lung; Macrophage; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Organ; Organogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Physiological; Pneumonia; Population; Proliferating; Pulmonary Edema; Pulmonary veins; Regenerative response; Regulation; Reporter; Respiratory Tract Infections; Risk Factors; Role; Signal Transduction; Source; Specific qualifier value; Techniques; Testing; Time; Transplantation; Umbilical vein; Vascular Endothelial Cell; Vascular Endothelium; Vascular regeneration; Vascular remodeling; Veins; Venous; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Zebrafish; angiogenesis; apoAI regulatory protein-1; beta-Chemokines; cell type; chemokine; chemokine receptor; conditional knockout; endothelial regeneration; endothelial repair; endothelial stem cell; gamma-Chemokines; improved; in vivo; influenza infection; innovation; interstitial; lung injury; lung regeneration; monocyte; mortality; paracrine; preservation; prevent; progenitor; pulmonary function; reconstitution; recruit; repaired; response; restoration; single-cell RNA sequencing; stem cells; targeted treatment; tissue regeneration; tissue repair; transcription factor; venule

Project Summary Respiratory viral infections represent a major risk factor for the development of acute respiratory distress syndrome. Moreover, severe influenza injury can result in ineffective repair and persistent loss of pulmonary function. The lung endothelium, especially the microvasculature, is damaged due to the robust inflammatory response from viral infections, but the mechanisms of pulmonary endothelium regeneration after severe influenza injury are not completely elucidated despite the vasculature’s central importance in gas exchange. This proposal aims to answer fundamental questions about pulmonary vascular regeneration regarding the origin of vascular progenitor(s) and the mechanisms driving endothelial repair in response to influenza injury. We recently demonstrated that COUP-TFII, a vein-specifying transcription factor enriched in proliferating endothelial cells, is necessary for lung regeneration. The venous endothelium is increasingly recognized as a vascular progenitor population for endothelial regeneration in various organs in zebrafish and mice, suggesting that pulmonary veins / venules may similarly harbor potent progenitor cells. In my own preliminary data, I observed that venous endothelial cell clones are highly proliferative and can span into the microvasculature. Aim 1 of this proposal will utilize clonal lineage tracing and orthotopic transplantation techniques to determine if the venous endothelium harbors potent progenitor and proliferative potential during lung regeneration. The second focus of this proposal is to elucidate the mechanisms and interactions that are required for endothelial proliferation. Along with expression of venous markers, proliferating endothelial cells secrete C-C Motif Chemokine Ligand 2 (CCL2), a chemokine involved in mediating the inflammatory response during injury. The CCL2-CCR2 signaling axis promotes inflammatory angiogenesis in mice through recruitment of monocyte derived inflammatory macrophages, indicating a role for endothelial-specific release of CCL2 during tissue repair. Therefore, Aim 2 will employ conditional, temporal deletion of CCL2 in endothelial cells and clodronate-liposome mediated depletion of macrophages to investigate if loss of endothelial-derived CCL2 impacts endothelial proliferation and consequent angiogenic repair. This proposal will address the central hypothesis that a pulmonary endothelial progenitor population present in the preexisting venous endothelium secretes CCL2 to recruit interstitial monocytes to provide an angiogenic niche. Completion of this project will validate the venous endothelium as an important contributor to pulmonary regeneration and will also facilitate identification of specific paracrine / immune pathways that could allow for precise regulation and preservation of the beneficial immune response.

项目概要 呼吸道病毒感染是发生急性呼吸窘迫的主要危险因素 综合症。此外，严重的流感损伤会导致肺功能修复无效和持续丧失。 功能。肺内皮，特别是微血管系统，由于强烈的炎症而受损 病毒感染的反应，但严重后肺内皮再生的机制 尽管脉管系统在气体交换中至关重要，但流感损伤尚未完全阐明。这 该提案旨在回答有关肺血管再生起源的基本问题 血管祖细胞和响应流感损伤而驱动内皮修复的机制。我们最近 证明 COUP-TFII（一种富含增殖内皮细胞的静脉特异性转录因子） 肺再生所必需的。静脉内皮越来越被认为是血管祖细胞 斑马鱼和小鼠各器官内皮再生的群体，表明肺静脉 / 小静脉可能同样含有强大的祖细胞。在我自己的初步数据中，我观察到静脉 内皮细胞克隆具有高度增殖性，并且可以跨越微血管系统。该提案的目标 1 将 利用克隆谱系追踪和原位移植技术来确定静脉内皮是否 在肺再生过程中具有强大的祖细胞和增殖潜力。本提案的第二个重点 目的是阐明内皮增殖所需的机制和相互作用。连同 静脉标志物的表达，增殖的内皮细胞分泌 C-C 基序趋化因子配体 2 (CCL2)， 趋化因子参与介导损伤期间的炎症反应。 CCL2-CCR2 信号轴 通过募集单核细胞衍生的炎症促进小鼠炎症血管生成 巨噬细胞，表明在组织修复过程中内皮特异性释放 CCL2 的作用。因此，目标2 将采用内皮细胞中 CCL2 的条件性暂时缺失和氯膦酸盐脂质体介导的 耗竭巨噬细胞以研究内皮源性 CCL2 的缺失是否会影响内皮增殖和 随后的血管生成修复。该提案将解决肺内皮细胞的中心假设 先前存在的静脉内皮中存在的祖细胞群分泌 CCL2 来募集间质 单核细胞提供血管生成生态位。该项目的完成将验证静脉内皮作为 肺再生的重要贡献者，也将有助于识别特定的旁分泌/ 免疫途径可以精确调节和保存有益的免疫反应。