Novel vascular smooth muscle cell progenitors in development and disease

发育和疾病中的新型血管平滑肌细胞祖细胞

• 批准号: 9893632
• 负责人: Daniel Greif
• 金额: $ 100.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9893632
• 关键词: Aorta; Arteries; Atherosclerosis; Blood Vessels; Bone Marrow; Cells; Clonal Expansion; Development; Disease; Distal; Endothelial Cells; GKLF protein; Gene Expression; Human; Hypoxia; Investigation; Ligands; Location; Lung; Maintenance; Mesenchyme; Molecular Profiling; Morphogenesis; Mus; Muscle; Myeloid Cells; Pathogenesis; Pathologic; Pathology; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Play; Process; Pulmonary Hypertension; Regulation; Research; Role; Seminal; Smooth Muscle; Smooth Muscle Myocytes; Therapeutic; Tunica Media; Undifferentiated; Vascular Diseases; Vascular Smooth Muscle; Work; arteriole; base; cell type; combat; human tissue; insight; macrophage; mouse model; novel; novel therapeutics; pluripotency; progenitor; programs; recruit; stem cells

Excessive and ectopic smooth muscle cells (SMCs) and smooth muscle-derived cells accumulate in diverse vascular diseases but underlying mechanisms are poorly understood. Seminal work from our lab as well as other labs indicate that SMC progenitors play a vital role in this process. In paradigm-shifting studies, we recently identified pools of SMC progenitors in the lung that we reasoned were primed to muscularize distal arterioles based on their location at the muscular- unmuscular border of each pulmonary arteriole and their molecular signature of expressing SMC markers and the undifferentiated mesenchyme marker platelet-derived growth factor receptor (PDGFR)-β. Upon exposing mice to hypoxia, expression of the ligand PDGF-B by lung endothelial cells and macrophages induces these "primed" cells to express the pluripotency factor Kruppel-like factor 4 (KLF4) and in each arteriole, one of them migrates distally and clonally expands. This pathological muscularization results in pulmonary hypertension. Similarly, in atherosclerosis of systemic arteries, our recent results indicate that a single or rare SMC marker+ cells gives rise to most of the cells in an advanced plaque, and the vast majority of these cells have been shown to express markers of macrophages, stem cells or undifferentiated mesenchyme but not SMCs. Remarkably, our findings demonstrate that bone marrow-derived cells (most likely macrophages) non-cell autonomously regulate the number of SMCs recruited into a plaque and suggest that the number of SMC progenitors recruited into a plaque dictates the progression of atherosclerosis. Thus, these novel SMC progenitors are critical to the pathogenesis of pulmonary hypertension and atherosclerosis, but little is known regarding their origin, development, gene expression, maintenance and the mechanisms underlying their role in disease pathogenesis. In this proposal, we will use mouse models, isolated murine cells, human tissue and myeloid cells isolated from humans. We will identify SMC progenitors in the aorta and meticulously characterize both these progenitors and those in the pulmonary arterioles. In addition, we will delineate progenitor cell origins and development as well as their role in morphogenesis of the tunica media. Mechanisms underlying their clonal expansion in disease and the non-cell autonomous regulation of progenitor cells will be investigated. Taken together, our research program promises to yield seminal insights into this novel progenitor cell type that is vitally important for vascular pathologies and thereby, provide therapeutic strategies for combatting lethal diseases of the vasculature, such as pulmonary hypertension and atherosclerosis.

过多的生态平滑肌细胞（SMC）和平滑肌衍生细胞积累 多样化的血管疾病，但基本的机制知之甚少。我们的开创性工作 实验室以及其他实验室表明，SMC祖细胞在此过程中起着至关重要的作用。在 范式转移研究，我们最近确定了肺中的SMC祖细胞池 根据肌肉 - 每种肺动脉am的无肌肉边界及其表达SMC的分子特征 标记和未分化的间充质标记血小板衍生的生长因子受体 （PDGFR）-β。暴露于小鼠缺氧后，肺内皮细胞表达配体PDGF-B 巨噬细胞诱导这些“底漆”细胞表达多能因子Kruppel样因子 4（KLF4）和每个动脉中，其中一个分别迁移，并在克隆上膨胀。这 病理肌肉化导致肺动脉高压。同样，在动脉粥样硬化中 系统性动脉，我们最近的结果表明单个或稀有的SMC标记+细胞产生 对于高级斑块中的大多数细胞，以及这些细胞的绝大多数已被证明 巨噬细胞，干细胞或未分化的间充质而不是SMC的表达标记。值得注意的是 我们的发现表明，骨髓衍生的细胞（最有可能巨噬细胞）非细胞 自主调节招募到牌匾的SMC数量，并建议SMC的数量 招募到斑块中的祖细胞决定了动脉粥样硬化的进展。那，这些小说 SMC祖细胞对于肺高血压和动脉粥样硬化的发病机理至关重要，但是 关于它们的起源，发育，基因表达，维护和 其在疾病发病机理中作用的机制。在此提案中，我们将使用鼠标 模型，分离的鼠细胞，人体组织和髓样细胞从人类中分离出来。我们将 识别主动脉中的SMC祖细胞，并精心列出这些祖细胞和 那些在肺部动物中。此外，我们将描述祖细胞的起源和 发育以及它们在Tunica培养基的形态发生中的作用。 其克隆扩张的基础机制和非单细胞自主调节的机制 将研究祖细胞。综上所述，我们的研究计划有望产生 对这种新型祖细胞类型的开创性见解，对血管至关重要 病理学，从而提供治疗策略来打击致命的疾病 脉管系统，例如肺高血压和动脉粥样硬化。