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: 10433824
• 负责人: Daniel Greif
• 金额: $ 100.4万
• 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/10433824
• 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; Muscle satellite cell; 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; human tissue; insight; macrophage; mouse model; novel; novel therapeutic intervention; pluripotency factor; 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.

过多和异位平滑肌细胞（SMC）和平滑肌衍生细胞在子宫内膜中积聚， 血管疾病多种多样，但其潜在机制知之甚少。我们的种子工作 实验室以及其他实验室表明SMC祖细胞在这一过程中起着至关重要作用。在 在范式转换研究中，我们最近发现了肺中的SMC祖细胞池， 根据远端小动脉在肌肉中的位置， 每个肺小动脉的无肌缘及其表达SMC的分子标记 标志物和未分化间充质标志物血小板衍生生长因子受体 （PDGFR）-β。在小鼠暴露于缺氧时，肺内皮细胞表达配体PDGF-B， 巨噬细胞诱导这些“致敏”细胞表达多能性因子Kruppel样因子 4（KLF 4），在每个小动脉中，有一个向远端迁移并克隆性扩张。这 病理性肌肉化导致肺动脉高压。同样，在动脉粥样硬化中， 我们最近的研究结果表明，单个或罕见的SMC标志物+细胞引起全身动脉， 大多数细胞在一个先进的斑块，这些细胞中的绝大多数已被证明， 表达巨噬细胞、干细胞或未分化间充质细胞的标志物，但不表达SMC。值得注意的是， 我们的研究结果表明，骨髓来源的细胞（最有可能是巨噬细胞）非细胞 自主调节SMC招募到斑块中的数量，并表明SMC的数量 聚集到斑块中的祖细胞决定了动脉粥样硬化的进展。这些小说 SMC祖细胞在肺动脉高压和动脉粥样硬化的发病机制中至关重要， 关于它们的起源、发育、基因表达、维持和 其在疾病发病机制中的作用的潜在机制。在本建议中，我们将使用鼠标 模型、分离的鼠细胞、人组织和从人分离的骨髓细胞。我们将 鉴定主动脉中的SMC祖细胞，并仔细表征这些祖细胞， 那些在肺小动脉里的此外，我们将描绘祖细胞的起源， 发育以及它们在图尼卡中膜形态发生中的作用。 它们在疾病中的克隆性扩增机制和非细胞自主调节 将研究祖细胞。综合起来，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， 病理学，从而提供了用于对抗人类致命疾病的治疗策略。 血管系统，如肺动脉高压和动脉粥样硬化。