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: 10670304
• 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/10670304
• 关键词: Aorta; Arteries; Atherosclerosis; Blood Vessels; Bone Marrow; Cell Separation; Cells; Clonal Expansion; Development; Disease; Distal; Endothelial Cells; GKLF protein; Gene Expression; Human; Hypoxia; Investigation; Ligands; Location; Lung; Macrophage; 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; cell type; human tissue; insight; migration; 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.

过多的异位平滑肌细胞 (SMC) 和平滑肌衍生细胞积聚在 血管疾病多种多样，但其潜在机制尚不清楚。我们的开创性工作 实验室以及其他实验室表明 SMC 祖细胞在此过程中发挥着至关重要的作用。在 通过范式转换研究，我们最近在肺部发现了 SMC 祖细胞池 推理是根据远端小动脉在肌层的位置来使远端小动脉肌肉化。 每个肺小动脉的非肌性边界及其表达 SMC 的分子特征 标记物和未分化间充质标记物血小板衍生生长因子受体 (PDGFR)-β。小鼠缺氧后，肺内皮细胞表达配体 PDGF-B 巨噬细胞诱导这些“启动”细胞表达多能性因子 Kruppel 样因子 4 (KLF4)，并且在每个小动脉中，其中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 全身动脉，我们最近的结果表明单个或罕见的 SMC 标记+细胞产生 晚期斑块中的大多数细胞，并且这些细胞中的绝大多数已被证明 表达巨噬细胞、干细胞或未分化间质的标记物，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 自主调节斑块中招募的 SMC 数量，并表明 SMC 数量 聚集到斑块中的祖细胞决定了动脉粥样硬化的进展。于是，这些小说 SMC 祖细胞对于肺动脉高压和动脉粥样硬化的发病机制至关重要，但是 关于它们的起源、发育、基因表达、维持和作用，人们知之甚少。 其在疾病发病机制中的作用机制。在本提案中，我们将使用鼠标 模型、分离的小鼠细胞、人体组织和从人体分离的骨髓细胞。我们将 识别主动脉中的 SMC 祖细胞，并仔细表征这些祖细胞和 那些在肺小动脉中的。此外，我们将描绘祖细胞的起源和 发育及其在中膜形态发生中的作用。 它们在疾病中克隆扩张的机制以及非细胞自主调节 将研究祖细胞。总而言之，我们的研究计划有望产生 对这种对血管至关重要的新型祖细胞类型的开创性见解 病理学，从而为对抗致命疾病提供治疗策略 血管系统，例如肺动脉高压和动脉粥样硬化。

项目成果

Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis.

• DOI: 10.1038/s41467-021-27499-8
• 发表时间: 2021-12-10
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Chandran RR;Xie Y;Gallardo-Vara E;Adams T;Garcia-Milian R;Kabir I;Sheikh AQ;Kaminski N;Martin KA;Herzog EL;Greif DM
• 通讯作者: Greif DM

SNCs meet SMCs in the atherosclerotic plaque.

SNC 在动脉粥样硬化斑块中与 SMC 相遇。

• DOI: 10.1038/s43587-021-00096-6
• 发表时间: 2021
• 期刊: Nature aging
• 作者: Kabir,Inamul;Greif,DanielM
• 通讯作者: Greif,DanielM

Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy.

• DOI: 10.1016/j.isci.2023.108636
• 发表时间: 2024-01-19
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Saito, Junichi;Dave, Jui M.;Lau, Freddy Duarte;Greif, Daniel M.
• 通讯作者: Greif, Daniel M.