The role of pericytes in scar formation following stroke and myocardial infarction

周细胞在中风和心肌梗死后疤痕形成中的作用

• 批准号: 10560595
• 负责人: Stanley Thomas Carmichael
• 金额: $ 44.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560595
• 关键词: Address; Adult; Area; Astrocytes; Behavior; Bioinformatics; Blood Vessels; Brain; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Central Nervous System; Cicatrix; Collaborations; Collagen; Communication; Data; Deposition; Development; Disease; Endothelial Cells; Equilibrium; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Grant; Heart; Heterogeneity; Homeostasis; Immune; In Vitro; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Ischemia; Ischemic Stroke; Knowledge; Label; Laboratories; Lead; Lesion; Literature; Maps; Mediator; Mesenchymal; Molecular; Molecular Profiling; Morbidity - disease rate; Myocardial Infarction; Necrosis; Neurologist; Neurosciences; Organ; Outcome; Paracrine Communication; Pathway interactions; Pattern; Pericytes; Population; Population Heterogeneity; Process; Proliferating; Property; Reaction; Recovery; Recovery of Function; Regenerative capacity; Regulator Genes; Role; Scientist; Site; Spinal Cord Lesions; Spinal cord injury; Stroke; Surface; System; Techniques; Tissues; Transgenic Mice; Up-Regulation; Viral; Work; antifibrotic treatment; body system; cell type; differential expression; experimental study; gain of function; immune cell infiltrate; in vivo Model; insight; ischemic injury; loss of function; migration; mortality; neuron loss; new growth; novel; population migration; post stroke; prevent; repaired; response to injury; single-cell RNA sequencing; tissue repair; tool; transcriptome; transcriptomics; viral gene delivery

Stroke and myocardial infarction (MI) are ischemic diseases that are leading causes of mortality and morbidity. Due to the limited regenerative capacity of the brain and the heart, injury leads to irreversible loss of neurons and cardiomyocytes, with subsequent scar formation. The process of scar formation is highlighted by excess deposition of extracellular matrix proteins which blocks tissue repair and prevents functional recovery in the brain and the heart. In the brain, recent evidence indicates that the traditional concepts of astrocytes forming scar may be incorrect. In the heart, there may be a key role for other mesenchymal cells in scar formation in addition to cardiac fibroblasts. Pericytes are a heterogeneous population of mural cells located on the abluminal surface of the microvasculature, where they communicate with endothelial cells by means of physical contact and paracrine signaling. Recent studies and work from our laboratories have suggested that pericytes may contribute to fibrosis after an ischemic injury by migration to the site of injury, where they contribute to collagen deposition. We have demonstrated expression of common genes in pericytes in both organ systems with similar migratory patterns to site of injury, suggestive of parallel pathways that regulate pericyte activation in the brain and the heart. This data suggests that pericytes are a scar-forming cell population that may be a target for modulating the balance between tissue fibrosis and repair. However, detailed study of pericytes has been hampered by lack of markers that hinder their isolation and the ability for targeting of key molecular pathways that may drive scar formation. Furthermore, it is not entirely clear whether the heterogeneous pericyte populations possess distinct functional roles, such that a subpopulation is responsive to and participates in fibrosis after injury. This grant brings together neuroscience and cardiovascular expertise to develop a novel platform for studying how pericytes may actively contribute to the fibrotic scar in the two most common and devastating adult ischemic diseases. We hypothesize that pericytes contain distinct subpopulations that preferentially localize to the site of ischemic injury and directly participate in scar formation. In specific aim 1, we will use novel lineage-tracing techniques to investigate proliferation and migration of pericytes to the site of injury and examine their participation in scar formation. In specific aim 2, we will perform single-cell gene expression profiling of brain and heart pericytes before and after injury to map the transcriptional changes of pericytes as they become pro-fibrotic. In specific aim 3, we will determine the molecular mechanisms that regulate pericyte activation by performing gain and loss of function using in vitro and in vivo models. Supported by our preliminary data, the proposed project addresses an important issue of how pericytes participate in the development and progression of scar after stroke and MI. This in turn may identify mechanisms responsible for pericyte activation and proliferation as targets for anti- fibrotic therapies.

中风和心肌梗塞(MI)是导致死亡和发病的主要原因之一的缺血性疾病。 由于大脑和心脏的再生能力有限，损伤会导致神经元不可逆转的丧失。 和心肌细胞，随之而来的疤痕形成。疤痕的形成过程被过度强调 细胞外基质蛋白的沉积阻碍了组织修复和大脑功能的恢复 还有心脏。在大脑中，最近的证据表明，星形胶质细胞形成疤痕的传统概念可能 是不正确的。在心脏，可能有其他间充质细胞在疤痕形成中起关键作用，除了 心脏成纤维细胞。 周细胞是一种异质性的壁细胞群体，位于皮肤的腔面。 微血管系统，它们通过身体接触和旁分泌与内皮细胞进行交流 发信号。我们实验室最近的研究和工作表明，周细胞可能导致纤维化。 在缺血损伤后，它们通过迁移到损伤部位，在那里促进胶原沉积。我们有 在具有相似迁移模式的两个器官系统中共同基因在周细胞中的表达 与损伤部位有关，提示存在调节大脑和心脏周细胞激活的平行通路。这 数据表明，周细胞是形成疤痕的细胞群，可能是调节平衡的目标。 组织纤维化和修复之间的关系。然而，由于缺乏标志物，对周细胞的详细研究一直受到阻碍。 这阻碍了它们的分离和靶向可能导致疤痕形成的关键分子途径的能力。 此外，不同的周细胞群体是否具有不同的功能尚不完全清楚。 作用，使一个亚群对损伤后的纤维化作出反应并参与其中。这笔赠款汇集了 神经科学和心血管专业知识开发一个研究周细胞如何活跃的新平台 导致两种最常见和最具破坏性的成人缺血性疾病中的纤维性瘢痕。 我们假设周细胞包含不同的亚群，它们优先定位于缺血部位。 损伤并直接参与疤痕形成。在具体目标1中，我们将使用新的血统追踪技术 观察周细胞向损伤部位的增殖和迁移，并探讨其在瘢痕形成中的作用。 队形。在特定目标2中，我们将对大脑和心脏周细胞进行单细胞基因表达谱分析。 绘制损伤前后周细胞促纤维化时的转录变化图。具体而言 目的3，我们将确定通过执行得失来调节周细胞激活的分子机制。 使用体外和体内模型进行功能研究。在我们初步数据的支持下，拟议的项目解决了 周细胞如何参与卒中和心肌梗死后瘢痕的发生和发展是一个重要的问题。 这反过来可能确定负责周细胞激活和增殖的机制作为抗 纤维化疗法。