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

中风和心肌梗塞（MI）是缺血性疾病，是死亡率和发病率的主要原因。 由于大脑和心脏的再生能力有限，损伤导致神经元不可逆的丧失 和心肌细胞，随后形成瘢痕。疤痕形成的过程是突出的过剩 细胞外基质蛋白沉积，阻碍组织修复并阻止脑功能恢复 还有心脏在大脑中，最近的证据表明，星形胶质细胞形成瘢痕的传统概念可能 不正确。在心脏中，除了细胞外，其他间充质细胞在瘢痕形成中可能也起着关键作用。 心脏成纤维细胞 周细胞是一种异质性的壁细胞群体，位于血管的近腔表面。 微血管系统，在那里它们通过物理接触和旁分泌与内皮细胞交流 信号我们实验室最近的研究和工作表明，周细胞可能有助于纤维化 在缺血性损伤后，通过迁移到损伤部位，在那里它们有助于胶原蛋白沉积。我们有 在两个器官系统中，周细胞中的共同基因表达具有相似的迁移模式 损伤部位，提示调节大脑和心脏周细胞活化的平行途径。这 数据表明周细胞是一种瘢痕形成细胞群，可能是调节平衡的靶点， 组织纤维化和修复之间的联系然而，由于缺乏标记物，对周细胞的详细研究受到阻碍 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，不完全清楚异质周细胞群体是否具有不同的功能， 作用，使得亚群响应于损伤后的纤维化并参与损伤后的纤维化。这笔赠款汇集了 神经科学和心血管专业知识，开发一个新的平台，研究周细胞如何积极 在两种最常见和最具破坏性的成人缺血性疾病中导致纤维化瘢痕。 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， 损伤并直接参与瘢痕形成。在具体目标1中，我们将使用新颖的谱系追踪技术 研究周细胞向损伤部位的增殖和迁移，并检查它们在瘢痕形成中的作用 阵在具体目标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 在损伤之前和之后绘制周细胞的转录变化，因为它们变得促纤维化。在特定 目的3，我们将确定调节周细胞活化的分子机制，通过执行增益和损失 的功能。在我们初步数据的支持下，拟议项目解决了 周细胞如何参与中风和MI后瘢痕的发生和发展是一个重要的问题。 这反过来又可以确定负责周细胞活化和增殖的机制，作为抗肿瘤药物的靶点。 纤维化治疗

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.