Regulators of extracellular matrix production during cardiac development and disease

心脏纤维化是几乎所有心肌损伤的严重后果。在心肌梗塞(MI)中， 最初为了防止室壁破裂而形成的保护性疤痕过程变成了一种病理 随着过量的细胞外基质(ECM)蛋白的积累，组织重塑。最终，这件事 适应性会阻碍心肌的机械和电学特性，导致心力衰竭。 最近，我们发现Periostin(Postn)表达细胞来源于心脏成纤维细胞(CFs)。 是一个潜在的治疗靶点，因为它们分化为与疤痕相关的、产生基质的细胞型 心肌梗死损伤后。事实上，在急性心肌梗死损伤后删除这些细胞可以消除间质纤维化，但会导致 心肌梗死急性期ECM沉积受损的标志性结局--脑室破裂。 然而，如果我们在慢性损伤期间删除这些细胞，例如压力超负荷导致的心脏纤维化 模型中，我们检测到持续的血管周围纤维化。以前的研究也报告了起源和异质性 与不同心脏疾病相关的细胞外基质产生细胞的功能。 因此，我们无法识别特定细胞和状态的治疗靶点，从而导致心脏纤维化。 然而，这是一种不治之症。因此，迫切需要确定细胞的组成和功能 产生细胞外基质的成纤维细胞的异质性。直到最近，主要的限制一直是无法 准确地询问和操纵从细胞分化出的不同的CF亚群的活动， 包括周细胞、内皮细胞、驻留在体内的炎性细胞缺乏细胞类型特异性 基因工具。最近，我们和其他人创造了几种新的基因工具，现在可以让我们 研究所有产生基质的细胞及其激活形式。利用这些新的遗传工具 血统追踪，功能获得和功能丧失的研究，我们将询问和确定起源和 所有细胞外基质产生细胞类型的功能以及调节持续CFs的分子机制 小鼠急、慢性病模型的病理激活与分化。我们最近的工作是 我们在单个细胞中有效地询问了表达Postn的CF谱系与Postn阴性的CFs RNA测序分析显示，这两个群体之间存在不同的基因表达谱。 根据损伤类型，如心肌梗死、TAC或血管紧张素诱导的纤维化，我们 观察到细胞外基质成分和细胞组成的差异。最后，我们的初步数据显示 这里确定了另一种涉及血管周围纤维化的细胞系。因此，我们假设 导致纤维化的病理性ECM沉积来自于疾病特异性的专门化亚群 具有明显基因表达的CFS。以下目标将严格询问CF亚群和 调节碳纤维活化和细胞外基质组成的分子机制。

Cardiac fibrosis is a grim consequence for almost all myocardial injuries. In myocardial infarction (MI), what starts as a protective scarring process to prevent ventricular wall rupture becomes a pathological remodeling of the tissue with the accumulation of excess extracellular matrix (ECM) proteins. Eventually, this adaptation impedes the mechanical and electrical properties of the myocardium resulting in heart failure. Recently, we showed that periostin (Postn) expressing cells that arise from resident cardiac fibroblasts (CFs) are a potential therapeutic target since they differentiate into the scar associated, matrix-producing cell-type after MI injury. In fact, deletion of these cells after an acute MI injury eliminates interstitial fibrosis but results in ventricular rupture which is a hallmark outcome of impaired ECM deposition during the acute phase of MI. However, if we delete these cells during a chronic injury such as pressure overload-induced cardiac fibrosis model, we detect sustained perivascular fibrosis. Previous studies also report heterogeneity of origin and function for ECM-producing cells associated with different cardiac diseases. Consequently, our inability to identify cell- and state-specific therapeutic targets render cardiac fibrosis yet an incurable disease. Therefore, there is a critical need to determine the cellular composition and functional heterogeneity within ECM-producing fibroblasts. Until very recently, the main limitation has been the inability to accurately interrogate and manipulate the activities of different CF sub-populations differentiated from cells, including pericytes, endothelial cells, resident inflammatory cells in vivo given a lack of cell type-specific genetic tools. Recently, we and others have generated several novel genetic tools that now allow us to investigate all of the matrix-producing cells and their activated forms. Utilizing these new genetic tools in lineage tracing, gain-of-function, and loss-of-function studies, we will interrogate and determine the origin and function of all ECM-producing cell types as well as the molecular mechanisms that regulate CF sustained pathological activation and differentiation after acute or chronic disease models in mice. Our recent work where we effectively interrogated Postn expressing CF lineage in comparison to Postn negative CFs in a single-cell RNA sequencing analysis revealed distinct gene expression profiles between these two populations. Depending on the injury type, such as hearts subjected to MI, TAC, or Angiotensin induced fibrosis, we observed differences in ECM components as well as cellular composition. Finally, our preliminary data showed here identify another cell lineage that involves perivascular fibrosis. Therefore, we hypothesize that pathological ECM deposition resulting in fibrosis comes from disease-specific specialized sub-populations of CFs with distinct gene expressions. The following aims will rigorously interrogate CF subpopulations and the molecular mechanisms that regulate CF activation and ECM composition.