Cardiac Mesenchymal Stem Cells and Myocardial Fibrosis: Role of Platelet Derived Growth Factor Receptor Signaling

该项目的中心目标是评估PDGF/PDGFR信号、炎症信号 反应调节衰竭状态下驻留的心脏间充质干细胞的功能结果 红心。缺血性心肌损伤启动两个自我放大事件的级联，这两个事件旨在促进 组织修复。最初的事件是由渗入的促炎免疫的协同作用所调节的 细胞。虽然最初是修复性的，但活化的单核/巨噬细胞群体在 损伤的心肌进一步夸大炎症反应，延迟伤口的出现 治愈。慢性地，这些过程通过激活细胞外基质的增殖来诱导细胞外基质(ECM)的重塑 产生胶原的肌成纤维细胞。尽管MSCs在本质上具有多能性，但通常会分化为肌成纤维细胞 在体内的许多病理中，表明组织微环境的影响在 指引着MSC的命运。CMSCs在缺血性心力衰竭的病因和进展中的确切作用尚不清楚。 更重要的是，心脏衰竭时调节cMSC功能和分化的因素尚不清楚。 明白了。在急性心肌梗死(MI)和慢性心力衰竭(HF)期间， 大量促炎症的心脏巨噬细胞。更重要的是，慢性心衰时巨噬细胞的扩张 伴随着促进心脏纤维化的肌成纤维细胞的持续激活。血小板衍生性生长 血小板衍生生长因子(PDGF)是公认的组织纤维化和血管生成的介质。像巨噬细胞一样，间充质干细胞 分泌PDGF和表达PDGF受体(PDGFRs)，产生富含PDGF和PDGF反应的细胞 心脏衰竭时的微环境。然而，重要的是，无论cMSC本地化的PDGF信号，在 对慢性炎症和巨噬细胞浸润等因素的反应，调节cMSC的命运和 对高频的反应是未知的。在本提案中，我们将检验增强的cMSC本地化的假设 PDGF信号优先引导cMSCs走向肌成纤维细胞的命运(和远离内皮细胞 在衰竭的心脏中)，从而增加纤维化，减少血管生成和修复。三个目标是 被求婚了。目的1将明确PDGFR信号转导和巨噬细胞相互作用在体外 正常和衰竭心脏来源的骨髓间充质干细胞的分化命运。目标2将确定在体内的作用 CMSC定位的PDGFRs对缺血性心力衰竭左室重构和功能的影响。这些研究将使用 可诱导和cMSC特异性消融PDGFRs的转基因小鼠。目标3将建立治疗方法 心肌梗死再灌流后联合应用PDGFR抑制对cMSC细胞治疗的影响。 这些研究将使用临床批准的PDGFR抑制剂甲磺酸伊马替尼(Gleevac®)。总而言之， 拟议的研究将回答与心力衰竭相关的关键问题，这些问题与心力衰竭的病理生理意义有关 心肌纤维化中细胞间充质干细胞命运的改变以及细胞间充质干细胞和药物的潜在治疗作用 抑制PDGFR诱导组织修复。 好了！

The central objective of this project is to evaluate how PDGF/PDGFR signaling, inflammatory signaling responses modulate the functional outcomes of resident cardiac mesenchymal stem cells (cMSCs) in failing hearts. Ischemic myocardial injury initiates a cascade of two self-amplifying events that intend to promote tissue repair. The initial events are mediated by the concerted action of infiltrating pro-inflammatory immune cells. Although, reparative initially, prolonged infiltration of activated monocyte/macrophage populations within the injured myocardium further exaggerate inflammatory responses and delay the manifestation of wound healing. Chronically these processes induce extracellular-matrix (ECM) remodeling by activating proliferation of collagen producing myofibroblasts. Although multipotent in nature, MSCs often differentiate into myofibroblasts in vivo in a number of pathologies, suggesting that tissue microenvironment influences are paramount in guiding MSC fate. The precise role of cMSCs in the etiology and progression of ischemic HF is unknown. More importantly, factors regulating cMSC function and differentiation in the failing hearts are not clearly understood. During both acute myocardial infarction (MI) and chronic heart failure (HF), there is increased abundance of pro-inflammatory cardiac macrophages. More importantly, macrophage expansion in chronic HF is accompanied by sustained activation of myofibroblasts that promote cardiac fibrosis. Platelet derived growth factor (PDGF) is a well-recognized mediator of tissue fibrosis and angiogenesis. Like macrophages, MSCs secrete PDGF and express PDGF receptors (PDGFRs), resulting in a PDGF-rich and PDGF-responsive microenvironment in the failing heart. Importantly, however, whether cMSC-localized PDGF signaling, in response to such factors as chronic inflammation and macrophage infiltration, regulates cMSC fate and responses in HF is unknown. In this proposal we will test the hypothesis that augmented cMSC-localized PDGF signaling preferentially channels cMSCs toward a myofibroblast fate (and away from an endothelial cell fate) in the failing heart, thereby augmenting fibrosis and reducing angiogenesis and repair. Three aims are being proposed. Aim 1 will define the role of PDGFR signaling and macrophage interactions on the in vitro differentiation fate of cMSCs derived from normal and failing hearts. Aim 2 will determine the in vivo role of cMSC-localized PDGFRs on LV remodeling and function during ischemic HF. These studies will use transgenic mice with inducible and cMSC-specific ablation of PDGFRs. Aim 3 will establish the therapeutic efficacy of cMSC cell therapy after reperfused-MI when used in combination with PDGFR inhibition in vivo. These studies will use the clinically approved PDGFR inhibitor imatinib mesylate (Gleevac®). Collectively the proposed studies will answer critical questions relevant to HF related to both the pathophysiological import of altered cMSC fate in myocardial fibrosis, and the potential therapeutic use of cMSCs and pharmacological PDGFR inhibition to induce tissue repair. !