The role of bioactive lipids in CMC-induced myocardial repair.

各种无菌疾病，包括心肌梗死(MI)和随后的修复，涉及 免疫系统。尽管未解决的炎症会加剧心力衰竭，但心脏中巨噬细胞的耗竭 心肌梗死可导致左心室破裂和死亡。因此，不分青红皂白的免疫抑制 不是一个可行的方法。然而，衰竭心脏中的持续性炎症必须得到解决。 不幸的是，取得进展的重大障碍仍然存在，因为我们不知道免疫细胞如何调节 心肌修复以及是什么决定了他们的有害和有益的行为。细胞疗法提供了一种独特的 了解免疫细胞如何促进心肌修复的机会，以及最近的发现 巨噬细胞作为细胞治疗介导的心肌修复的直接贡献者。尽管注射的细胞很少 在接受者中长期存活，共同的好处包括减少纤维化，增强血管生成，以及 左心室功能的改善。这些改善与注射细胞的分化无关。 进入心肌细胞，这表明细胞治疗必须招募内源性修复机制；然而，这些 机制仍未确定。我们的初步数据显示，注射心脏间充质细胞 (CMCs)进入梗塞的心脏促进修复性巨噬细胞的积累，减少纤维化，以及 改善左心室功能。巨噬细胞与巨噬细胞共培养有利于修复性的巨噬细胞程序，而且它 可能是由于CMC衍生的生物活性脂类--如前列腺素、白三烯和溶血素--它们提供 对细胞介导的修复的‘旁分泌假说’的可检验的解释。因此，我们建议CMCS招募 单核细胞和激活修复性巨噬细胞，促进有利的抗纤维化心脏重塑和 改善梗塞心脏的心功能。在当前项目中，我们将确定 巨噬细胞的生物活性脂肪合成和分泌。将进行质谱分析，以探索 巨噬细胞生物活性脂质合成中的COX和LOX途径。接下来，我们将确定生物活性的作用 巨噬细胞募集中的脂质及其修复功能，尤其是巨噬细胞BLT-1 受体及其CMC衍生配体。最后，我们将确定增强的CMCs的修复效果 心衰小鼠模型的生物活性脂肪合成。该项目将是首次对生物活性进行系统分析。 修复性巨噬细胞中的脂质合成特征。该项目不仅将为以下方面提供新的见解 CMC中生物活性的脂质合成也是调控细胞治疗介导的心肌修复的机制。

A variety of sterile diseases, including myocardial infarction (MI) and subsequent repair, involve the immune system. Although unresolved inflammation exacerbates heart failure, depletion of macrophages in the infarcted myocardium leads to left ventricular (LV) rupture and death. Thus, indiscriminate immunosuppression is not a viable approach. Nevertheless, persistent inflammation in the failing heart must be addressed. Unfortunately, significant barriers to progress remain because we do not know how immune cells regulate myocardial repair and what determines their harmful versus salutary actions. Cell therapy provides a unique opportunity for understanding how immune cells contribute to myocardial repair, and recent findings implicate macrophages as direct contributors to cell therapy-mediated myocardial repair. Although few injected cells survive long-term in the recipient, common benefits include reduction of fibrosis, enhanced angiogenesis, and improvement in LV function. These improvements occur independently of differentiation of the injected cells into cardiomyocytes, suggesting that cell therapy must recruit endogenous repair mechanisms; however, these mechanisms remain unidentified. Our preliminary data show that injection of cardiac mesenchymal cells (CMCs) into the infarcted heart promotes accumulation of reparative macrophages, decreases fibrosis, and improves LV function. Co-culture of CMCs with macrophages favors a reparative macrophage program, and it may be due to CMC-derived bioactive lipids—such as prostaglandins, leukotrienes, and resolvins— which offer testable explanations of the `paracrine hypothesis' of cell-mediated repair. Thus, we propose that CMCs recruit monocytes and activate reparative macrophages, which promote favorable anti-fibrotic cardiac remodeling and improve cardiac function in the infarcted heart. In the current project we will determine the capacity for the bioactive lipid synthesis and secretion in CMCs. Mass spectrometry will be performed to explore the role of Cox and Lox pathways in bioactive lipid synthesis in CMCs. Moving forward we will ascertain the role bioactive lipids in macrophage recruitment and their reparative function, with the particular focus on macrophage BLT-1 receptor and its CMC-derived ligands. Finally, we will determine the reparative effect of CMCs with enhanced bioactive lipid synthesis in mouse model of HF. This project will be the first systematic analysis of bioactive lipid synthesis profile in reparative CMCs. This project will provide novel insights into not only pathways of bioactive lipid synthesis in CMC but also the mechanisms regulating cell therapy-mediated myocardial repair.