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

各种无菌性疾病，包括心肌梗死（MI）和随后的修复，都涉及心肌梗死。 免疫系统尽管未解决的炎症会加重心力衰竭，但心肌中巨噬细胞的消耗 心肌梗塞导致左心室（LV）破裂和死亡。因此，无差别免疫抑制 不是一个可行的方法。然而，必须解决衰竭心脏中的持续炎症。 不幸的是，由于我们不知道免疫细胞是如何调节的， 心肌修复和什么决定他们的有害与有益的行动。细胞疗法提供了一种独特的 有机会了解免疫细胞如何有助于心肌修复，最近的研究结果表明， 巨噬细胞作为细胞疗法介导的心肌修复的直接贡献者。虽然注射的细胞很少 在接受者中长期存活，常见的益处包括减少纤维化，增强血管生成， LV功能改善。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， 机制仍然不明。我们的初步数据显示，注射心脏间充质细胞 向梗死心脏中释放CMC促进修复性巨噬细胞的积累，减少纤维化， 改善LV功能。CMCs与巨噬细胞的共培养有利于巨噬细胞的修复程序， 这可能是由于CMC衍生的生物活性脂质-如白藜芦醇、白三烯和消退素-提供了 对细胞介导修复的"旁分泌假说"的可检验的解释。因此，我们建议中医药管理公司招聘 单核细胞和激活修复巨噬细胞，促进有利的抗纤维化心脏重塑， 改善梗塞心脏的心脏功能。在当前项目中，我们将确定 CMC中的生物活性脂质合成和分泌。将进行质谱分析，以探索 CMC中生物活性脂质合成的考克斯和Lox途径。展望未来，我们将确定生物活性 脂质在巨噬细胞募集及其修复功能中的作用，特别关注巨噬细胞BLT-1 受体及其CMC衍生配体。最后，我们将确定CMC的修复效果， HF小鼠模型中生物活性脂质的合成。该项目将是第一个系统分析生物活性 修复性CMC中的脂质合成谱。该项目将提供新的见解，不仅途径， CMC中的生物活性脂质合成以及调节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.