Macrophages as effectors of cell therapy for heart failure

巨噬细胞作为心力衰竭细胞疗法的效应器

• 批准号: 10112296
• 负责人: Ahmed Ibrahim
• 金额: $ 42.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112296
• 关键词: Acute; Acute myocardial infarction; Adoptive Transfer; Allogenic; Arteries; Attenuated; Biological Assay; Cardiac Myocytes; Cell Therapy; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Clinical; Clinical Treatment; Coculture Techniques; Data; Effector Cell; Exhibits; Green Fluorescent Proteins; Heart failure; In Vitro; Infarction; Injury; Intervention; Ischemia; Knock-out; Lead; Mediating; Mus; Muscle Cells; Myocardium; Natural regeneration; Neonatal; Phase; Prevention; Process; Production; Proto-Oncogenes; Publishing; Rattus; Recovery; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Risk; Role; Signal Pathway; Stress; Testing; Transgenic Mice; Translations; Tyrosine-Kinase Oncogenes; Ventricular; Work; cardioprotection; clinical practice; cytokine; efficacy testing; exosome; experimental study; heart function; improved; in vitro Assay; in vivo; insight; macrophage; monocyte; mouse model; neutrophil; novel; novel strategies; novel therapeutics; optimal treatments; preservation; prevent; red fluorescent protein; research clinical testing; therapeutic candidate

PROJECT SUMMARY/ABSTRACT Novel approaches to reduce infarct size (IS) have stalled in translation. Given that clinical treatment of acute myocardial infarction (AMI) is dominated by a rush to open the infarct-related artery, adjunctive therapies which work after reperfusion are highly desirable. Here I propose to investigate the mechanism of cellular postconditioning: cell therapy delivered 20 mins post-reperfusion can reduce the extent of lethal injury, improve functional recovery, and attenuate the progression toward heart failure (HF). The timing is compatible with standard clinical practice in that the decision to treat can be delayed until after the artery has been opened, if an efficacious off-the-shelf product is available. Allogeneic cardiosphere-derived cells (CDCs) are available for immediate use and are in phase 2 clinical testing for chronic MI. Preliminary data from rats show that CDCs, and their secreted exosomes (CDCexo), are cardioprotective when given with a reasonable delay after reflow in AMI. I examined 48 hr and 2 wk endpoints to focus on the acute and chronic benefits of cardioprotection, respectively. To determine the optimal treatment paradigm, I varied systematically the interval between reperfusion and delivery of CDCs or CDCexo. Twenty mins after a 45-min ischemic episode, I saw the greatest decreases of IS, and the best improvements in cardiac function. In published work, I found that macrophages (Mϕ) are essential effectors of cellular postconditioning; their depletion abrogates cellular postconditioning. Conversely, adoptive transfer of CDC- or CDCexo-primed Mϕ is cardioprotective. The major mechanistic objective here is to understand how exosome-mediated changes in Mϕ lead to acute cardioprotection (days after MI) and long-term protection against HF (weeks after MI). Specifically, I will test the concept that CDCexo-primed Mϕ exhibit enhanced efferocytosis (the ability to scavenge toxic cellular debris), thereby improving recovery and preventing progression toward HF. The focus here is on cardioprotection (prevention of cardiomyocyte death), rather than regeneration, and the mechanism of CDC- and CDCexo-mediated enhanced efferocytosis. Mice will be used for all our mechanistic studies. The role of efferocytosis will be probed both by novel in vitro co-culture assays of macrophages, neutrophils, and stressed cardiomyocytes, as well as by in vivo experiments in transgenic mice with MI to quantify and determine the mechanism of CDCexo-mediated efferocytosis. This work has the potential to elucidate the cardioprotective mechanisms of cell therapy that prevent progression to HF.

项目概要/摘要 减少梗塞面积（IS）的新方法的转化已陷入停滞。鉴于临床治疗急性 心肌梗塞（AMI）主要是急于打开梗塞相关动脉，辅助治疗 再灌注后的工作是非常理想的。在这里我建议研究细胞的机制 后处理：再灌注后20分钟进行细胞治疗可以减少致命损伤的程度，改善 功能恢复，并减缓心力衰竭（HF）的进展。时序兼容 标准的临床实践是，治疗的决定可以推迟到动脉开通之后，如果 有有效的现成产品可供使用。同种异体心肌细胞 (CDC) 可用于 立即使用，并正在进行慢性 MI 的 2 期临床测试。来自大鼠的初步数据表明，CDC 和 它们分泌的外泌体 (CDCexo) 在 AMI 复流后合理延迟给予时具有心脏保护作用。 我检查了 48 小时和 2 周的终点，分别关注心脏保护的急性和慢性益处。 为了确定最佳治疗模式，我系统地改变了再灌注和再灌注之间的间隔。 CDC 或 CDCexo 的交付。 45 分钟的缺血发作后 20 分钟，我看到 IS 下降幅度最大， 以及心脏功能的最佳改善。在已发表的作品中，我发现巨噬细胞 (Mφ) 是必不可少的 细胞后处理的效应器；它们的耗尽会消除细胞后处理。反之，收养 CDC 或 CDCexo 引发的 M 的转移具有心脏保护作用。这里的主要机械目标是理解 外泌体介导的 Mψ 变化如何导致急性心脏保护（MI 后几天）和长期保护 对抗 HF（MI 后几周）。具体来说，我将测试 CDCexo 引发的 Mphi 表现出增强的概念 胞吞作用（清除有毒细胞碎片的能力），从而改善恢复并预防 进展为心力衰竭。这里的重点是心脏保护（预防心肌细胞死亡），而不是 再生，以及 CDC 和 CDCexo 介导的增强胞吞作用的机制。小鼠将用于 我们所有的机制研究。胞吞作用的作用将通过新型体外共培养测定来探讨 巨噬细胞、中性粒细胞和应激心肌细胞，以及转基因小鼠的体内实验 与 MI 来量化和确定 CDCexo 介导的胞吞作用的机制。这项工作有潜力 阐明细胞疗法预防心力衰竭进展的心脏保护机制。