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

基本信息

批准号：
10569536
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
项目类别：
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/10569536
关键词：
Acute Acute myocardial infarction Adoptive Transfer Allogenic Arteries Attenuated Biological Assay Cardiac Myocytes Cell Therapy Cells 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 MERTK gene Macrophage Mediating Mus Muscle Cells Myocardium Natural regeneration Neonatal Phase Prevention Process Production Publishing Rattus Recovery Recovery of Function Reperfusion Injury Reperfusion Therapy Risk Role Signal Pathway Stress Testing Transgenic Mice Translations Ventricular Work cardioprotection clinical practice conditioning cytokine efficacy evaluation efficacy testing exosome experimental study heart function improved in vitro Assay in vivo insight monocyte monomer mouse model neutrophil novel novel strategies novel therapeutics optimal treatments preservation prevent red fluorescent protein research clinical testing therapeutic candidate

项目摘要

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/摘要鉴于急性梗塞的临床治疗，减少梗塞面积（IS）的新方法已陷入停滞。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可取的，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。时机与此相一致。标准临床实践中，治疗决定可以推迟到动脉开通后，如果可以使用有效的现成产品同种异体心肌细胞 (CDC)。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。在 45 分钟的缺血发作后 20 分钟，我看到 IS 的最大下降，在已发表的著作中，我发现巨噬细胞 (Mψ) 是必不可少的。细胞后处理的效应子；它们的耗尽会消除细胞后处理的离线、过继性。 CDC 或 CDCexo 引发的 M 的转移具有心脏保护作用。这里的主要机制目标是了解。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心力衰竭的进展重点是心脏保护（预防心肌细胞死亡），而不是。再生，CDC 和 CDCexo 介导的增强胞吞作用的机制将用于。我们所有的机制研究都将通过新颖的体外共培养测定来探讨胞吞作用的作用。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具有潜力。阐明细胞疗法预防心力衰竭进展的心脏保护机制。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exosomally derived Y RNA fragment alleviates hypertrophic cardiomyopathy in transgenic mice.

DOI：
10.1016/j.omtn.2021.04.014
发表时间：
2021-06-04
期刊：
Molecular therapy. Nucleic acids
影响因子：
0
作者：
Huang F;Na N;Ijichi T;Wu X;Miyamoto K;Ciullo A;Tran M;Li L;Ibrahim A;Marbán E;de Couto G
通讯作者：
de Couto G

Engineered Fibroblast Extracellular Vesicles Attenuate Pulmonary Inflammation and Fibrosis in Bleomycin-Induced Lung Injury.

DOI：
10.3389/fcell.2021.733158
发表时间：
2021
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
Ibrahim A;Ciullo A;Li C;Akhmerov A;Peck K;Jones-Ungerleider KC;Morris A;Marchevsky A;Marbàn E;Ibrahim AG
通讯作者：
Ibrahim AG

Extracellular Vesicles Secreted by TDO2-Augmented Fibroblasts Regulate Pro-inflammatory Response in Macrophages.