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.

项目摘要/摘要减少梗塞大小（IS）的新方法已经停滞了翻译。鉴于急性的临床治疗心肌梗塞（AMI）以急于打开基础设施相关的辅助疗法的主导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发现：重新灌注后接受20分钟的细胞疗法可以减少致命损伤的程度，改善功能恢复，并衰减心力衰竭的进展（HF）。时机与标准临床实践是，可以将治疗的决定延迟到开放动脉后，如果可提供简单的现成产品。同种异体心圈衍生的细胞（CDC）可用于立即使用，并在第二阶段进行慢性MI的临床测试。来自大鼠的初步数据表明CDC和他们的分泌外泌体（CDCEXO）是在AMI回流后以合理的延迟给予的心脏保护。我检查了48个小时和2个WK端点，分别专注于心脏保护的急性和慢性益处。为了确定最佳治疗范式，我系统地改变了再灌注和之间的间隔递送CDC或CDCEXO。 45分钟的缺血性发作后二十分钟，我看到了最大的IS下降，以及心脏功能的最佳改进。在已发表的工作中，我发现巨噬细胞（Mϕ）是必不可少的细胞后处理的影响；他们的部署消除了细胞后的调节。相反，自适应 CDC或CDCEXO培养的Mϕ的转移是心脏保护性的。这里的主要机械目标是了解外泌体介导的M ϕ的变化如何导致急性心脏保护（MI后几天）和长期保护反对HF（MI后几周）。具体而言，我将测试CDCEXO启动的Mϕ暴露增强的概念衰减（清除有毒细胞碎屑的能力），从而改善恢复并防止向HF进展。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介导的增强肿瘤的机制。老鼠将用于我们所有的机械研究。胚细胞增多症的作用将通过新型的体外共培养测定法进行探讨巨噬细胞，中性粒细胞和应力的心肌细胞以及通过体内实验在转基因小鼠中使用MI来量化和确定CDCEXO介导的胞吞作用的机理。这项工作有潜力阐明细胞疗法的心脏保护机制，以防止进展到HF。

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.