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Cardioprotective mechanisms of cell therapy for myocardial infarction

细胞治疗心肌梗死的心脏保护机制

基本信息

批准号：
9906252
负责人：
EDUARDO MARBAN
金额：
$ 43.75万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906252
关键词：
Acute Acute myocardial infarction Address Aftercare Allogenic Animal Model Arteries Biological Assay Cardiac Myocytes Cell Therapy Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Clinical Treatment Clinical Trials Design Coculture Techniques Data Ensure Exhibits Family suidae Heart In Vitro Inbred WKY Rats Infarction Infusion procedures Injury Ischemia Laboratories Lead Measures Mediating MicroRNAs Miniature Swine Modeling Muscle Cells Myocardial Infarction Neonatal Obstruction Pathway interactions Phase Physicians Process RNA Rattus Recovery Recovery of Function Reperfusion Therapy Role Stress Structure Testing Time Transfer RNA Transgenic Organisms Translations Ventricular Work cardioprotection clinical care clinical practice clinically relevant exosome experience experimental study improved in vivo insight macrophage neutrophil novel novel strategies recruit regenerative research clinical testing response translational study uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Novel approaches to reduce infarct size (IS) have stalled in translation. A major obstacle is the fact that the clinical care paradigm for acute myocardial infarction (AMI) has one dominant objective: to open the infarct- related artery as quickly as possible. Only after flow is restored might the treating physician take time to think about adjunctive therapies, but by then the window of opportunity to recruit classical cardioprotection has most likely closed, or at least narrowed significantly. Here we characterize the novel phenomenon of cellular postconditioning: cell therapy delivered 30 min post-reperfusion (or even longer; defining the precise timing is an aim of this R01) can reduce the extent of lethal injury and improve functional recovery. 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 off-the-shelf product is available. Allogeneic cardiosphere-derived cells (CDCs) are available for immediate use and are currently in phase 2 clinical testing for chronic MI. Here we show preliminary data, from both rats and pigs, that CDCs and their exosomes are cardioprotective when given with a reasonable delay after reflow in AMI. We looked at 48 hr structural and functional endpoints to ensure a focus on acute cardioprotection; otherwise it is impossible to exclude some contribution from longer-term regenerative effects of CDCs, which are evident only weeks after treatment. In pigs subjected to 90 mins of ischemia and 30 mins of reflow, the intracoronary infusion of CDCs decreased IS and also reduced the extent of microvascular obstruction. In rats we see large decreases of IS when CDCs are administered 20 mins after a 45 min ischemic episode, a finding now independently confirmed by a major unaffiliated laboratory. We further show preliminary data that implicate macrophages as key players in the mechanism of cardioprotection. The major focus here is on defining the mechanisms whereby CDCs reduce IS. We test the following overarching hypothesis: CDCs secrete exosomes which modify macrophages so as to enhance efferocytosis. Precisely how macrophages are modulated by CDCs (are RNAs transferred by exosomes involved?), and how macrophages mitigate lethal injury, are major questions addressed here. Although we focus on the cardioprotective effects of CDCs, we expect these to synergize with the regenerative effects, augmenting overall benefit. Two well-established animal models will be subjected to AMI: rats for mechanistic studies, and Yucatan minipigs for translational 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 rats to quantify efferocytosis. The work has the potential to elucidate the cardioprotective mechanisms of cell therapy.

项目总结/摘要减少梗死面积（IS）的新方法在翻译中停滞不前。一个主要障碍是，急性心肌梗死（AMI）的临床护理范例有一个主要目标：打开梗死灶，相关的动脉尽快。只有在血流恢复后，治疗医生才可能需要时间思考但到那时，招募经典心脏保护的机会之窗已经占据了大多数。可能会关闭，或者至少会大幅缩小。在这里，我们描述了细胞的新现象，后处理：再灌注后30分钟（或甚至更长时间;定义精确的时间是该R 01的目的）可以降低致死性损伤的程度并改善功能恢复。时机这与标准临床实践相容，因为治疗的决定可以延迟到动脉已经如果有现成的产品，则打开。同种异体心肌球衍生细胞（CDC）目前正在进行慢性心肌梗死的2期临床试验。这里我们展示的是初步数据，从大鼠和猪，CDC和他们的外来体是心脏保护时，给予合理的延迟 AMI再流后。我们研究了48小时的结构和功能终点，以确保重点放在急性心脏保护;否则不可能排除长期再生效应的一些贡献 CDCs，这是明显的，只有在治疗后几周。在经受90分钟缺血和30分钟缺血的猪中，冠脉内输注CDCs降低了IS，也减少了微血管病变的程度。梗阻在大鼠中，当在45分钟缺血后20分钟给予CDC时，我们看到IS大幅下降。这一发现现在被一个主要的独立实验室独立证实。我们进一步显示初步这些数据表明巨噬细胞是心脏保护机制中的关键参与者。这里的主要焦点是确定疾病控制和预防中心减少基础设施服务的机制。我们测试了以下总体假设：分泌修饰巨噬细胞的外泌体，从而增强巨噬细胞的吞噬作用。正是巨噬细胞由CDC调节（RNA是否由外泌体转移？），以及巨噬细胞如何减轻伤害，是这里要解决的主要问题。虽然我们关注CDC的心脏保护作用，期望这些与再生效应协同作用，增加整体效益。两个公认的动物将对模型进行AMI：大鼠用于机制研究，尤卡坦小型猪用于转化研究。的巨噬细胞增多症的作用将通过巨噬细胞、中性粒细胞和应激的心肌细胞，以及通过在转基因大鼠中的体内实验来定量胞浆细胞增多症。工作有可能阐明细胞治疗的心脏保护机制。