Intravenously Delivered Mesenchymal Stem Cells Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy
Intravenously Delivered Mesenchymal Stem Cells Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy
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静脉注射的间充质干细胞的全身抗炎作用改善急性心肌梗死和缺血性心肌病中的左心室功能障碍
DOI：
10.1161/circresaha.117.310599
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发表时间：
2017-05-12
影响因子：
20.1
通讯作者：
Epstein, Stephen E.
中科院分区：
文献类型：
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作者：
Luger, Dror;Lipinski, Michael J.;Epstein, Stephen E.
基本原理：几乎所有的间充质干细胞（MSC）研究都假设移植的间充质干细胞的局部心肌效应产生治疗效果。由于很少有静脉给药的MSCs移植到心肌中，研究主要采用直接心肌输送。我们采用了不同的范例。目的：测试静脉给药MSCs是否能减少急性心肌梗死后和缺血性心肌病患者左心室功能障碍，以及这些作用至少部分是由全身抗炎活动引起的。方法和结果：小鼠左前降支闭塞45分钟。在5% O-2条件下长期培养的人间充质干细胞经静脉注射。左室功能通过连续超声心动图评估，2,3,5-三苯四唑氯染色确定梗死面积，荧光激活细胞分选评估细胞组成。在心肌梗死后24小时注射荧光和放射性标记的MSCs (1x10(6))，并将其归巢到心肌损伤区域；然而，心肌只含有总MSCs的一小部分。小鼠心肌梗死后24小时静脉注射2x10(6)个MSCs或生理盐水（每组16只）。第21天，采集血液和脾脏进行荧光活化细胞分选，心脏进行2,3,5-三苯四唑氯化染色。在大梗死（>= 25% LV）的对照组小鼠中发生了不良左室重构和左室射血分数恶化。静脉注射间充质干细胞消除了左室舒张末容积和左室收缩末容积的进行性恶化。骨髓间充质干细胞显著降低心脏和脾脏的自然杀伤细胞和心脏的中性粒细胞。急性心肌梗死前24小时特异性自然杀伤细胞耗竭可显著改善梗死面积、左室射血分数和不良左室重构，这些变化与心脏中性粒细胞减少有关。在缺血性心肌病模型中，心肌梗死后4周的小鼠随机接受尾静脉注射2x10(6)个MSCs，并在第3周（n=16）与PBS对照组（n=16）重复注射。间充质干细胞显著增加左室射血分数，降低左室收缩末期容积。结论：静脉给药MSCs治疗急性心肌梗死可减轻大梗死小鼠左室功能的进行性恶化和不良重构，在缺血性心肌病中，MSCs可改善左室功能，其作用明显部分由全身抗炎活性调节。
Rationale: Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm.Objective: To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post-acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities.Methods and Results: Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O-2, were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1x10(6)) were injected 24 hours post-myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2x10(6) MSCs or saline intravenously 24 hours post-myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (>= 25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre-acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post-myocardial infarction were randomized to tail-vein injection of 2x10(6) MSCs, with injection repeated at week 3 (n=16) versus PBS control (n=16). MSCs significantly increased LV ejection fraction and decreased LV end-systolic volume.Conclusions: Intravenously administered MSCs for acute myocardial infarction attenuate the progressive deterioration in LV function and adverse remodeling in mice with large infarcts, and in ischemic cardiomyopathy, they improve LV function, effects apparently modulated in part by systemic anti-inflammatory activities.