缺血性心肌病中血液生长内皮细胞衍生的外泌体的心脏保护潜力,European Heart Journal

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缺血性心肌病中血液生长内皮细胞衍生的外泌体的心脏保护潜力
European Heart Journal ( IF 37.6 ) Pub Date : 2023-11-11 , DOI: 10.1093/eurheartj/ehad655.1316
M Wu ₁ , A Wibowo ₁ , L Delrue ₂ , D Veltman ₁ , M Vanhaverbeke ₁ , S Trenson ₁ , H Gillijns ₁ , E Caluwe ₁ , P Pokreisz ₁ , A Luttun ₃ , J Bartunek ₂ , S Janssens ₁

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简介血液生长内皮细胞 (BOEC) 衍生的外泌体可以有效诱导体外血管网络形成，并在皮肤伤口愈合模型中介导治疗性新血管形成。我们假设 BOEC 衍生的外泌体可以增强小鼠缺血再灌注 (I/R) 损伤后的心肌修复。方法在常氧和低氧（1%O2）条件下从严重缺血性心肌病（ICMP）患者的外周血中分离并培养扩增BOEC。通过差速超速离心从培养基中分离外泌体，并通过纳米追踪分析（NTA）和免疫印迹分析确定其大小、数量和表面标记。通过短暂 LAD 结扎 60 分钟然后再灌注诱导心肌梗塞 (MI)。BOEC 衍生的外泌体以小部分（每 10 µl 120x10^8 颗粒）重悬，2.5 µl 将 4 等份在直视下注射到梗死周围区域的心外膜壁中。一个月后，使用 7T Bruckner MRI 和商业软件 Segment 对接受外泌体注射或安慰剂注射的小鼠（分别为 n=10 和 n=8）进行左心室（LV）结构和功能分析。结果 NTA 定量显示外泌体在缺氧培养的 BOEC 培养基中浓度较高。免疫印迹分析证实了外泌体标记物 TSG101 和 Flotilin-1 的强劲表达。心肌内注射外泌体 1 个月后，在边界区接受心肌外泌体注射的小鼠 (n=10) 与接受安慰剂的小鼠 (n=8) 相比，心率、左室容积或左室射血分数相似。然而，体内外泌体转移在MI后介导了有利的结构重塑，具有较低的LV质量指数(p＝0.01)并且在接受外泌体等分试样的所有4个节段中更好地保存了区域壁厚度(p＜0.05)(图)。结论我们的结果表明 BOEC 衍生的外泌体具有良好的梗死后心肌结构重塑作用。外泌体可能构成一种有吸引力的无细胞治疗方式。图

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Cardioprotective potential of exosomes derived from blood outgrowth endothelial cells in ischemic cardiomyopathy

Introduction Blood outgrowth endothelial cell (BOEC)-derived exosomes can effectively induce vascular network formation in vitro and mediate therapeutic neovascularization in a skin wound healing model. We hypothesized that BOEC-derived exosomes can enhance myocardial repair in mice after ischemia-reperfusion (I/R) injury. Methods BOECs were isolated and culture-expanded from peripheral blood of patients with severe ischemic cardiomyopathy (ICMP) in normoxic and hypoxic (1% O2) conditions. Exosomes were isolated from the medium by differential ultracentrifugation, and their size, number, and surface markers were determined by nano tracking analysis (NTA) and immunoblot analysis. Myocardial infarction (MI) was induced via transient LAD ligation for 60 min followed by reperfusion. BOEC-derived exosomes and were resuspended in small fractions (120x10^8 particles per 10 µl) 2.5 µl 4 aliquots were injected under direct vision into the epicardial wall of the peri-infarct region. One month later, left ventricular (LV) structure and function were analyzed using a 7T Bruckner MRI with commercial software Segment in mice that received exosome injections or placebo injections (n=10 and n=8, respectively). Results Quantification of exosomes by NTA showed higher concentrations in the medium of BOECs cultured in hypoxia. Immunoblot analysis confirmed robust expression of exosome markers TSG101 and Flotilin-1. One month after intramyocardial exosome injections, heart rate, LV volumes or LV ejection fraction were similar between mice receiving myocardial exosomes injections (n=10) in the border zone as compared to those receiving placebo (n=8). However, in vivo exosome transfer mediated favorable structural remodeling after MI with lower LV mass indices (p=0.01) and better preserved regional wall thickness in all 4 segments receiving exosomes aliquots (p<0.05) (Figure). Conclusions Our results suggest that BOEC-derived exosomes have favorable post-infarction myocardial structural remodeling. Exosomes may constitute an attractive cell-free therapeutic modality.Figure

更新日期：2023-11-11

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