Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.
Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.
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DOI：
10.1186/s13287-018-0774-8
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发表时间：
2018-01-29
影响因子：
7.5
通讯作者：
Meulia T
中科院分区：
文献类型：
--
作者：
Khatri M;Richardson LA;Meulia T
间充质干细胞（MSCs）通过分泌包括细胞外囊泡（EVs）在内的旁分泌因子来调节其免疫调节和组织修复功能。在几种人类疾病动物模型中，间充质干细胞- ev模拟了间充质干细胞的有益作用。流感病毒每年引起急性呼吸道疾病的爆发，造成大量的死亡率和发病率。流感病毒不断进化，从而产生耐药菌株，并使现有疫苗对新产生的菌株的效果降低。因此，需要能够控制病毒复制和宿主炎症反应的新疗法。本研究的目的是在临床前模型中检验MSC-EV治疗是否可以减轻流感病毒诱导的急性肺损伤。我们从猪骨髓来源的间充质干细胞中分离出ev。电镜观察msc - ev的形态，流式细胞术检测间充质标记物的表达。接下来，我们在体外肺上皮细胞中检测了msc - ev的抗流感活性，并在猪流感病毒模型中检测了其抗病毒和免疫调节特性。用超离心方法从msc -条件培养基中分离出msc - ev。msc - ev呈圆形，与MSCs相似，表达间充质标记物，缺乏猪白细胞抗原I和II的表达。pkh -26标记的ev与肺上皮细胞孵育发现msc - ev与上皮细胞结合。接下来，我们检测了msc - ev的抗流感和抗炎特性。在1.25 ~ 5 μg/ml浓度下，msc - ev对禽流感病毒、猪流感病毒和人流感病毒的血凝活性有抑制作用。msc - ev抑制流感病毒复制和病毒诱导的肺上皮细胞凋亡。msc - ev的抗流感活性是由于rna从ev转移到上皮细胞，因为用RNase酶预先孵育msc - ev可以消除其抗流感活性。在猪流感病毒模型中，在流感病毒感染后12小时气管内给予msc - ev可显著减少流感感染猪鼻拭子中的病毒脱落、流感病毒在肺部的复制以及病毒诱导的促炎细胞因子的产生。组织病理学结果显示，msc - ev可减轻流感病毒引起的猪肺部病变。我们的数据在相关的流感病毒临床前大型动物模型中证明，msc - ev具有抗流感和抗炎特性，并且ev可用于人类流感的无细胞治疗。
Mesenchymal stem (stromal) cells (MSCs) mediate their immunoregulatory and tissue repair functions by secreting paracrine factors, including extracellular vesicles (EVs). In several animal models of human diseases, MSC-EVs mimic the beneficial effects of MSCs. Influenza viruses cause annual outbreaks of acute respiratory illness resulting in significant mortality and morbidity. Influenza viruses constantly evolve, thus generating drug-resistant strains and rendering current vaccines less effective against the newly generated strains. Therefore, new therapies that can control virus replication and the inflammatory response of the host are needed. The objective of this study was to examine if MSC-EV treatment can attenuate influenza virus-induced acute lung injury in a preclinical model. We isolated EVs from swine bone marrow-derived MSCs. Morphology of MSC-EVs was determined by electron microscopy and expression of mesenchymal markers was examined by flow cytometry. Next, we examined the anti-influenza activity of MSC-EVs in vitro in lung epithelial cells and anti-viral and immunomodulatory properties in vivo in a pig model of influenza virus. MSC-EVs were isolated from MSC-conditioned medium by ultracentrifugation. MSC-EVs were round-shaped and, similarly to MSCs, expressed mesenchymal markers and lacked the expression of swine leukocyte antigens I and II. Incubation of PKH-26-labeled EVs with lung epithelial cells revealed that MSC-EVs incorporated into the epithelial cells. Next, we examined the anti-influenza and anti-inflammatory properties of MSC-EVs. MSC-EVs inhibited the hemagglutination activity of avian, swine, and human influenza viruses at concentrations of 1.25–5 μg/ml. MSC-EVs inhibited influenza virus replication and virus-induced apoptosis in lung epithelial cells. The anti-influenza activity of MSC-EVs was due to transfer of RNAs from EVs to epithelial cells since pre-incubation of MSC-EVs with RNase enzyme abrogated the anti-influenza activity of MSC-EVs. In a pig model of influenza virus, intratracheal administration of MSC-EVs 12 h after influenza virus infection significantly reduced virus shedding in the nasal swabs, influenza virus replication in the lungs, and virus-induced production of proinflammatory cytokines in the lungs of influenza-infected pigs. The histopathological findings revealed that MSC-EVs alleviated influenza virus-induced lung lesions in pigs. Our data demonstrated in a relevant preclinical large animal model of influenza virus that MSC-EVs possessed anti-influenza and anti-inflammatory properties and that EVs may be used as cell-free therapy for influenza in humans.
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影响因子：
24.3
作者：
Herold, Susanne;Becker, Christin;Budinger, G. R. Scott
通讯作者：
Budinger, G. R. Scott
影响因子：
3.3
作者：
Budoni, Manuela;Fierabracci, Alessandra;Muraca, Maurizio
通讯作者：
Muraca, Maurizio
间充质基质细胞来源的外泌体的免疫调节作用
影响因子：
4.4
作者：
Chen, Wancheng;Huang, Yukai;Xiao, Yang
通讯作者：
Xiao, Yang
DOI：
10.1152/ajplung.00110.2014
发表时间：
2014-09-01
影响因子：
4.9
作者：
Gotts, Jeffrey E.;Abbott, Jason;Matthay, Michael A.
通讯作者：
Matthay, Michael A.
影响因子：
158.5
作者：
de Jong, MD;Van Cam, B;Farrar, J
通讯作者：
Farrar, J