Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10
Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10
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DOI：
10.1186/s13287-019-1352-4
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发表时间：
2019-08-01
影响因子：
7.5
通讯作者：
Lotvall, Jan
中科院分区：
文献类型：
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作者：
Park, Kyong-Su;Svennerholm, Kristina;Lotvall, Jan
背景：脓毒症仍然是住院患者高死亡率的来源，尽管适当的抗生素治疗。令人鼓舞的是，间充质基质细胞（MSCs）及其产生的细胞外囊泡（EVs）已被证明在包括败血症在内的多种炎症条件下具有抗炎作用。然而，通常从哺乳动物细胞中释放的ev数量相对较少，并且由于程序复杂，高产量的ev分离仍然具有挑战性。为了克服这些限制，可以通过连续挤压细胞产生与ev非常相似的囊泡，之后它们被称为纳米囊泡（NVs）。我们假设msc来源的NVs可以减弱小鼠细菌外膜囊泡（OMVs）诱导的细胞因子风暴，并旨在阐明其机制。方法：从MSCs中通过连续挤压细胞分解产生NVs，然后以密度梯度漂浮。通过透射电镜和纳米颗粒跟踪分析分析了NVs的形态和数量。小鼠腹腔注射大肠杆菌衍生的omv以建立败血症，然后注射2 × 10(9) nv。通过研究细胞浸润和细胞因子的产生来评估腹膜液和血液中的先天性炎症。用近红外成像技术分析了Cy7染料标记的NVs的生物分布。结果：电镜显示nv具有纳米大小的球形，并含有经典的EV标记蛋白。在小鼠实验中，NVs抑制眼部分泌物和体温过低，这是由OMVs腹腔注射引起的全身细胞因子风暴的迹象。此外，NVs显著抑制细胞因子释放进入体循环，以及中性粒细胞和单核细胞在腹膜的浸润。经抗白细胞介素(IL)-10单克隆抗体治疗后，NVs的保护作用明显降低。在生物分布研究中，NVs可扩散至小鼠全身，并在6 h时定位于肺、肝和肾。结论：综上所述，这些数据表明msc衍生的NVs通过上调IL-10的产生对脓毒症小鼠模型有有益作用，提示人工NVs可能是临床上适用于脓毒症患者的新型ev模拟物。
Background: Sepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches. Encouragingly, mesenchymal stromal cells (MSCs) and their produced extracellular vesicles (EVs) have been shown to elicit anti-inflammatory effects in multiple inflammatory conditions including sepsis. However, EVs are generally released from mammalian cells in relatively low amounts, and high-yield isolation of EVs is still challenging due to a complicated procedure. To get over these limitations, vesicles very similar to EVs can be produced by serial extrusions of cells, after which they are called nanovesicles (NVs). We hypothesized that MSC-derived NVs can attenuate the cytokine storm induced by bacterial outer membrane vesicles (OMVs) in mice, and we aimed to elucidate the mechanism involved.Methods: NVs were produced from MSCs by the breakdown of cells through serial extrusions and were subsequently floated in a density gradient. Morphology and the number of NVs were analyzed by transmission electron microscopy and nanoparticle tracking analysis. Mice were intraperitoneally injected with Escherichia coli-derived OMVs to establish sepsis, and then injected with 2 x 10(9) NVs. Innate inflammation was assessed in peritoneal fluid and blood through investigation of infiltration of cells and cytokine production. The biodistribution of NVs labeled with Cy7 dye was analyzed using near-infrared imaging.Results: Electron microscopy showed that NVs have a nanometer-size spherical shape and harbor classical EV marker proteins. In mice, NVs inhibited eye exudates and hypothermia, signs of a systemic cytokine storm, induced by intraperitoneal injection of OMVs. Moreover, NVs significantly suppressed cytokine release into the systemic circulation, as well as neutrophil and monocyte infiltration in the peritoneum. The protective effect of NVs was significantly reduced by prior treatment with anti-interleukin (IL)-10 monoclonal antibody. In biodistribution study, NVs spread to the whole mouse body and localized in the lung, liver, and kidney at 6 h.Conclusions: Taken together, these data indicate that MSC-derived NVs have beneficial effects in a mouse model of sepsis by upregulating the IL-10 production, suggesting that artificial NVs may be novel EV-mimetics clinically applicable to septic patients.