Mesenchymal stem cell-derived exosomes for treatment of sepsis.
Mesenchymal stem cell-derived exosomes for treatment of sepsis.
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DOI：
10.3389/fimmu.2023.1136964
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发表时间：
2023
影响因子：
7.3
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中科院分区：
文献类型：
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脓毒症的发病机制是促炎和抗炎反应之间的失衡。在败血症发作时，肺部受到严重影响，损伤进展为急性呼吸窘迫综合征（ARDS），死亡率高达40%。目前，没有有效的治疗败血症。基于大量的临床前数据，使用间充质干细胞（MSC）的细胞疗法已在ARDS和脓毒症的临床试验中启动。然而，仍然存在的问题是，当向患者施用MSC时，可能会造成肿瘤风险。最近的临床前研究已经证明了MSC衍生的细胞外囊泡（EV）用于治疗急性肺损伤（ALI）和脓毒症的有益作用。在恢复初始手术准备后，在麻醉和镇痛下通过支气管镜将铜绿假单胞菌（约1.0×1011 CFU）滴入肺部，在14只成年雌性绵羊中诱导肺炎/脓毒症。损伤后，在ICU环境中，对绵羊进行机械通气并在清醒状态下连续监测24小时。损伤后，将绵羊随机分为两组：对照组，用溶剂治疗的脓毒症绵羊，n=7;治疗组，用MSC-EV治疗的脓毒症绵羊，n=7。伤后1小时静脉输注MSC-EV（4 ml）。MSCs-EV输注耐受性良好，无不良事件。肺损伤后6 ~ 21 h，治疗组PaO 2/FiO 2比值有高于对照组的趋势，但组间差异无统计学意义。其他肺功能两组间无显著性差异。虽然治疗组的血管加压药需求倾向于低于对照组，但随着脓毒症严重程度的进展，两组的净液体平衡相似地增加。反映微血管通透性过高的变量在两组中相当。我们之前已经证明了骨髓来源的MSC（10×106个细胞/kg）在相同的脓毒症模型中的有益作用。然而，尽管肺气体交换有一些改善，但本研究表明，从相同数量的骨髓来源的MSC中分离的EV未能减轻多器官功能障碍的严重程度。
The pathogenesis of sepsis is an imbalance between pro-inflammatory and anti-inflammatory responses. At the onset of sepsis, the lungs are severely affected, and the injury progresses to acute respiratory distress syndrome (ARDS), with a mortality rate of up to 40%. Currently, there is no effective treatment for sepsis. Cellular therapies using mesenchymal stem cells (MSCs) have been initiated in clinical trials for both ARDS and sepsis based on a wealth of pre-clinical data. However, there remains concern that MSCs may pose a tumor risk when administered to patients. Recent pre-clinical studies have demonstrated the beneficial effects of MSC-derived extracellular vesicles (EVs) for the treatment of acute lung injury (ALI) and sepsis. After recovery of initial surgical preparation, pneumonia/sepsis was induced in 14 adult female sheep by the instillation of Pseudomonas aeruginosa (~1.0×1011 CFU) into the lungs by bronchoscope under anesthesia and analgesia. After the injury, sheep were mechanically ventilated and continuously monitored for 24 h in a conscious state in an ICU setting. After the injury, sheep were randomly allocated into two groups: Control, septic sheep treated with vehicle, n=7; and Treatment, septic sheep treated with MSC-EVs, n=7. MSC-EVs infusions (4ml) were given intravenously one hour after the injury. The infusion of MSCs-EVs was well tolerated without adverse events. PaO2/FiO2 ratio in the treatment group tended to be higher than the control from 6 to 21 h after the lung injury, with no significant differences between the groups. No significant differences were found between the two groups in other pulmonary functions. Although vasopressor requirement in the treatment group tended to be lower than in the control, the net fluid balance was similarly increased in both groups as the severity of sepsis progressed. The variables reflecting microvascular hyperpermeability were comparable in both groups. We have previously demonstrated the beneficial effects of bone marrow-derived MSCs (10×106 cells/kg) in the same model of sepsis. However, despite some improvement in pulmonary gas exchange, the present study demonstrated that EVs isolated from the same amount of bone marrow-derived MSCs failed to attenuate the severity of multiorgan dysfunctions.