Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss, and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24, and 48 h after lethal whole-body irradiation (10 Gy). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3), and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. We demonstrated that MSC-derived extracellular vesicle treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Gy whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.

中文翻译：

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源自间充质基质细胞的细胞外囊泡减轻了急性辐射综合征小鼠模型的肠道毒性。

如果发生核事故或恐怖主义，人类暴露于高剂量辐射会导致急性辐射综合症和死亡，并可能迅速升级为大规模伤亡灾难。主要原因是目前没有有效的治疗选择，特别是对于辐射引起的胃肠综合征。该综合征是由于粘膜屏障完整性破坏导致严重脱水、失血和败血症所致。在这项研究中，我们测试了源自间充质基质细胞 (MSC) 的细胞外囊泡是否可以减少与辐射相关的粘膜屏障损伤并降低辐射引起的动物死亡率。在致死性全身照射 (10 Gy) 后 3、24 和 48 小时，将人 MSC 衍生的细胞外囊泡静脉内给药于 NUDE 小鼠。小肠上皮屏障的完整性通过形态学分析、紧密连接蛋白 (claudin-3) 的免疫染色以及对 4 kDa FITC 标记的葡聚糖的体内渗透性进行评估。通过量化上皮细胞凋亡（TUNEL 染色）和增殖（Ki67 免疫染色）来确定小肠上皮细胞的更新。使用单向 ANOVA 进行统计分析，然后进行 Tukey 检验。使用 Kaplan-Meier 和 Cox 方法对小鼠存活率进行统计分析。我们证明，MSC 衍生的细胞外囊泡治疗使接受 10 Gy 全身照射的小鼠的瞬时死亡风险降低了 85%，从而延长了它们的存活时间。这种效果可归因于 MSC 衍生的细胞外囊泡在减少粘膜屏障破坏方面的功效。我们表明，MSC 衍生的细胞外囊泡通过刺激增殖和抑制上皮隐窝细胞的凋亡来改善小肠上皮细胞的更新。MSC 衍生的细胞外囊泡还降低了辐射诱导的粘膜通透性，上皮紧密连接处 claudin-3 免疫染色的保存证明了这一点。MSC 衍生的细胞外囊泡促进上皮修复和再生，并保持暴露于辐射引起的胃肠道毒性的小鼠肠上皮的结构完整性。我们的结果表明，施用 MSC 衍生的细胞外囊泡可能是限制急性放射综合征的有效疗法。