Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France.
Department of Research in Radiobiology and Regenerative Medicine, Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France.
Stem Cell Res Ther. 2020 Aug 27;11(1):371. doi: 10.1186/s13287-020-01887-1.
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.
在核事故或恐怖袭击中，人类一旦遭受大剂量辐射，导致急性辐射综合征和死亡，可能会迅速引发大规模伤亡灾难。主要原因是目前尚无有效的治疗方法，尤其是针对辐射诱导的胃肠道综合征。这种综合征是由于黏膜屏障完整性受到破坏，导致严重脱水、失血和败血症。在这项研究中，我们测试了间充质基质细胞（MSC）衍生的细胞外囊泡是否可以减少辐射相关的黏膜屏障损伤，并降低辐射诱导的动物死亡率。
在致死性全身照射（10Gy）后 3、24 和 48 小时，将人 MSC 衍生的细胞外囊泡静脉内给予无胸腺裸鼠。通过形态分析、紧密连接蛋白（闭合蛋白-3）免疫染色和体内 4kDa FITC 标记的葡聚糖通透性评估小肠上皮屏障的完整性。通过定量上皮细胞凋亡（TUNEL 染色）和增殖（Ki67 免疫染色）来确定小肠上皮的更新。使用单向方差分析（ANOVA）和 Tukey 检验进行统计分析。使用 Kaplan-Meier 和 Cox 方法进行小鼠生存的统计分析。
我们证明，MSC 衍生的细胞外囊泡治疗可将接受 10Gy 全身照射的小鼠的即时死亡率风险降低 85%，从而延长其存活时间。这种效果可能归因于 MSC 衍生的细胞外囊泡在减少黏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上皮隐窝细胞的增殖和抑制凋亡来改善小肠上皮的更新。MSC 衍生的细胞外囊泡还通过保留上皮紧密连接处的闭合蛋白-3免疫染色来降低辐射诱导的黏膜通透性。
MSC 衍生的细胞外囊泡促进了暴露于辐射诱导的胃肠道毒性的小鼠的上皮修复和再生，并保持了肠上皮的结构完整性。我们的结果表明，MSC 衍生的细胞外囊泡的给药可能是限制急性辐射综合征的有效治疗方法。
