早期单次给予外泌体治疗可提供神经保护作用，并改善创伤性脑损伤和失血性休克猪模型的血脑屏障完整性。
Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock.
机构信息
From the Department of Surgery (A.M.W., U.F.B., J.F.B., B.E.B., R.G.K., N.J.G., K.C., A.Z.S., S.E.D., zH.B.A.), Department of Neuropathology (A.A.), and Department of Bioinformatics and Computational Medicine (G.A.H.), University of Michigan, Ann Arbor; and Department of Neurology (B.B.), Henry Ford Health System, Detroit, Michigan.
出版信息
J Trauma Acute Care Surg. 2020 Feb;88(2):207-218. doi: 10.1097/TA.0000000000002563.
BACKGROUND
Administration of human mesenchymal stem cell (MSC)-derived exosomes can enhance neurorestoration in models of traumatic brain injury (TBI) and hemorrhagic shock (HS). The impact of early treatment with MSC-derived exosomes on brain injury in a large animal model remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on brain swelling and lesion size, blood-based cerebral biomarkers, and blood-brain barrier (BBB) integrity.
METHODS
Female Yorkshire swine were subjected to a severe TBI (12-mm cortical impact) and HS (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or LR + exosomes (1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Cerebral hemodynamics and blood-based biomarkers of brain injury were compared. Immunofluorescence and RNA sequencing with differential gene expression and pathway analysis were used to assess the integrity of the perilesion BBB.
RESULTS
Exosome-treated animals had significantly less (p < 0.05) brain swelling and smaller lesion size. They also had significantly decreased (p < 0.05) intracranial pressures and increased cerebral perfusion pressures. Exosome-treated animals had significantly decreased (p < 0.05) albumin extravasation and significantly higher (p < 0.05) laminin, claudin-5, and zonula occludens 1 levels. Differential gene expression and pathway analysis confirmed these findings. Serum glial fibrillary acidic protein levels were also significantly lower (p < 0.05) in the exosome-treated cohort at the end of the experiment.
CONCLUSION
In a large animal model of TBI and HS, early treatment with a single dose of MSC-derived exosomes significantly attenuates brain swelling and lesion size, decreases levels of blood-based cerebral biomarkers, and improves BBB integrity.
背景
施用人间充质干细胞（MSC）衍生的外泌体可增强创伤性脑损伤（TBI）和出血性休克（HS）模型中的神经修复。早期施用 MSC 衍生的外泌体对大型动物模型中脑损伤的影响尚不清楚。我们旨在评估早期单次外泌体治疗对脑水肿和病变大小、基于血液的脑生物标志物以及血脑屏障（BBB）完整性的影响。
方法
雌性约克夏猪接受严重 TBI（12mm 皮质撞击）和 HS（40%估计总血容量）。休克后 1 小时，动物随机分组（n=5/队列），分别接受乳酸林格氏液（LR；5ml）或 LR+外泌体（5mlLR 中 1×10 个外泌体颗粒）。然后，动物再次经历休克（1 小时），随后进行生理盐水复苏。观察 6 小时后，评估脑水肿（与未受伤侧相比的百分比增加）和病变大小（mm）。比较脑血流动力学和基于血液的脑损伤生物标志物。免疫荧光和 RNA 测序以及差异基因表达和途径分析用于评估病变 BBB 的完整性。
结果
外泌体治疗的动物脑水肿明显减少（p<0.05），病变大小更小。颅内压显著降低（p<0.05），脑灌注压升高。外泌体治疗的动物白蛋白外渗明显减少（p<0.05），层粘连蛋白、claudin-5 和 zonula occludens 1 水平明显升高（p<0.05）。差异基因表达和途径分析证实了这些发现。实验结束时，外泌体治疗组血清胶质纤维酸性蛋白水平也明显降低（p<0.05）。
结论
在 TBI 和 HS 的大型动物模型中，早期施用单次剂量的 MSC 衍生外泌体可显著减轻脑水肿和病变大小，降低基于血液的脑生物标志物水平，并改善 BBB 完整性。
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