From the Department of Surgery (A.M.W., Z.W., U.F.B., B.E.B., M.T.K., G.K.W., C.A.V., K.C., A.Z.S., Z.P., S.E.D., Y.T., B.L., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan; Xiangya 2nd Hospital of Central South University (Z.W.), Changsha, Hunan, China; and Department of Neurology (B.B.), Henry Ford Health System, Detroit, Michigan.
J Trauma Acute Care Surg. 2020 Aug;89(2):388-396. doi: 10.1097/TA.0000000000002698.
Early single-dose treatment with human mesenchymal stem cell-derived exosomes promotes neuroprotection and promotes blood-brain barrier integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7 days), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model.
Yorkshire swine were subjected to a severe TBI (8-mm cortical impact) and HS (40% estimated total blood volume). After 1 hour of shock, animals were randomized (n = 4/cohort) to receive either lactated Ringer's (5 mL) or lactated Ringer's with exosomes (1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (brain-derived neurotrophic factor) in brain tissue were compared between groups.
Exosome-treated animals had significantly lower neurologic severity scores (first 4 days; p < 0.05) and faster neurologic recovery. At 7 days, exosome-treated animals had significantly smaller (p < 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (interleukin [IL]-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony-stimulating factor levels compared with the control animals, indicating specific impacts on various cytokines. The BAX and NF-κB levels were significantly lower (p < 0.05) in exosome-treated animals, while brain-derived neurotrophic factor levels were significantly higher (p < 0.05) in the exosome-treated animals.
In a large animal model of TBI and HS, early single-dose exosome treatment attenuates neurologic injury, decreases brain lesion size, inhibits inflammation and apoptosis, and promotes neural plasticity over a 7-day period.
早期单次剂量的人骨髓间充质干细胞衍生的外泌体治疗可促进创伤性脑损伤（TBI）和猪出血性休克（HS）模型中的神经保护作用，并促进血脑屏障完整性。然而，早期单次剂量的外泌体对晚期存活（7 天）的影响尚不清楚。我们试图评估早期单次剂量外泌体治疗对 7 天存活模型中神经功能结局、脑损伤大小、炎症细胞因子、细胞凋亡标志物和神经可塑性介质的影响。
将约克夏猪进行严重 TBI（8-mm 皮质撞击）和 HS（估计总血容量的 40%）。在休克 1 小时后，动物随机（n = 4/队列）接受乳酸林格氏液（5 mL）或乳酸林格氏液加外泌体（1×10 个外泌体颗粒）。在休克再额外 1 小时后，动物用生理盐水复苏。比较每日神经严重程度评分。在损伤后 7 天，比较各组之间的脑损伤大小、炎症标志物和炎症介质（NF-κB）、细胞凋亡（BAX）和神经可塑性（脑源性神经营养因子）。
外泌体治疗组动物的神经严重程度评分（前 4 天；p < 0.05）明显更低，神经恢复更快。在 7 天时，外泌体治疗组动物的脑损伤明显较小（p < 0.05）。与对照组相比，外泌体治疗组动物的炎症标志物（白细胞介素[IL]-1、IL-6、IL-8 和 IL-18）水平显著降低，粒细胞巨噬细胞集落刺激因子水平显著升高，表明对各种细胞因子有特定的影响。外泌体治疗组的 BAX 和 NF-κB 水平明显降低（p < 0.05），而脑源性神经营养因子水平明显升高（p < 0.05）。
在 TBI 和 HS 的大动物模型中，早期单次剂量的外泌体治疗可减轻神经损伤，减小脑损伤大小，抑制炎症和细胞凋亡，并在 7 天内促进神经可塑性。
