Background. Mesenchymal stem cell (MSC)-derived exosomes play a critical role in regenerative medicine. Objective. To determine the dose- and time-dependent efficacy of exosomes for treatment of traumatic brain injury (TBI). Methods. Male rats were subjected to a unilateral moderate cortical contusion. In the dose-response study, animals received a single intravenous injection of exosomes (50, 100, 200 µg per rat) or vehicle, with treatment initiated at 1 day after injury. In the therapeutic window study, animals received a single intravenous injection of 100 µg exosomes or vehicle starting at 1, 4, or 7 days after injury. Neurological functional tests were performed weekly after TBI for 5 weeks. Spatial learning was measured on days 31 to 35 after TBI using the Morris water maze test. Results. Compared with the vehicle, regardless of the dose and delay in treatment, exosome treatment significantly improved sensorimotor and cognitive function, reduced hippocampal neuronal cell loss, promoted angiogenesis and neurogenesis, and reduced neuroinflammation. Exosome treatment at 100 µg per rat exhibited a significant therapeutic effect compared with the 50- or 200-µg exosome groups. The time-dependent exosome treatment data demonstrated that exosome treatment starting at 1 day post-TBI provided a significantly greater improvement in functional and histological outcomes than exosome treatments at the other 2 delayed treatments. Conclusions. These results indicate that exosomes have a wide range of effective doses for treatment of TBI with a therapeutic window of at least 7 days postinjury. Exosomes may provide a novel therapeutic intervention in TBI.

中文翻译：

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间充质干细胞衍生的外泌体改善大鼠创伤性脑损伤后的功能恢复：剂量反应和治疗窗口研究

背景。间充质干细胞 (MSC) 衍生的外泌体在再生医学中发挥着关键作用。目标。确定外泌体治疗创伤性脑损伤 (TBI) 的剂量和时间依赖性功效。方法。雄性大鼠遭受单侧中度皮质挫伤。在剂量反应研究中，动物接受单次静脉注射外泌体（每只大鼠 50、100、200 µg）或载体，在受伤后 1 天开始治疗。在治疗窗研究中，动物在受伤后 1、4 或 7 天开始接受单次静脉注射 100 µg 外泌体或载体。TBI 后每周进行神经功能测试，持续 5 周。使用莫里斯水迷宫测试在 TBI 后第 31 至 35 天测量空间学习。结果。与车辆相比，无论剂量和治疗延迟如何，外泌体治疗都显着改善了感觉运动和认知功能，减少了海马神经元细胞损失，促进了血管生成和神经发生，并减少了神经炎症。与 50 或 200 微克外泌体组相比，每只大鼠 100 微克外泌体治疗表现出显着的治疗效果。时间依赖性外泌体治疗数据表明，与其他两种延迟治疗的外泌体治疗相比，在 TBI 后 1 天开始的外泌体治疗在功能和组织学结果方面提供了显着更大的改善。结论。这些结果表明，外泌体具有广泛的治疗 TBI 的有效剂量，治疗窗口至少为伤后 7 天。外泌体可能为 TBI 提供一种新的治疗干预措施。外泌体治疗显着改善感觉运动和认知功能，减少海马神经元细胞损失，促进血管生成和神经发生，并减少神经炎症。与 50 或 200 微克外泌体组相比，每只大鼠 100 微克外泌体治疗表现出显着的治疗效果。时间依赖性外泌体治疗数据表明，与其他两种延迟治疗的外泌体治疗相比，在 TBI 后 1 天开始的外泌体治疗在功能和组织学结果方面提供了显着更大的改善。结论。这些结果表明，外泌体具有广泛的治疗 TBI 的有效剂量，治疗窗口至少为伤后 7 天。外泌体可能为 TBI 提供一种新的治疗干预措施。外泌体治疗显着改善感觉运动和认知功能，减少海马神经元细胞损失，促进血管生成和神经发生，并减少神经炎症。与 50 或 200 微克外泌体组相比，每只大鼠 100 微克外泌体治疗表现出显着的治疗效果。时间依赖性外泌体治疗数据表明，与其他两种延迟治疗的外泌体治疗相比，在 TBI 后 1 天开始的外泌体治疗在功能和组织学结果方面提供了显着更大的改善。结论。这些结果表明，外泌体具有广泛的治疗 TBI 的有效剂量，治疗窗口至少为伤后 7 天。外泌体可能为 TBI 提供一种新的治疗干预措施。