Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, United States.
Research Center for Translational Medicine, Koç University School of Medicine, Turkey.
Exp Neurol. 2021 Mar;337:113540. doi: 10.1016/j.expneurol.2020.113540. Epub 2020 Nov 29.
Cortical injury, such as stroke, causes neurotoxic cascades that lead to rapid death and/or damage to neurons and glia. Axonal and myelin damage in particular, are critical factors that lead to neuronal dysfunction and impair recovery of function after injury. These factors can be exacerbated in the aged brain where white matter damage is prevalent. Therapies that can ameliorate myelin damage and promote repair by targeting oligodendroglia, the cells that produce and maintain myelin, may facilitate recovery after injury, especially in the aged brain where these processes are already compromised. We previously reported that a novel therapeutic, Mesenchymal Stem Cell derived extracellular vesicles (MSC-EVs), administered intravenously at both 24 h and 14 days after cortical injury, reduced microgliosis (Go et al. 2019), reduced neuronal pathology (Medalla et al. 2020), and improved motor recovery (Moore et al. 2019) in aged female rhesus monkeys. Here, we evaluated the effect of MSC-EV treatment on changes in oligodendrocyte maturation and associated myelin markers in the sublesional white matter using immunohistochemistry, confocal microscopy, stereology, qRT-PCR, and ELISA. Compared to vehicle control monkeys, EV-treated monkeys showed a reduction in the density of damaged oligodendrocytes. Further, EV-treatment was associated with enhanced myelin maintenance, evidenced by upregulation of myelin-related genes and increases in actively myelinating oligodendrocytes in sublesional white matter. These changes in myelination correlate with the rate of motor recovery, suggesting that improved myelin maintenance facilitates this recovery. Overall, our results suggest that EVs act on oligodendrocytes to support myelination and improves functional recovery after injury in the aged brain. SIGNIFICANCE: We previously reported that EVs facilitate recovery of function after cortical injury in the aged monkey brain, while also reducing neuronal pathology (Medalla et al. 2020) and microgliosis (Go et al. 2019). However, the effect of injury and EVs on oligodendrocytes and myelination has not been characterized in the primate brain (Dewar et al. 1999; Sozmen et al. 2012; Zhang et al. 2013). In the present study, we assessed changes in myelination after cortical injury in aged monkeys. Our results show, for the first time, that MSC-EVs support recovery of function after cortical injury by enhancing myelin maintenance in the aged primate brain.
皮质损伤，如中风，会导致神经毒性级联反应，导致神经元和神经胶质细胞迅速死亡和/或损伤。特别是轴突和髓鞘损伤，是导致神经元功能障碍和损伤后功能恢复受损的关键因素。在老年人的大脑中，这些因素可能会加剧，因为白质损伤很普遍。通过靶向少突胶质细胞（产生和维持髓鞘的细胞）来减轻髓鞘损伤并促进修复的治疗方法，可能有助于损伤后的恢复，特别是在这些过程已经受损的老年大脑中。我们之前报道过一种新型治疗药物，间充质干细胞衍生的细胞外囊泡（MSC-EV），在皮质损伤后 24 小时和 14 天静脉给药，可减少小胶质细胞增生（Go 等人，2019 年），减少神经元病变（Medalla 等人，2020 年），并改善运动功能恢复（Moore 等人，2019 年）在老年雌性恒河猴中。在这里，我们使用免疫组织化学、共聚焦显微镜、体视学、qRT-PCR 和 ELISA 评估了 MSC-EV 治疗对亚病变白质中少突胶质细胞成熟和相关髓鞘标记物变化的影响。与载体对照猴子相比，EV 治疗猴子的受损少突胶质细胞密度降低。此外，EV 治疗与髓鞘维持增强有关，这表现在亚病变白质中髓鞘相关基因上调和活跃髓鞘形成的少突胶质细胞增加。这些髓鞘变化与运动恢复速度相关，表明髓鞘维持的改善促进了这种恢复。总的来说，我们的结果表明，EV 作用于少突胶质细胞以支持髓鞘形成，并改善老年大脑损伤后的功能恢复。意义：我们之前报道过 EV 促进老年猴脑皮质损伤后的功能恢复，同时还减少神经元病变（Medalla 等人，2020 年）和小胶质细胞增生（Go 等人，2019 年）。然而，损伤和 EV 对少突胶质细胞和髓鞘的影响在灵长类动物大脑中尚未得到描述（Dewar 等人，1999 年；Sozmen 等人，2012 年；Zhang 等人，2013 年）。在本研究中，我们评估了老年猴子皮质损伤后髓鞘的变化。我们的结果首次表明，MSC-EV 通过增强老年灵长类动物大脑中的髓鞘维持，支持皮质损伤后的功能恢复。
