Huang Zhonghai, Li Jing, Wo Jin, Li Cheng-Lin, Wu Zi-Cong, Deng Xiao-Hui, Liang Yaying, Li Fuxiang, Chen Boli, Jia Bin, Wang Lu, Wang Ying, Sun Guodong, Li Zhizhong, Zhu Hui, Guest James D, So Kwok-Fai, Fu Qing-Ling, Zhou Libing
Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, China.
Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangdong Key Laboratory of Non-Human Primate Research, Jinan University, Guangzhou, China.
J Extracell Vesicles. 2025 Apr;14(4):e70066. doi: 10.1002/jev2.70066.
Besides surgical decompression, neuroprotection and neuroinflammation reduction are critical for acute spinal cord injury (SCI). In this study, we prepared small extracellular vesicles (sEVs) from immortalised mesenchymal stem cells overexpressing brain-derived neurotrophic factor (BDNF) and evaluated whether intranasal administration of BDNF-sEVs is a therapeutic option for acute SCI. In cultured neurons, BDNF loading enhanced neurite outgrowth promoted by sEVs. After intranasal administration, mCherry-labelled sEVs were transported to the injured spinal cords of rats and monkeys and mainly taken up by neurons. In acute SCI rats, intranasal administration of sEVs and BDNF-sEVs reduced glial responses and proinflammatory cytokine production, enhanced neuronal survival and angiogenesis in the lesion, promoted injured axon rewiring, delayed lumbar spinal motoneuron atrophy below the lesion, and improved functional performance. The rats receiving BDNF-sEV treatment showed improved neural repair and functional recovery compared to those with sEV treatment. Intranasal administration of BDNF-sEVs, but not of sEVs, increased BDNF levels and phosphorylation of downstream signals in the rat-injured spinal cord samples, indicating activation of the BDNF/TrkB signalling pathway. In acute SCI monkeys, intranasal administration of BDNF-sEVs was further confirmed to inhibit glial reactivities and proinflammatory cytokine release, increasing BDNF levels in the cerebrospinal fluid, enhancing neural network rewiring of injured spinal cords and neuronal activities of the brain, and improving functional performances in behavioural tests and electrophysiological recordings. In conclusion, BDNF-sEVs play a combinatory therapeutic role of sEVs and BDNF, and intranasal administration of BDNF-sEVs is a potential option for the clinical treatment of acute SCI.
除了手术减压外，神经保护和减轻神经炎症对急性脊髓损伤（SCI）至关重要。在本研究中，我们从过表达脑源性神经营养因子（BDNF）的永生化间充质干细胞中制备了小细胞外囊泡（sEVs），并评估经鼻给予BDNF-sEVs是否是急性SCI的一种治疗选择。在培养的神经元中，BDNF负载增强了sEVs促进的神经突生长。经鼻给药后，mCherry标记的sEVs被转运至大鼠和猴子的损伤脊髓，主要被神经元摄取。在急性SCI大鼠中，经鼻给予sEVs和BDNF-sEVs可减少胶质细胞反应和促炎细胞因子产生，增强损伤部位的神经元存活和血管生成，促进损伤轴突重新布线，延缓损伤平面以下腰段脊髓运动神经元萎缩，并改善功能表现。与接受sEV治疗的大鼠相比，接受BDNF-sEV治疗的大鼠神经修复和功能恢复更好。经鼻给予BDNF-sEVs而非sEVs可增加大鼠损伤脊髓样本中的BDNF水平和下游信号的磷酸化，表明BDNF/TrkB信号通路被激活。在急性SCI猴子中，经鼻给予BDNF-sEVs进一步证实可抑制胶质细胞反应性和促炎细胞因子释放，增加脑脊液中的BDNF水平，增强损伤脊髓的神经网络重新布线和大脑的神经元活动，并改善行为测试和电生理记录中的功能表现。总之，BDNF-sEVs发挥了sEVs和BDNF的联合治疗作用，经鼻给予BDNF-sEVs是急性SCI临床治疗的一种潜在选择。
