Department Two of Spine, Luoyang Orthopedic-Traumatological Hospital of Henan Province (Henan Provincial Orthopedic Hospital), Luoyang, 471000, Henan, PR China.
Hunan University of Chinese Medicine, Changsha, 410208, Hunan, PR China.
Brain Res Bull. 2021 May;170:199-210. doi: 10.1016/j.brainresbull.2021.02.015. Epub 2021 Feb 17.
Spinal cord injury (SCI) may cause loss of locomotor function, and macrophage is a major cell type in response to SCI with M1- and M2-phenotypes. The protective role of bone marrow mesenchymal stem cells (BMMSC)-derived exosomes (B-Exo) in SCI has been underscored, while their regulation on M2 macrophage polarization and the mechanism remain to be clarified.
A rat model of SCI was developed and treated with extracted B-Exo. Recovery of motor function was assessed by Basso-Beattie-Bresnahan (BBB) score. The apoptosis and degeneration of neurons, and macrophage polarization were evaluated. Subsequently, genes differentially expressed in the rat spinal cord after B-Exo treatment were analyzed. Later, the relationships between B-Exo and interferon regulatory factor 5 (IRF5) or macrophage polarization were clarified. Later, the upstream microRNAs (miRNAs) of IRF5 were validated by bioinformatics prediction and dual-luciferase experiments. Finally, the role of miR-125a in the neuroprotection of SCI was verified by rescue experiments.
B-Exo promoted the recovery of locomotor function and M2-phenotype polarization, whereas inhibited neuronal apoptosis and degeneration and the inflammatory response caused by SCI in rats. In addition, IRF5 expression was reduced after B-Exo treatment. IRF5 promoted macrophage polarization towards M1-phenotype and secretion of inflammatory factors. There is a binding relationship between miR-125a and IRF5. Knockdown of miR-125a in B-Exo increased IRF5 expression in spinal cord tissues of SCI rats and attenuated the neuroprotective effect of B-Exo against SCI.
Exosomal miR-125a derived from BMMSC exerts neuroprotective effects by targeting and negatively regulating IRF5 expression in SCI rats.
脊髓损伤（SCI）可能导致运动功能丧失，巨噬细胞是对 SCI 产生反应的主要细胞类型，具有 M1 和 M2 表型。骨髓间充质干细胞（BMMSC）衍生的外泌体（B-Exo）在 SCI 中的保护作用已得到强调，但其对 M2 巨噬细胞极化的调节及其机制仍需阐明。
建立 SCI 大鼠模型，并用提取的 B-Exo 进行治疗。通过 Basso-Beattie-Bresnahan（BBB）评分评估运动功能的恢复。评估神经元的凋亡和变性以及巨噬细胞的极化。随后，分析大鼠脊髓在 B-Exo 处理后差异表达的基因。之后，阐明 B-Exo 与干扰素调节因子 5（IRF5）或巨噬细胞极化之间的关系。之后，通过生物信息学预测和双荧光素酶实验验证 IRF5 的上游 microRNAs（miRNAs）。最后，通过挽救实验验证 miR-125a 在 SCI 神经保护中的作用。
B-Exo 促进了大鼠运动功能的恢复和 M2 表型的极化，同时抑制了 SCI 引起的神经元凋亡和变性以及炎症反应。此外，B-Exo 处理后 IRF5 的表达降低。IRF5 促进巨噬细胞向 M1 表型极化和炎症因子的分泌。miR-125a 与 IRF5 之间存在结合关系。在 SCI 大鼠脊髓组织中敲低 miR-125a 会增加 B-Exo 中的 IRF5 表达，并减弱 B-Exo 对 SCI 的神经保护作用。
BMMSC 衍生的外泌体 miR-125a 通过靶向和负调控 SCI 大鼠中 IRF5 的表达发挥神经保护作用。
