骨髓间充质干细胞外泌体衍生的微小RNA-216a-5p对脊髓损伤后运动功能、神经元损伤和小胶质细胞炎症的影响
Bone marrow mesenchymal stem cell exosomes-derived microRNA-216a-5p on locomotor performance, neuronal injury, and microglia inflammation in spinal cord injury.
作者信息
Xue Hao, Ran Bo, Li Jie, Wang Guorui, Chen Baolin, Mao Honggang
机构信息
Department of Orthopaedic Medicine, Inner Mongolia Baogang Hospital, Baotou, Mongolia, China.
Orthopaedic Research, Inner Mongolia Medical University, Hohhot, Mongolia, China.
出版信息
Front Cell Dev Biol. 2023 Sep 12;11:1227440. doi: 10.3389/fcell.2023.1227440. eCollection 2023.
MicroRNA-216a-5p (miR-216a-5p) mediates inflammatory responses and neuronal injury to participate in the pathology of spinal cord injury (SCI). This study intended to explore the engagement of bone marrow mesenchymal stem cell exosomes (BMSC-Exo)-derived miR-216a-5p in locomotor performance, neuronal injury, and microglia-mediated inflammation in SCI rats. Rat BMSC or BMSC-Exo was injected into SCI rats. GW4869 treatment was adopted to suppress the exosome secretion from BMSC. Subsequently, miR-216a-5p-overexpressed BMSC-Exo (BMSC-miR-Exo) or negative-control-overexpressed BMSC-Exo (BMSC-NC-Exo) were injected into SCI rats. The injection of BMSC or BMSC-Exo enhanced locomotor performance reflected by Basso, Beattie & Bresnahan score ( < 0.001), and neuronal viability reflected by NeuN cells ( < 0.01), but attenuated neuronal apoptosis reflected by TUNEL positive rate, cleaved-caspase-3 expression, and B-cell leukemia/lymphoma-2 expression ( < 0.05). Additionally, the injection of BMSC or BMSC-Exo suppressed microglia M1 polarization-mediated inflammation reflected by IBA1iNOS cells, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 ( < 0.01). Notably, the effect of BMSC on the above functions was retarded by the GW4869 treatment (most < 0.05). Subsequently, the injection of BMSC-miR-Exo further improved locomotor performance ( < 0.05), while inhibiting neuronal apoptosis ( < 0.05) and microglia M1 polarization-mediated inflammation ( < 0.05) compared to BMSC-NC-Exo. Interestingly, the injection of BMSC-miR-Exo reduced toll-like receptor 4 (TLR4) ( < 0.01), myeloid differentiation factor 88 ( < 0.05), and nuclear factor kappa B (NF-κB) ( < 0.05) expressions versus BMSC-NC-Exo. BMSC-Exo-derived miR-216a-5p enhances functional recovery by attenuating neuronal injury and microglia-mediated inflammation in SCI, which may be attributable to its inhibition of the TLR4/NF-κB pathway.
微小RNA-216a-5p（miR-216a-5p）介导炎症反应和神经元损伤，参与脊髓损伤（SCI）的病理过程。本研究旨在探讨骨髓间充质干细胞外泌体（BMSC-Exo）来源的miR-216a-5p在SCI大鼠运动功能、神经元损伤及小胶质细胞介导的炎症中的作用。将大鼠BMSC或BMSC-Exo注射到SCI大鼠体内。采用GW4869处理抑制BMSC的外泌体分泌。随后，将过表达miR-216a-5p的BMSC-Exo（BMSC-miR-Exo）或过表达阴性对照的BMSC-Exo（BMSC-NC-Exo）注射到SCI大鼠体内。注射BMSC或BMSC-Exo可提高Basso、Beattie和Bresnahan评分所反映的运动功能（<0.001），以及NeuN细胞所反映的神经元活力（<0.01），但可降低TUNEL阳性率、裂解的半胱天冬酶-3表达和B细胞淋巴瘤/白血病-2表达所反映的神经元凋亡（<0.05）。此外，注射BMSC或BMSC-Exo可抑制IBA1/iNOS细胞、肿瘤坏死因子-α、白细胞介素（IL）-1β和IL-6所反映的小胶质细胞M1极化介导的炎症（<0.01）。值得注意的是，GW4869处理削弱了BMSC对上述功能的作用（大多<0.05）。随后，与BMSC-NC-Exo相比，注射BMSC-miR-Exo可进一步改善运动功能（<0.05），同时抑制神经元凋亡（<0.05）和小胶质细胞M1极化介导的炎症（<0.05）。有趣的是，与BMSC-NC-Exo相比，注射BMSC-miR-Exo可降低Toll样受体4（TLR4）（<0.01）、髓样分化因子88（<0.05）和核因子κB（NF-κB）（<0.05）的表达。BMSC-Exo来源的miR-216a-5p通过减轻SCI中的神经元损伤和小胶质细胞介导的炎症来促进功能恢复，这可能归因于其对TLR4/NF-κB通路的抑制作用。
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