Zhu Zhaokui, Meng Meng, Mo Sisi, Wang Xinyu, Qiao Lixing
Department of Pediatrics, Zhongda Hospital, The School of Medicine, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Nanjing, 210009, Jiangsu, China.
The School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.
Mol Biotechnol. 2025 Jan 22. doi: 10.1007/s12033-025-01364-1.
Perinatal white matter injury (WMI), which is prevalent in premature infants, involves M2 microglia affecting oligodendrocyte precursor cells (OPCs) through exosomes, promoting OPC growth and reducing WMI. The molecular mechanism of WMI remains unclear, and this study explored the role of M2 microglia-derived exosomes in WMI. A tMCAO rat model was constructed to simulate WMI characteristics in vivo. Cresyl violet staining, neurobehavioral tests, rotarod tests, immunofluorescence and immunochemistry were used to assess the role of exos-derived miR-144-5p in pathological and neurological changes in rats. OGD/R cellular models were constructed to mimic WMI characteristics in vitro. CCK-8, TUNEL, Western blotting and immunofluorescence were used to assess the role of exos-derived miR-144-5p in OPC phenotypes. Rescue assays were used to assess the role of the PTEN/AKT pathway in miR-144-5p-mediated OPC phenotypes. Bioinformatics and mechanistic experiments were used to assess the association of PTEN or KLF12 with miR-144-5p in OPCs. M2-Exos suppressed cerebral injury and facilitated demyelination repair in rats post WMI. M2-Exos suppressed OGD/R-stimulated OPC apoptosis and facilitated OGD/R-stimulated OPC differentiation. M2-Exo-derived miR-144-5p suppressed OGD/R-stimulated OPC apoptosis and facilitated OGD/R-stimulated OPC differentiation. M2-Exo-derived miR-144-5p suppressed cerebral injury and facilitated demyelination repair in rats post WMI. MiR-144-5p suppressed OGD/R-stimulated OPC apoptosis and facilitated OGD/R-stimulated OPC differentiation through PTEN downregulation. MiR-144-5p targeted the KLF12 3'UTR to repress PTEN transcription in OPCs. M2 microglia secrete miR-144-5p to reduce WMI by targeting KLF12 in OPCs, inhibiting PTEN/AKT pathway activity, and offering potential targeted therapeutic insights for WMI.
围产期脑白质损伤（WMI）在早产儿中很常见，涉及M2小胶质细胞通过外泌体影响少突胶质前体细胞（OPC），促进OPC生长并减少WMI。WMI的分子机制尚不清楚，本研究探讨了M2小胶质细胞衍生的外泌体在WMI中的作用。构建tMCAO大鼠模型以在体内模拟WMI特征。采用甲酚紫染色、神经行为测试、转棒试验、免疫荧光和免疫化学来评估外泌体衍生的miR-144-5p在大鼠病理和神经变化中的作用。构建OGD/R细胞模型以在体外模拟WMI特征。采用CCK-8、TUNEL、蛋白质免疫印迹和免疫荧光来评估外泌体衍生的miR-144-5p在OPC表型中的作用。采用拯救实验来评估PTEN/AKT通路在miR-144-5p介导的OPC表型中的作用。利用生物信息学和机制实验来评估PTEN或KLF12与OPC中miR-144-5p的关联。M2外泌体抑制WMI后大鼠的脑损伤并促进脱髓鞘修复。M2外泌体抑制OGD/R刺激的OPC凋亡并促进OGD/R刺激的OPC分化。M2外泌体衍生的miR-144-5p抑制OGD/R刺激的OPC凋亡并促进OGD/R刺激的OPC分化。M2外泌体衍生的miR-144-5p抑制WMI后大鼠的脑损伤并促进脱髓鞘修复。MiR-144-5p通过下调PTEN抑制OGD/R刺激的OPC凋亡并促进OGD/R刺激的OPC分化。MiR-144-5p靶向KLF12的3'UTR以抑制OPC中PTEN的转录。M2小胶质细胞分泌miR-144-5p，通过靶向OPC中的KLF12、抑制PTEN/AKT通路活性来减少WMI，并为WMI提供潜在的靶向治疗思路。
