Yang Huaitao, Chen Jincao
Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, No. 169, Donghu Road, Wuchang District, 430071, Wuhan, Hubei, P.R. China.
Metab Brain Dis. 2022 Oct;37(7):2545-2557. doi: 10.1007/s11011-022-00997-4. Epub 2022 Jul 30.
BACKGROUND/AIM: Bone marrow mesenchymal stem cell (BMSC)-derived exosomes can prevent oxidative stress and inflammation in cerebral ischemia-reperfusion injury. This study intended to assess influences of BMSC-released exosomes on oxidative stress and inflammation following ischemic stroke.
In vitro and in vivo models were developed using oxygen-glucose deprivation/reperfusion (OGD/R) and middle cerebral artery occlusion (MCAO), respectively. After exosome isolation, co-culture experiments of BMSCs or BMSC-derived exosomes and OGD/R-treated BV-2 cells were implemented to evaluate the impacts of BMSCs or BMSC-secreted exosomes on proliferation, inflammation, oxidative stress, and apoptosis. The gain-of-function experiments of ZFAS1 or microRNA (miR)-15a-5p were conducted to investigate the associated mechanisms. Besides, MCAO mice were injected with exosomes from BMSCs overexpressing ZFAS1 for in vivo verification. The binding of ZFAS1 to miR-15a-5p was assessed through dual-luciferase reporter gene assay.
Co-culture with BMSCs accelerated proliferation and downregulated IL-1β, IL-6, and TNF-α in OGD/R-exposed BV-2 cells, accompanied by increased SOD level and decreased MDA level and apoptosis, all of which were nullified by inhibiting exosome secretion. Mechanistically, ZFAS1 bound to miR-15a-5p to negatively orchestrate its expression. In addition, BMSC-released exosomes or BMSC-secreted exosomal ZFAS1 augmented proliferation but reduced oxidative stress, apoptosis, and inflammation in OGD/R-exposed BV-2 cells, whereas these impacts of BMSC-released exosomal ZFAS1 were nullified by overexpressing miR-15a-5p. Moreover, BMSC-derived exosomal ZFAS1 diminished MCAO-induced oxidative stress, cerebral infarction, and inflammation in mice.
Conclusively, BMSC-released exosomes might carry long noncoding RNA ZFAS1 to curb oxidative stress and inflammation related to ischemic stroke, which was possibly realized through miR-15a-5p inhibition.
背景/目的：骨髓间充质干细胞（BMSC）衍生的外泌体可预防脑缺血再灌注损伤中的氧化应激和炎症。本研究旨在评估BMSC释放的外泌体对缺血性中风后氧化应激和炎症的影响。
分别使用氧糖剥夺/再灌注（OGD/R）和大脑中动脉闭塞（MCAO）建立体外和体内模型。分离外泌体后，进行BMSCs或BMSC衍生的外泌体与OGD/R处理的BV-2细胞的共培养实验，以评估BMSCs或BMSC分泌的外泌体对增殖、炎症、氧化应激和细胞凋亡的影响。进行ZFAS1或微小RNA（miR）-15a-5p的功能获得实验以研究相关机制。此外，给MCAO小鼠注射过表达ZFAS1的BMSCs的外泌体进行体内验证。通过双荧光素酶报告基因测定评估ZFAS1与miR-15a-5p的结合。
与BMSCs共培养可加速OGD/R处理的BV-2细胞的增殖并下调IL-1β、IL-6和TNF-α，同时SOD水平升高，MDA水平和细胞凋亡降低，而抑制外泌体分泌可消除所有这些作用。机制上，ZFAS1与miR-15a-5p结合以负向调控其表达。此外，BMSC释放的外泌体或BMSC分泌的外泌体ZFAS1可增强OGD/R处理的BV-2细胞的增殖，但降低氧化应激、细胞凋亡和炎症，而BMSC释放的外泌体ZFAS1的这些作用可通过过表达miR-15a-5p而消除。此外，BMSC衍生的外泌体ZFAS1可减轻MCAO诱导的小鼠氧化应激、脑梗死和炎症。
总之，BMSC释放的外泌体可能携带长链非编码RNA ZFAS1来抑制与缺血性中风相关的氧化应激和炎症，这可能是通过抑制miR-15a-5p实现的。
