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Mesenchymal stem cell-derived exosomal microRNA-367–3p alleviates experimental autoimmune encephalomyelitis via inhibition of microglial ferroptosis by targeting EZH2

Jingyi FanDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaYusen HanDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaHuanhuan SunDepartment of Vascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaShichao SunDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaYing WangDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaRuoyi GuoDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaJiangyuan GuoDepartment of Neurology, Shanxi Provincial People's Hospital, No. 29 Shuangtasi Street, Taiyuan, Hebei 030012, Shanxi, ChinaXin-Yi TianDepartment of Rheumatology and Clinical Immunology, the Affiliated Hospital of Qingdao University, Qingdao, ChinaJinli WangDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaJinli WangDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaJueqiong WangDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, ChinaJueqiong WangDepartment of Neurology, Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, China

2023en

ABI

Annotatsiya

Multiple sclerosis (MS) is an autoimmune, inflammatory demyelinating disorder of the central nervous system. Accumulating evidence has underscored the therapeutic potential of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-Exos) containing bioactive compounds in MS. Herein, the current study sought to characterize the mechanism of BMSC-Exos harboring miR-367-3p both in BV2 microglia by Erastin-induced ferroptosis and in experimental autoimmune encephalomyelitis (EAE), a typical animal model of MS. Exosomes were firstly isolated from BMSCs and identified for further use. BV2 microglia were co-cultured with miR-367-3p-containing BMSC-Exos, followed by an assessment of cell ferroptosis. Mechanistic exploration was furthered by the interaction of miR-367-3p and its downstream regulators. Lastly, BMSC-Exos harboring miR-367-3p were injected into EAE mice for in vivo validation. BMSC-Exos carrying miR-367-3p restrained microglial ferroptosis in vitro. Mechanistically, miR-367-3p could bind to Enhancer of zeste homolog 2 (EZH2) and restrain EZH2 expression, leading to the over-expression of solute carrier family 7 member 11 (SLC7A11). Meanwhile, over-expression of SLC7A11 resulted in Glutathione Peroxidase 4 (GPX4) activation and ferroptosis suppression. Ectopic expression of EZH2 in vitro negated the protective effects of BMSC-Exos. Furthermore, BMSC-Exos containing miR-367-3p relieved the severity of EAE by suppressing ferroptosis and restraining EZH2 expression in vivo. Collectively, our findings suggest that BMSC-Exos carrying miR-367-3p brings about a significant decline in microglia ferroptosis by repressing EZH2 and alleviating the severity of EAE in vivo, suggesting a possible role of miR-367-3p overexpression in the treatment strategy of EAE. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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DOI: 10.1016/j.biopha.2023.114593

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