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

• Published in: Biomedicine & pharmacotherapy Vol. 162; p. 114593
• Main Authors: Fan, Jingyi, Han, Yusen, Sun, Huanhuan, Sun, Shichao, Wang, Ying, Guo, Ruoyi, Guo, Jiangyuan, Tian, Xinyi, Wang, Jinli, Wang, Jueqiong
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.06.2023; Elsevier
• Subjects: Animals; Bone mesenchymal stem cells; Encephalomyelitis, Autoimmune, Experimental - metabolism; Enhancer of Zeste Homolog 2 Protein - metabolism; Exosome; Experimental autoimmune encephalomyelitis; EZH2; Ferroptosis; Mesenchymal Stem Cells - metabolism; Mice; Microglia - metabolism; MicroRNA-367–3p; MicroRNAs - metabolism; SLC7A11; Exosome; MicroRNA-367–3p; Experimental autoimmune encephalomyelitis; Bone mesenchymal stem cells; Ferroptosis; SLC7A11; EZH2
• DOI: 10.1016/j.biopha.2023.114593
• ISSN: 0753-3322

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. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. •Mesenchymal stem cell-derived exosomes (BMSC-Exos) suppress microglial ferroptosis•BMSC-Exos carrying miR-367–3p inhibit microglial ferroptosis via EZH2/SLC7A11 axis.•BMSC-Exos carrying miR-367–3p alleviate the severity of experimental autoimmune encephalomyelitis.•The role of BMSC-Exos carrying miR-367–3p in experimental autoimmune encephalomyelitis may be through the regulation of EZH2/SLC7A11-mediated ferroptosis.