Neural stem cell-derived exosomal FTO protects neuron from microglial inflammatory injury by inhibiting microglia NRF2 mRNA m6A modification

AbstractIschemic stroke (IS) can cause neuronal cell loss and function defects. Exosomes derived from neural stem cells (NSC-Exos) improve neural plasticity and promote neural function repair following IS. However, the potential mechanism remains unclear. In this study, NSC-Exos were characterized and co-cultured with microglia. We found that NSC-Exos increased NRF2 expression in oxygen–glucose deprivation/reoxygenation and LPS-induced microglia and converted microglia from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype. NSC-Exos reduced m6A methylation modification of nuclear factor erythroid 2-related factor 2 (NRF2) mRNA via obesity-associated gene (FTO). Furthermore, NSC-Exos reduced the damage to neurons caused by microglia's inflammatory response. Finally, the changes in microglia polarization and neuron damage caused by FTO knockdown in NSE-Exos were attenuated by NRF2 overexpression in microglia. These findings revealed that NSC-Exos promotes NRF2 expression and M2 polarization of microglial via transferring FTO, thereby resulting in neuroprotective effects.Keywords: NSC-Exosm6AFTONRF2 Author contributionsConception of manuscript: Zhiyong Li, Zhenggang Chen, Jun Peng. Manuscript design and writing: Zhiyong Li. Manuscript reviewing and editing: Zhiyong Li, Zhenggang Chen, Jun Peng. All authors read and agreed to the final version of the manuscript.Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementData sharing not applicable to this article as no datasets were generated or analysed during the current study.Additional informationFundingThis work was supported by High-level Talents Project of Hainan Natural Science Foundation [822RC865] and Hainan Cerebrovascular Disease Clinical Medical Research Center Project [LCYX202309].