BMSC-derived exosomal miR-219-5p alleviates ferroptosis in neuronal cells caused by spinal cord injury via the UBE2Z/NRF2 pathway

•BMSC-exosomes inhibit ferroptosis and alleviate spinal cord injury in rats.•BMSC-exosomes inhibit ferroptosis of neuronal cells PC12.•BMSC-exosomes inhibits ferroptosis in PC12 cells by regulating NRF2.•BMSC- exosomes regulates NRF2 protein stability through miR-219-5p.•UBE2Z plays a role in the re...

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Published in:Neuroscience 2024-09, Vol.556, p.73-85
Main Authors: Dong, Junjie, Gong, Zhiqiang, Bi, Hangchuan, Yang, Jin, Wang, Bing, Du, Kaili, Zhang, Chunqiang, Chen, Lingqiang
Format: Article
Language:English
Subjects:
Ferroptosis
miR-219-5p
NRF2
Spinal cord injury
UBE2Z
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Summary:•BMSC-exosomes inhibit ferroptosis and alleviate spinal cord injury in rats.•BMSC-exosomes inhibit ferroptosis of neuronal cells PC12.•BMSC-exosomes inhibits ferroptosis in PC12 cells by regulating NRF2.•BMSC- exosomes regulates NRF2 protein stability through miR-219-5p.•UBE2Z plays a role in the regulation of NRF2 by miR-219-5p. The aim of this study was to investigate the molecular mechanism of exosomal miR-219-5p derived from bone marrow mesenchymal stem cells (BMSCs) in the treatment of spinal cord injury (SCI). Basso Beattie Bresnahan (BBB) score and tissue staining were used to assess SCI and neuronal survival in rats. The contents of Fe2+, malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were detected by a kit. The expression levels of ubiquitin-conjugating enzyme E2 Z (UBE2Z), nuclear factor erythroid 2-related Factor 2 (NRF2) and ferroptosis-related proteins were detected by Western blotting. In addition, the ability of BMSC-derived exosomes to inhibit ferroptosis in neuronal cells in rats with SCI was validated by in vivo injection of ferroptosis inhibitors/inducers. In this study, we found that miR-219-5p-rich BMSC-derived exosomes inhibited ferroptosis in SCI rats and that the alleviating effect of BMSC-Exos on SCI was achieved by inhibiting the ferroptosis signaling pathway and that NRF2 played a key role in this process. Our study confirmed that BMSC exosome-specific delivery of miR-219-5p can target UBE2Z to regulate its stability and that overexpression of UBE2Z reverses miR-219-5p regulation of NRF2. In addition, in vivo experiments showed that BMSC exosomes alleviated ferroptosis in neuronal SCI progression, and inhibiting the expression of miR-219-5p in BMSCs reduced the alleviating effect of exosomes on ferroptosis in neuronal cells and SCI. miR-219-5p in BMSC-derived exosomes can repair the injured spinal cord. In addition, miR-219-5p alleviates ferroptosis in neuronal cells induced by SCI through the UBE2Z/NRF2 pathway.
ISSN:0306-4522
1873-7544
1873-7544
DOI:10.1016/j.neuroscience.2024.06.011