Exosomal miR ‐221‐3p derived from bone marrow mesenchymal stem cells alleviates endoplasmic reticulum stress‐mediated apoptosis in nucleus pulposus cells via the Nrf2/ HO ‐1 signalling pathway

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Excessive endoplasmic reticulum (ER) stress can lead to apoptosis of nucleus pulposus cells (NPCs), a hallmark of intervertebral disc degeneration (IVDD). Our study aimed to determine whether bone marrow mesenchymal stem cells (BMSCs-exos) alleviate ER stress-related NPC apoptosis through the delivery of miR-221-3p. Human NPCs were stimulated by advanced glycation end products (AGEs) for 24 h to construct a cellular model of ER stress. Exosomes were isolated from BMSCs transfected with miR-NC and miR-221-3p inhibitor and co-cultured together with AGEs in NPCs. MiR-221-3p expression in NPCs was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). The protein levels of ER stress and apoptosis markers and nuclear factor erythroid 2 p45-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway-related molecules in NPCs were measured by western blotting and immunofluorescence staining. The Nrf2 agonist tert-butylhydroquinone (TBHQ) was used to verify whether exosomal miR-221-3p affected ER stress-mediated apoptosis by regulating the Nrf2/HO-1 pathway. MiR-221-3p expression was decreased in AGEs-stimulated NPCs, while co-culture with BMSCs-exos rescued such a decline. AGEs-induced reduction in NPC viability and elevation in cell apoptosis and ER stress were overturned by BMSCs-exos treatment, whereas miR-221-3p knockdown further antagonized these effects of BMSCs-exos. MiR-221-3p knockdown reversed the enhancement of BMSCs-exos on Nrf2 and HO-1 levels and Nrf2 nuclear translocation in AGEs-induced NPCs. Importantly, TBHQ abrogated the promotion of Exos-miR-221-3p inhibitor on ER stress and apoptosis in NPCs. BMSCs-exos reduced ER stress-mediated apoptosis in NPCs by promoting the Nrf2/HO-1 pathway through delivering miR-221-3p.