Selenomethionine preconditioned mesenchymal stem cells derived extracellular vesicles exert enhanced therapeutic efficacy in intervertebral disc degeneration

Extracellular vesicles (EVs) derived from Mesenchymal Stromal Cells (MSCs) have shown promising therapeutic potential for multiple diseases, including intervertebral disc degeneration (IDD). Nevertheless, the limited production and unstable quality of EVs hindered the clinical application of EVs in IDD. Selenomethionine (Se -Met), the major form of organic selenium present in the cereal diet, showed various beneficial effects, including antioxidant, immunomodulatory and anti-apoptotic effects. In the current study, Se -Met was employed to treat MSCs to investigate whether Se -Met can facilitate the secretion of EVs by MSCs and optimize their therapeutic effects on IDD. On the one hand, Se -Met promoted the production of EVs by enhancing the autophagy activity of MSCs. On the other hand, Se -Met pretreated MSC -derived EVs (Se-EVs) exhibited an enhanced protective effects on alleviating nucleus pulposus cells (NPCs) senescence and attenuating IDD compared with EVs isolated from control MSCs (C-EVs) in vitro and in vivo . Moreover, we performed a miRNA microarray sequencing analysis on EVs to explore the potential mechanism of the protective effects of EVs. The result indicated that miR-125a-5p is markedly enriched in Se-EVs compared to C-EVs. Further in vitro and in vivo experiments revealed that knockdown of miR-125a-5p in Se-EVs (miR KD -Se-EVs) impeded the protective effects of Se-EVs, while overexpression of miR-125a-5p (miR OE -Se-EVs) boosted the protective effects. In conclusion, Se -Met facilitated the MSC -derived EVs production and increased miR-125a-5p delivery in Se-EVs, thereby improving the protective effects of MSCderived EVs on alleviating NPCs senescence and attenuating IDD.