Extracellular vesicles derived from mesenchymal stem cells confer protection against intervertebral disc degeneration through a microRNA-217-dependent mechanism

Objective: Extracellular vesicles released by mesenchymal stem cells (MSC-EVs) can be applied to alle-viate intervertebral disc degeneration (IVDD) by curbing apoptosis of nucleus pulposus cells (NPCs). The current study aims to evaluate the effect of MSC-EVs on NPC apoptosis and IVDD and the related reg-ulatory mechanisms involving microRNA (miR)-217.Method: Expression of miR-217 was examined in tumor necrosis factor -a (TNF-a)-induced NPCs and MSC-EVs, followed by identification in the relationship between miR-217, enhancer of zeste homolog 2 (EZH2) and forkhead box O-3 (FOXO3). After isolation of EVs from MSCs and subsequent co-culture with NPCs, we assessed effects of miR-217 on NPC viability, autophagy, senescence and apoptosis along with extracellular matrix (ECM) degradation. Further in vivo experiments were conducted in rat models of IVDD to substantiate the effect of miR-217 on IVDD.Results: Poor miR-217 expression was found in TNF-a-induced NPCs, while high miR-217 expression was identified in MSC-EVs (P < 0.05). MSC-EVs transferred miR-217 to NPCs and increased its expression, thus attenuating NPC apoptosis and ECM degradation (elevated collagen II and aggrecan but reduced MMP13 and ADAMTS5) (P < 0.05). miR-217 targeted EZH2, and EZH2 bound to the FOXO3 promoter and consequently downregulated its expression. FOXO3 restrained NPC apoptosis and ECM degradation by stimulating cell autophagy (P < 0.05). Furthermore, in vivo experimental results confirmed the sup-pressive role of miR-217 shuttled by MSC-EVs in IVDD.Conclusion: Overall, the delivery of miR-217 may be a novel mechanism underlying the effect of MSC-EVs on NPC apoptosis and ECM degradation following IVDD. (c) 2022 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Automated summary

MSC-EVs can alleviate intervertebral disc degeneration (IVDD) by transferring miR-217 to nucleus pulposus cells (NPCs), which inhibits NPC apoptosis and extracellular matrix (ECM) degradation. MiR-217 targets EZH2 and downregulates FOXO3 expression, leading to increased cell autophagy and reduced NPC apoptosis and ECM degradation.