Exosomes derived from mesenchymal stromal cells (MSCs) have emerged as novel drug and gene delivery tools. Current study aimed to elucidate the potential therapeutic role of human placental MSC (hPLMSC)-derived exosomes carrying AntagomiR-4450 (EXO-AntagomiR-4450) in intervertebral disc degeneration (IDD) progression. Initially, the differentially expressed miRNAs related to IDD were identified by microarray analysis, which provided data predicting the interaction between microRNA-4450 (miR-4450) and zinc finger protein-121 (ZNF121) in IDD. Next, miR-4450 and ZNF121 were elevated or silenced to determine their effects on the damage of nucleus pulposus cells (NPCs) treated with tumor necrosis factor α (TNF-α). The therapeutic effects of EXO-AntagomiR-4450 on NPCs were verified both in vitro and in vivo (15-week-old C57BL/6 male mice); especially gait analysis and fluorescent molecular tomography were used in live mice with IDD. Our results revealed that miR-4450 was highly expressed, while ZNF121 was poorly expressed in IDD patients and NPCs treated with TNF-α. Furthermore, miR-4450 was identified to specifically target ZNF121. In addition, the inhibition of miR-4450 exerted an alleviatory effect on the inflammation, apoptosis, and damage of the NPCs by upregulating ZNF121 (all P < 0.05). Moreover, EXO-AntagomiR-4450 retarded damage of NPCs in vitro, alleviated IDD damage, and ameliorated gait abnormality in vivo (all P < 0.05). hPLMSC-derived exosomes could be a feasible nanovehicle to deliver inhibitory oligonucleotides like AntagomiR-4450 in IDD.

中文翻译：

---

源自携带 AntagomiR-4450 的人胎盘间充质基质细胞的外泌体通过 ZNF121 的上调缓解椎间盘退变。

源自间充质基质细胞 (MSC) 的外泌体已成为新型药物和基因递送工具。目前的研究旨在阐明携带 AntagomiR-4450（EXO-AntagomiR-4450）的人胎盘 MSC（hPLMSC）衍生的外泌体在椎间盘退变（IDD）进展中的潜在治疗作用。最初，通过微阵列分析鉴定了与 IDD 相关的差异表达 miRNA，这提供了预测 IDD 中 microRNA-4450 (miR-4450) 和锌指蛋白-121 (ZNF121) 之间相互作用的数据。接下来，升高或沉默 miR-4450 和 ZNF121 以确定它们对用肿瘤坏死因子 α (TNF-α) 处理的髓核细胞 (NPC) 损伤的影响。EXO-AntagomiR-4450对NPCs的治疗作用在体外和体内得到验证（15周龄的C57BL/6雄性小鼠）；特别是步态分析和荧光分子断层扫描被用于 IDD 的活小鼠。我们的结果表明，miR-4450 在 IDD 患者和接受 TNF-α 治疗的 NPC 中高表达，而 ZNF121 低表达。此外，miR-4450 被鉴定为特异性靶向 ZNF121。此外，抑制 miR-4450 通过上调 ZNF121（所有P  < 0.05)。此外，EXO-AntagomiR-4450在体外延缓了NPCs的损伤，减轻了IDD损伤，并改善了体内步态异常（均P  < 0.05）。hPLMSC 衍生的外泌体可能是一种可行的纳米载体，可在 IDD 中递送抑制性寡核苷酸，如 AntagomiR-4450。