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Exosomes Derived from Human Placental Mesenchymal Stromal Cells Carrying AntagomiR-4450 Alleviate Intervertebral Disc Degeneration Through Upregulation of ZNF121.
Stem Cells and Development ( IF 2.5 ) Pub Date : 2020-08-14 , DOI: 10.1089/scd.2020.0083
Qiling Yuan 1, 2 , Xinyi Wang 3 , Liang Liu 1 , Yongsong Cai 2 , Xiaoming Zhao 1 , Hongyun Ma 1 , Yingang Zhang 1
Affiliation  

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。
更新日期:2020-08-19
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