Exosomes Derived from Human Placental Mesenchymal Stromal Cells Carrying AntagomiR-4450 Alleviate Intervertebral Disc Degeneration Through Upregulation of ZNF121.

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  < 0.05). Moreover, EXO-AntagomiR-4450 retarded damage of NPCs in vitro, alleviated IDD damage, and ameliorated gait abnormality in vivo (all  < 0.05). hPLMSC-derived exosomes could be a feasible nanovehicle to deliver inhibitory oligonucleotides like AntagomiR-4450 in IDD.