Engineering Extracellular Vesicles Restore the Impaired Cellular Uptake and Attenuate Intervertebral Disc Degeneration,ACS Nano

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Engineering Extracellular Vesicles Restore the Impaired Cellular Uptake and Attenuate Intervertebral Disc Degeneration
ACS Nano ( IF 15.8 ) Pub Date : 2021-09-03 , DOI: 10.1021/acsnano.1c04514
Zhiwei Liao ₁ , Hui Liu ₁ , Liang Ma ₁ , Jie Lei ₁ , Bide Tong ₁ , Gaocai Li ₁ , Wencan Ke ₁ , Kun Wang ₁ , Xiaobo Feng ₁ , Wenbin Hua ₁ , Shuai Li ₁ , Cao Yang ₁

Affiliation

Extracellular vesicles (EVs) are potential alternatives for mesenchymal stem cells (MSCs) in the treatment of musculoskeletal degenerative diseases, including intervertebral disc degeneration (IDD). Usually, EVs are internalized and then deliver bioactive molecules that impart phenotypic changes in recipient cells. For effective utilization of EVs in the IDD therapy, understanding the mechanism of EV uptake is of vital importance. In this study, we found that EVs delivered antioxidant proteins to protect against pyroptosis of nucleus pulposus cells (NPCs). In particular, the therapeutic effect of EVs decreased in TNF-α-treated NPCs due to the impaired caveolae-mediated endocytosis pathway. Transcriptome sequencing and functional verification revealed that caveolae associated protein 2 (Cavin-2) played an important role in the uptake process of EVs. We then constructed the Cavin-2-modified engineering EVs via the gene-editing of parental MSCs. These kinds of modified EVs presented an improved uptake rate in TNF-α-treated NPCs, which effectively ameliorated the cell death of NPCs in a three-dimensional hydrogel culture model and retarded the progression of IDD in the ex vivo organ culture model. Collectively, these findings illustrate the mechanism of EV uptake in NPCs and explore the application of engineering EVs in the treatment of IDD.

中文翻译：

工程细胞外囊泡恢复受损的细胞摄取并减轻椎间盘退变

细胞外囊泡 (EV) 是间充质干细胞 (MSC) 治疗肌肉骨骼退行性疾病，包括椎间盘退行性变 (IDD) 的潜在替代品。通常，EVs 被内化，然后传递生物活性分子，使受体细胞发生表型变化。为了在 IDD 治疗中有效利用 EV，了解 EV 摄取的机制至关重要。在这项研究中，我们发现 EVs 提供抗氧化蛋白以防止髓核细胞 (NPCs) 的细胞焦亡。特别是，由于细胞膜穴样内陷介导的内吞通路受损，EVs 在 TNF-α 处理的 NPC 中的治疗效果降低。转录组测序和功能验证表明，小窝相关蛋白 2（Cavin-2）在 EV 的摄取过程中发挥了重要作用。通过亲本 MSC 的基因编辑。这些修饰的 EVs 在 TNF-α 处理的 NPCs 中表现出更高的摄取率，在三维水凝胶培养模型中有效地改善了 NPCs 的细胞死亡，并在离体器官培养模型中延缓了 IDD 的进展。总的来说，这些发现说明了 NPC 摄取 EV 的机制，并探索了工程 EV 在治疗 IDD 中的应用。

更新日期：2021-09-28

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