期刊
ACS NANO
卷 15, 期 9, 页码 14709-14724出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c04514
关键词
extracellular vesicles; mesenchymal stem cells; intervertebral disc degeneration; endocytosis; organ culture
类别
资金
- National Natural Science Foundation of China [82072505, 81902261, 81904020, 81902260, 81772401]
- Application Foundation and Advanced Program of Wuhan Science and Technology Bureau [2019020701011457]
EVs deliver antioxidant proteins to protect against pyroptosis of nucleus pulposus cells; Cavin-2-modified engineering EVs exhibit an improved uptake rate in TNF-alpha-treated NPCs, ameliorating cell death and retarding IDD progression.
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-alpha-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-alpha-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.
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