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

被引：121

作者：

Liao, Zhiwei ^{[1
]}

Liu, Hui ^{[1
]}

Ma, Liang ^{[1
]}

Lei, Jie ^{[1
]}

Tong, Bide ^{[1
]}

Li, Gaocai ^{[1
]}

Ke, Wencan ^{[1
]}

Wang, Kun ^{[1
]}

Feng, Xiaobo ^{[1
]}

Hua, Wenbin ^{[1
]}

Li, Shuai ^{[1
]}

Yang, Cao ^{[1
]}

机构：

[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Orthopaed, Wuhan 430022, Peoples R China

来源：

ACS NANO | 2021年 / 15卷 / 09期

基金：

中国国家自然科学基金;

关键词：

extracellular vesicles; mesenchymal stem cells; intervertebral disc degeneration; endocytosis; organ culture; EXOSOMES; ACTIVATION; MECHANISMS; DEATH;

D O I：

10.1021/acsnano.1c04514

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

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.

引用

页码：14709 / 14724

页数：16

共 55 条

[1]

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8 [J].