MSC-Derived Exosomes Protect Vertebral Endplate Chondrocytes against Apoptosis and Calcification via the miR-31-5p/ATF6 Axis

Lin Xie; Zhenhao Chen; Ming Liu; Weibo Huang; Fei Zou; Xiaosheng Ma; Jie Tao; Jingkang Guo; Xinlei Xia; Feizhou Lyu; Hongli Wang; Chaojun Zheng; Jianyuan Jiang

doi:10.1016/j.omtn.2020.09.026

MSC-Derived Exosomes Protect Vertebral Endplate Chondrocytes against Apoptosis and Calcification via the miR-31-5p/ATF6 Axis

Mol Ther Nucleic Acids. 2020 Sep 26:22:601-614. doi: 10.1016/j.omtn.2020.09.026. eCollection 2020 Dec 4.

Authors

Lin Xie¹, Zhenhao Chen¹, Ming Liu², Weibo Huang¹, Fei Zou¹, Xiaosheng Ma¹, Jie Tao³, Jingkang Guo³, Xinlei Xia¹, Feizhou Lyu^{1

4}, Hongli Wang¹, Chaojun Zheng¹, Jianyuan Jiang¹

Affiliations

¹ Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai 200040, China.
² Department of Orthopedic Surgery, Wuhan Fourth Hospital, Huazhong University of Science and Technology, Wuhan 430000, China.
³ Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200436, China.
⁴ Department of Orthopedic Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 201100, China.

Abstract

Apoptosis and calcification of endplate chondrocytes (EPCs) can exacerbate intervertebral disc degeneration (IVDD). Mesenchymal stem cell-derived exosomes (MSC-exosomes) are reported to have the therapeutic potential in IVDD. However, the effects and related mechanisms of MSC-exosomes on EPCs are still unclear. We aimed to investigate the role of MSC-exosomes on EPCs with a tert-butyl hydroperoxide (TBHP)-induced oxidative stress cell model and IVDD rat model. First, our study revealed that TBHP could result in apoptosis and calcification of EPCs, and MSC-exosomes could inhibit the detrimental effects. We also found that these protective effects were inhibited after miroRNA (miR)-31-5p levels were downregulated in MSC-exosomes. The target relationship between miR-31-5p and ATF6 was tested. miR-31-5p negatively regulated ATF6-related endoplasmic reticulum (ER) stress and inhibited apoptosis and calcification in EPCs. Our in vivo experiments indicated that sub-endplate injection of MSC-exosomes can ameliorate IVDD; however, after miR-31-5p levels were downregulated in MSC-exosomes, these protective effects were inhibited. In conclusion, MSC-exosomes reduced apoptosis and calcification in EPCs, and the underlying mechanism may be related to miR-31-5p/ATF6/ER stress pathway regulation.

Keywords: ATF6; Mesenchymal stem cells; endoplasmic reticulum stress; endplate chondrocytes; exosomes; intervertebral disc degeneration; miR-31-5p.