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MSC-Derived Exosomes Ameliorate Intervertebral Disc Degeneration By Regulating the Keap1/Nrf2 Axis

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Abstract

Bone marrow mesenchymal stem cell derived exosomes (BMSC-exos) are a crucial means of intercellular communication and can regulate a range of biological processes by reducing inflammation, decreasing apoptosis and promoting tissue repair. The process of intervertebral disc degeneration (IVDD) is accompanied by increased reactive oxygen species (ROS) because of a decrease in the expression of Nrf2, a critical transcription factor that resists excessive ROS. Our study demonstrated that BMSC-exos decreased ROS production by inhibiting Keap1 and promoting Nrf2 expression, attenuating the apoptosis, inflammation, and degeneration of nucelus pulposus (NP) cells. BMSC-exos promoted an increase in Nrf2 and nuclear translocation, while NF-κB expression was downregulated during this process. Additionally, the expression of antioxidative proteins was elevated after treatment with BMSC-exos. In vivo, we found more NP tissue retention in the BMSC-exos-treated group, along with more expression of Nrf2 and antioxidant-related proteins. Our findings demonstrated for the first time that BMSC-exos could restore the down-regulated antioxidant response system in degenerating NP cells by modulating the Keap1/Nrf2 axis. BMSC-exos could be used as an immediate ROS modulator in the treatment of intervertebral disc degeneration.

Graphical Abstract

When BMSC-exos were uptaken by NPCs, the expression of Keap1 decreased and this led to increased expression of Nrf2. Nuclear translocation of Nrf2 then promoted the synthesis of antioxidants against ROS and inhibited NF-kB signalling. Cellular inflammation, apoptosis, and ECM-related indicators were further reduced. Together, the process of IVDD was alleviated

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Data Availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Code Availability

Not applicable.

Abbreviations

BMSC-exos :

Bone marrow mesenchymal stem cell derived exosomes

DAPI :

4′,6-diamidino-2-phenylindole

DHI :

Disc height index

DMEM :

Dulbecco’s modified Eagle’s medium

ECM :

Extracellular matrix

FBS :

Foetal bovine serum

HO-1 :

Heme-oxygenase-1

IVDD :

Intervertebral disc degeneration

Keap1 :

Kelch-like ECH-associated protein 1

NP :

Nucleus pulposus

NQO1 :

NADP(H) quinone oxidoreductase 1

Nrf2 :

Transcription factor nuclear factor erythroid-2 related factor 2

ROS :

Reactive oxygen species

SODs :

Superoxide dismutases

TEM :

Transmission electron microscopy

8-OHdG :

8-Hydroxy-1,2 deoxyguanosine

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Acknowledgements

We thanked Professor Mingxia Fan, the director of Key Laboratory of Magnetic Resonance, East China Normal University, for her help in the MRI of rat tails.

Funding

This work was supported by Shanghai Sailing Program, Shanghai, China (20YF1429900); National Natural Science Foundation of China, China (81972093, 81972109, 82102620, 82172490 and 82272549).

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Author notes

  1. Gungayu Xu, Xiao Lu and Siyang Liu contributed equally.

Authors and Affiliations

  1. Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Guangyu Xu, Xiao Lu, Siyang Liu, Yuxuan Zhang, Xiaosheng Ma, Xinlei Xia, Feizhou Lu, Fei Zou, Hongli Wang, Jian Song & Jianyuan Jiang

  2. Department of Orthopedics, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, 200240, China

    Shun Xu & Feizhou Lu

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  1. Guangyu Xu
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Contributions

JS, JYJ, HLW, FZ designed the experiments. GYX, XL, SYL, YXZ, SX and FZ performed the experiments and acquired the data. GYX, XL, XLX and XSM analysed the data. GYX, SYL and FZL supervised the project and wrote the manuscript.

Corresponding authors

Correspondence to Jian Song or Jianyuan Jiang.

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The study was approved by the Ethics Committee of Huashan Hospital, Fudan University (2022-042) and the procedures followed were in accordance with the Helsinki Declaration.

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The nucleus pulposus tissue were collected after obtaining informed consent from the donors.

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Xu, G., Lu, X., Liu, S. et al. MSC-Derived Exosomes Ameliorate Intervertebral Disc Degeneration By Regulating the Keap1/Nrf2 Axis. Stem Cell Rev and Rep 19, 2465–2480 (2023). https://doi.org/10.1007/s12015-023-10570-w

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