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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Urolithin a alleviates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells through SIRT1/PGC-1α pathway
Peng-Zhi Shi, Jun-Wu Wang, Ping-Chuan Wang, Bo Han, Xu-Hua Lu, Yong-Xin Ren, Xin-Min Feng, Xiao-Fei Cheng, Liang Zhang
Peng-Zhi Shi, Department of Orthopedic, Dalian Medical University, Dalian 116000, Liaoning Province, China
Jun-Wu Wang, Ping-Chuan Wang, Xin-Min Feng, Liang Zhang, Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
Bo Han, Department of Orthopedic, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
Xu-Hua Lu, Department of Orthopedics, Changzheng Hospital of The Second Military Medical University, Shanghai 200003, China
Yong-Xin Ren, Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Xiao-Fei Cheng, Department of Orthopedic Surgery, Shanghai Key Laboratory of Orthopedics Implants, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China
Author contributions: Shi PZ and Wang JW contributed to data curation, Writing- Original draft preparation, contributed equally to this work; Wang PC contributed to Visualization, Validation; Han B performed Investigation; Lu XH, Ren YX and Feng XM performed conceptualization, methodology; Cheng XF and Zhang L performed supervision, writing- reviewing, editing and share corresponding author.
Supported by National Natural Science Foundation of China, No. 81972136; Young Medical Scholars Major Program of Jiangsu Province, No. QNRC2016342; Key Funding Project of Maternal and Child Health Research of Jiangsu Province, No. F201801; and High-level Health Professionals "Six projects" Top-notch Talent Research Program of Jiangsu Province, No. LGY2019035.
Institutional review board statement: This study was approved by the Ethical Committee of the Clinical Medical College of Yangzhou University (SBYY2020-023).
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (Shanghai Institute of Family Planning Science, License No. SCXK (Hu) 2018-0006).
Conflict-of-interest statement: The authors have no relevant financial or non-financial interests to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Liang Zhang, Doctor, PhD, Chief Doctor, Professor, Surgeon, Department of Orthopedics, Clinical Medical College of Yangzhou University, No. 98 Nantong west Road, Yangzhou 225000, Jiangsu Province, China. zhangliang6320@sina.com
Received: July 2, 2021
Peer-review started: July 2, 2021
First decision: July 29, 2021
Revised: August 12, 2021
Accepted: November 28, 2021
Article in press: November 28, 2021
Published online: December 26, 2021
BACKGROUND
In degenerative intervertebral disc (IVD), an unfavorable IVD environment leads to increased senescence of nucleus pulposus (NP)-derived mesenchymal stem cells (NPMSCs) and the inability to complete the differentiation from NPMSCs to NP cells, leading to further aggravation of IVD degeneration (IDD). Urolithin A (UA) has been proven to have obvious effects in delaying cell senescence and resisting oxidative stress.
AIM
To explore whether UA can alleviate NPMSCs senescence and to elucidate the underlying mechanism.
METHODS
In vitro, we harvested NPMSCs from rat tails, and divided NPMSCs into four groups: the control group, H2O2 group, H2O2 + UA group, and H2O2 + UA + SR-18292 group. Senescence-associated β-Galactosidase (SA-β-Gal) activity, cell cycle, cell proliferation ability, and the expression of senescence-related and silent information regulator of transcription 1/PPAR gamma coactivator-1α (SIRT1/ PGC-1α) pathway-related proteins and mRNA were used to evaluate the protective effects of UA. In vivo, an animal model of IDD was constructed, and X-rays, magnetic resonance imaging, and histological analysis were used to assess whether UA could alleviate IDD in vivo.
RESULTS
We found that H2O2 can cause NPMSCs senescence changes, such as cell cycle arrest, reduced cell proliferation ability, increased SA-β-Gal activity, and increased expression of senescence-related proteins and mRNA. After UA pretreatment, the abovementioned senescence indicators were significantly alleviated. To further demonstrate the mechanism of UA, we evaluated the mitochondrial membrane potential and the SIRT1/PGC-1α pathway that regulates mitochondrial function. UA protected mitochondrial function and delayed NPMSCs senescence by activating the SIRT1/PGC-1α pathway. In vivo, we found that UA treatment alleviated an animal model of IDD by assessing the disc height index, Pfirrmann grade and the histological score.
CONCLUSION
In summary, UA could activate the SIRT1/PGC-1α signaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro.
Core Tip: In degenerative intervertebral disc (IVD), an unfavorable IVD environment leads to increased senescence of nucleus pulposus-derived mesenchymal stem cells (NPMSCs), which seriously affects endogenous repair of IVD. Urolithin A (UA) alleviated oxidative stress-induced NPMSCs senescence by activating the silent information regulator of transcription 1/PPAR gamma coactivator-1α signaling pathway and protecting mitochondrial function in vitro. UA could also delay extracellular matrix degradation and IVD degeneration (IDD) in vivo. The results provide the possibility to promote endogenous repair and retard IDD.
