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

doi:10.4252/wjsc.v13.i12.1928

Urolithin a alleviates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells through SIRT1/PGC-1α pathway

World J Stem Cells. 2021 Dec 26;13(12):1928-1946. doi: 10.4252/wjsc.v13.i12.1928.

Authors

Peng-Zhi Shi¹, Jun-Wu Wang², Ping-Chuan Wang², Bo Han³, Xu-Hua Lu⁴, Yong-Xin Ren⁵, Xin-Min Feng², Xiao-Fei Cheng⁶, Liang Zhang⁷

Affiliations

¹ Department of Orthopedic, Dalian Medical University, Dalian 116000, Liaoning Province, China.
² Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China.
³ Department of Orthopedic, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
⁴ Department of Orthopedics, Changzheng Hospital of The Second Military Medical University, Shanghai 200003, China.
⁵ Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
⁶ Department of Orthopedic Surgery, Shanghai Key Laboratory of Orthopedics Implants, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China.
⁷ Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China. [email protected].

Abstract

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.

Keywords: Mitochondrial function; Nucleus pulposus-derived Mesenchymal stem cells; Oxidative stress; Senescence; The silent information regulator of transcription 1/PPAR gamma coactivator-1α pathway; Urolithin A.