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.
Peng-Zhi Shi  1 ,  Jun-Wu Wang  2 ,  Ping-Chuan Wang  2 ,  Bo Han  3 ,  Xu-Hua Lu  4 ,  Yong-Xin Ren  5 ,  Xin-Min Feng  2 ,  Xiao-Fei Cheng  6 ,  Liang Zhang  7
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].
PMID: 35069991 DOI: 10.4252/wjsc.v13.i12.1928
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.
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