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

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.

• Citation: Shi PZ, Wang JW, Wang PC, Han B, Lu XH, Ren YX, Feng XM, Cheng XF, Zhang L. Urolithin a alleviates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells through SIRT1/PGC-1α pathway. World J Stem Cells 2021; 13(12): 1928-1946
• URL: https://www.wjgnet.com/1948-0210/full/v13/i12/1928.htm
• DOI: https://dx.doi.org/10.4252/wjsc.v13.i12.1928