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

Abstract

BACKGROUND In degenerative intervertebral disc (IVD), an unfavorable IVD environment leads to increased senescence of nucleus pulposus (NP)-derived mesenchymal stemcells (NPMSCs) and the inability to complete the differentiation from NPMSCs toNP cells, leading to further aggravation of IVD degeneration (IDD). Urolithin A(UA) has been proven to have obvious effects in delaying cell senescence andresisting oxidative stress.AIMTo explore whether UA can alleviate NPMSCs senescence and to elucidate theunderlying mechanism.METHODSIn vitro, we harvested NPMSCs from rat tails, and divided NPMSCs into fourgroups: 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 silentinformation regulator of transcription 1/PPAR gamma coactivator-1α (SIRT1/PGC-1α) pathway-related proteins and mRNA were used to evaluate theprotective effects of UA. In vivo, an animal model of IDD was constructed, and Xrays,magnetic resonance imaging, and histological analysis were used to assesswhether UA could alleviate IDD in vivo.RESULTSWe found that H2O2 can cause NPMSCs senescence changes, such as cell cyclearrest, reduced cell proliferation ability, increased SA-β-Gal activity, andincreased expression of senescence-related proteins and mRNA. After UApretreatment, the abovementioned senescence indicators were significantlyalleviated. To further demonstrate the mechanism of UA, we evaluated themitochondrial membrane potential and the SIRT1/PGC-1α pathway that regulatesmitochondrial function. UA protected mitochondrial function and delayedNPMSCs senescence by activating the SIRT1/PGC-1α pathway. In vivo, we foundthat UA treatment alleviated an animal model of IDD by assessing the disc heightindex, Pfirrmann grade and the histological score.CONCLUSIONIn summary, UA could activate the SIRT1/PGC-1α signaling pathway to protectmitochondrial function and alleviate cell senescence and IDD in vivo and vitro