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 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, H 2 O 2 group, H 2 O 2 + UA group, and H 2 O 2 + 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 H 2 O 2 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 .

1,25(OH)2D3 Mitigates Oxidative Stress-Induced Damage to Nucleus Pulposus-Derived Mesenchymal Stem Cells through PI3K/Akt Pathway

“…The results showed that 1,25(OH) 2 D 3 showed no cytotoxic effect on cell viability at a concentration of 10 −8 M to 10 −12 M for the different exposure times (0, 12, 24, and 48 h) ( Figure 2(a) ); 10 −10 M of 1,25(OH) 2 D 3 was chosen for the subsequent experiments. Additionally, cell proliferation was appropriately inhibited when treated with 100 μ M H 2 O 2 for 6 h, which was the same result as our previous study [ 24 , 33 ] ( Figure 2(b) ). Therefore, this condition was used to induce oxidative stress damage in NPMSCs in the following experiments.…”

“…The separated NPMSCs gathered into a chrysanthemum shape and formed into a long spindle shape after passage ( Figure 1(a) ). Similar to our previous studies [ 18 , 23 , 33 ], the MSC-associated surface markers CD73, CD90, and CD105 in NPMSCs presented high fluorescence expression, whereas the surface markers CD34 and CD45 showed presented low fluorescence expression ( Figure 1(b) ). The results of osteogenic, adipogenic, and chondrogenic induction in vitro confirmed the multipotential differentiation of NPMSCs ( Figure 1(c) ).…”

Melatonin alleviat es oxidative stress -induced injury to nucleus pulposus-derived mesenchymal stem cells through activating PI3K/Akt pathway

“…The cells were spindle-shaped after passage (Figure 2(A)). Similar to our previous studies [11,31], NPMSC can induce osteogenesis, chondrogenesis and adipogenic differentiation in vitro (Figure 2(B)), so its multilineage differentiation ability has been con rmed. In addition, the related antigens CD105 97.5±0.12 , CD90 98.9±0.06 and CD73 98.7±0.13 marked on the surface of MSC were highly expressed in NPMSC, while CD45 0.83±0.07 and CD11b/c 2.45±0.09 were lowly expressed(Figure 2(C)).…”

Scientific literature landscape analysis of researches on oxidative stress in intervertebral disc degeneration in web of science

“…Orthopedics had the most highly cited papers ( n = 2), followed by Research Experimental Medicine, Pharmacology Pharmacy, and Rheumatology. In addition, National Natural Science Foundation of China had the most records ( n = 143), the highest H-index of 30, the highest total citations ( n = 2,852) and average citations ( n = 19.94) ( Shi et al, 2021 ). National Institutes of Health was the second with records ( n = 27), H-index of 16, the total citations ( n = 1,044) and average citations ( n = 38.67).…”

“…Cell senescence in IDD results from the general aging process and the structure and tissue specificity of discs ( Zhang et al, 2020 ). A recent study proved that Urolithin A could activate the SIRT1/PGC-1α signaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro ( Shi et al, 2021 ).…”