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Protective effect of MitoQ on oxidative stress-mediated senescence of canine bone marrow mesenchymal stem cells via activation of the Nrf2/ARE pathway

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Abstract

The destruction of biological activity such as senescence and apoptosis caused by oxidative stress could play a pivotal role in the poor therapeutic efficiency of bone marrow mesenchymal stem cells (BMSCs) transplantation. Mitoquinone (MitoQ) has a highly effective mitochondrial antioxidant effect, and has been widely used in many oxidative damage models. This study aimed to investigate the protective effect of MitoQ on the oxidative stress-mediated senescence of canine BMSCs and the underlying mechanism. The senescence of BMSCs was determined by senescence-associated β-galactosidase staining and quantitative real-time PCR. The expression of p-Nrf2 protein was detected by Western blotting. The results demonstrated that, as BMSCs were expanded in vitro, the senescent phenotype appeared. And the senescence of BMSCs may be caused by oxidative stress, manifested by increasing the level of ROS and decreasing the activity of antioxidant enzymes. Treatment of MitoQ down-regulated the mRNA levels of senescence-related and apoptosis-related genes, but up-regulated the mRNA levels of proliferation-related genes. Meanwhile, ROS generation and senescent activity were reduced in MitoQ-treated BMSCs. Further mechanism studies showed that MitoQ obviously promoted Nrf2 phosphorylation, and also facilitated the translocation of Nrf2 into the nucleus. Moreover, treatment of MitoQ increased the mRNA levels of downstream antioxidant genes and enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase. Thus, our study revealed that MitoQ, via the Nrf2/ARE signaling pathway, exerts an antioxidant effect as well as potentially delays OS-mediated senescence during BMSCs that were expanded in vitro, which may serve as a novel strategy to optimize the clinical application of BMSCs.

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Acknowledgements

We would like to thank the owners and their dogs for their participation.

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Correspondence to Shumin Yu.

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All animal experiments were conducted in strict accordance with regulations of the animal protection laws of China (a draft of an animal protection laws was released on September 18, 2009) and in compliance with the Sichuan Agricultural University for Laboratory Animal Care recommendations for the care and use of laboratory animals (Ya’an, China; Approval No.2013-028).

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The authors declare no competing interests.

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Editor: Tetsuji Okamoto

Lijun Zhong and Jiaqiang Deng should be considered joint first authors.

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Zhong, L., Deng, J., Gu, C. et al. Protective effect of MitoQ on oxidative stress-mediated senescence of canine bone marrow mesenchymal stem cells via activation of the Nrf2/ARE pathway. In Vitro Cell.Dev.Biol.-Animal 57, 685–694 (2021). https://doi.org/10.1007/s11626-021-00605-2

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  • DOI: https://doi.org/10.1007/s11626-021-00605-2

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