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Superoxide dismutase 1-modified dental pulp stem cells alleviate high-altitude pulmonary edema by inhibiting oxidative stress through the Nrf2/HO-1 pathway

Gene Therapy (2024)Cite this article

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Abstract

High-altitude pulmonary edema (HAPE) is a deadly form of altitude sickness, and there is no effective treatment for HAPE. Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cell isolated from dental pulp tissues and possess various functions, such as anti-inflammatory and anti-oxidative stress. DPSCs have been used to treat a variety of diseases, but there are no studies on treating HAPE. In this study, Sprague-Dawley rats were exposed to acute low-pressure hypoxia to establish the HAPE model, and SOD1-modified DPSCs (DPSCsHiSOD1) were administered through the tail vein. Pulmonary arterial pressure, lung water content (LWC), total lung protein content of bronchoalveolar lavage fluid (BALF) and lung homogenates, oxidative stress, and inflammatory indicators were detected to evaluate the effects of DPSCsHiSOD1 on HAPE. Rat type II alveolar epithelial cells (RLE-6TN) were used to investigate the effects and mechanism of DPSCsHiSOD1 on hypoxia injury. We found that DPSCs could treat HAPE, and the effect was better than that of dexamethasone treatment. SOD1 modification could enhance the function of DPSCs in improving the structure of lung tissue, decreasing pulmonary arterial pressure and LWC, and reducing the total lung protein content of BALF and lung homogenates, through anti-oxidative stress and anti-inflammatory effects. Furthermore, we found that DPSCsHiSOD1 could protect RLE-6TN from hypoxic injury by reducing the accumulation of reactive oxygen species (ROS) and activating the Nrf2/HO-1 pathway. Our findings confirm that SOD1 modification could enhance the anti-oxidative stress ability of DPSCs through the Nrf2/HO-1 signalling pathway. DPSCs, especially DPSCsHiSOD1, could be a potential treatment for HAPE.

Schematic diagram of the antioxidant stress mechanism of DPSCs in the treatment of high-altitude pulmonary edema. DPSCs can alleviate oxidative stress by releasing superoxide dismutase 1, thereby reducing ROS production and activating the Nrf2/HO-1 signalling pathway to ameliorate lung cell injury in HAPE.

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Fig. 1: DPSCs could repair hypoxic injury of RLE-6TN.
Fig. 2: DPSCs could prevent and treat HAPE.
Fig. 3: Evaluation of the efficacy of SOD1-modified DPSCs in the treatment of HAPE.
Fig. 4: Antioxidative stress and anti-inflammatory effect of SOD1-modified DPSCs for the treatment of HAPE.
Fig. 5: SOD1 enhances the anti-oxidative stress of DPSCs by activating the Nrf2/HO-1 signalling pathway.

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Acknowledgements

We are grateful to professor Rili Ge, Feng Tang and Haijie Wang for suggestions on establishing the HAPE model. We thank AJE for language polishing.

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Author notes

  1. These authors contributed equally: Zhuang Mao, Changyao Wang, Juanli Liu.

Authors and Affiliations

  1. Beijing Institute of Radiation Medicine, Beijing, 100850, China

    Zhuang Mao, Changyao Wang, Xue Li, Lin Lv, Zhichao He & Hua Wang

  2. School of Life Sciences, Hebei University, Baoding, 071002, China

    Changyao Wang, Han Duan & Hua Wang

  3. Key Laboratory for Application of High-Altitude Medicine, Qinghai University, Xi’ning, 810008, China

    Juanli Liu, Yi Ye, Huifang Liu, Guanzhen Xue & Tana Wuren

  4. Research Center for High Altitude Medicine, Qinghai University, Xi’ning, 810008, China

    Juanli Liu, Yi Ye, Huifang Liu, Guanzhen Xue & Tana Wuren

  5. Department of Critical Care Medicine, Qinghai Provincial People’s Hospital, Xi’ning, 810007, China

    Juanli Liu

  6. College of Life Science, Anhui Medical University, Hefei, 230032, China

    Xue Li, Zhichao He & Hua Wang

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Contributions

ZM, TW, and HW, conception and design of the work; ZM, CW, and JL, the acquisition, analysis, and interpretation of data; XL, HD, YY, LL, and ZH, acquisition of data; HL and GX, the creation of new software used in the work; ZM and HW, have draughted the work and substantively revised it. All authors reviewed the manuscript.

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Correspondence to Tana Wuren or Hua Wang.

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All animal experiments were approved by the Institutional Animal Care and Use Committee of Laboratory Animal Centre (IACUC-DWZX-2021-714).

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Mao, Z., Wang, C., Liu, J. et al. Superoxide dismutase 1-modified dental pulp stem cells alleviate high-altitude pulmonary edema by inhibiting oxidative stress through the Nrf2/HO-1 pathway. Gene Ther (2024). https://doi.org/10.1038/s41434-024-00457-x

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