hPMSCs protects against d -galactose-induced oxidative damage of CD4 + T cells through activating Akt-mediated Nrf2 anti
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RESEARCH
Open Access
hPMSCs protects against D-galactoseinduced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling Yanlian Xiong1†, Yueming Wang1†, Jiashen Zhang2†, Nannan Zhao2, Hengchao Zhang2, Aiping Zhang2, Dongmei Zhao1, Zhenhai Yu1, Yancun Yin1, Lele Song2, Yanlei Xiong3* and Xiying Luan2*
Abstract Background: Mesenchymal stem cells (MSCs) were considered a regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4+ T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal-induced mouse aging model. Methods: In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, Dgal group, hPMSC group, and PBS group. In in vitro experiment, human naive CD4+ T (CD4CD45RA) cells were prepared using a naive CD4+ T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4+ T cell were co-cultured with hPMSCs for 72 h in the absence or presence of antiCD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of agingrelated proteins was detected by Western blotting, RT-PCR, and confocal microscopy. Results: We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal-positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression, and aging-related protein (P16 and P21) expression in senescent CD4+ T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC, and NQO1) in senescent CD4+ T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4+ T cell senescence by upregulating the Akt/ GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4+ T cells. (Continued on next page)
* Correspondence: [email protected]; [email protected] † Yanlian Xiong, Yueming Wang and Jiashen Zhang contributed equally to this work. 3 Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China 2 Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriat
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