hPMSCs protects against d-galactose-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

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, d-gal 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 anti-CD3/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 aging-related 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. Conclusions Our results indicate that hPMSCs attenuate d-gal-induced CD4+ T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.

Human placental mesenchymal stem cells ameliorate chemotherapy-induced damage in the testis by reducing apoptosis/oxidative stress and promoting autophagy

“…5 ). Similar to our findings, hPMSCs were shown to protect against oxidative damage in CD4 + T cells by activating Akt-regulated Nrf2 antioxidant signaling [ 32 ].…”

hPMSCs-Derived Exosomal miRNA-21 Protects Against Aging-Related Oxidative Damage of CD4+ T Cells by Targeting the PTEN/PI3K-Nrf2 Axis

“…MSCs have been thought to be the source of seed cells for anti-aging biological therapeutics based on the immunomodulatory and antioxidant effects ( 29 , 30 ). Our previous research demonstrated that hPMSCs weaken D-gal induced CD4 + T cell senescence via targeting Nrf2-mediated antioxidant defenses ( 5 ). However, due to immune rejection and limited sources, MSCs are still limited in broad clinical application.…”

“…suggested that hfPMSCs alleviate H 2 O 2 -induced cell apoptosis and oxidative stress by promoting the expression of Nrf2/Keap1/ARE antioxidant signaling ( 38 ). Our previous study found that hPMSCs played a protective effect by improving the Nrf2-mediated antioxidant pathway in senescent CD4 + T cells ( 5 ). In this study, we found that hPMSC-Exo treatment significantly increased antioxidant capacity and decreased aging-related damage and secretion phenotype in senescent CD4 + T cells.…”

“…Recently, the role of mesenchymal stem cells (MSCs) in aging progression has aroused widespread attention. Currently, our laboratory have found that placenta-derived mesenchymal stromal cells (hPMSCs) attenuate D-gal induced CD4 + T cell senescence by targeting nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated antioxidant defenses ( 5 ). However, the direct link between hPMSCs intervention and activation of the Nrf2 pathway in senescent CD4 + T cells remains to be elucidated.…”

“…Among the target genes of miR-21, the Phosphatase and tensin homolog deleted on chromosome 10/phosphoinositide 3-kinase/protein kinase B (PTEN/PI3K/Akt) signaling pathway has been implicated as an important regulator of the proliferation, differentiation, and apoptosis of a variety of cells ( 14 , 15 ). Interestingly, our previous results indicated that hPMSCs weaken CD4 + T cell senescence by activating the Akt-mediated Nrf2 antioxidant signaling ( 5 ). However, the protection effect and mechanism of hPMSCs derived exosomes (hPMSC-Exo) on aging-related T cell dysfunction remain unknown.…”