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

Yanlian Xiong,Hengchao Zhang,Xiying Luan,Jiashen Zhang,Kaiyue Han,Dongmei Zhao,Yueming Wang,Zhenhai Yu,Yanlei Xiong,Yaxuan Zhao,Longfei Wang,Ziran Geng

doi:10.3389/fimmu.2021.780897

Yanlian Xiong, Hengchao Zhang + Show 10 more

Open Access

https://doi.org/10.3389/fimmu.2021.780897

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Abstract

Mesenchymal stem cells (MSCs)-derived exosomes were considered a novel therapeutic approach in many aging-related diseases. This study aimed to clarify the protective effects of human placenta MSCs-derived exosomes (hPMSC-Exo) in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model. Senescent T cells were detected SA-β-gal stain. The degree of DNA damage was evaluated by detecting the level of 8-OH-dG. The superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities were measured. The expression of aging-related proteins and senescence-associated secretory phenotype (SASP) were detected by Western blot and RT-PCR. We found that hPMSC-Exo treatment markedly decreased oxidative stress damage (ROS and 8-OH-dG), SA-β-gal positive cell number, aging-related protein expression (p53 and γ-H2AX), and SASP expression (IL-6 and OPN) in senescent CD4+ T cells. Additionally, hPMSC-Exo containing miR-21 effectively downregulated the expression of PTEN, increased p-PI3K and p-AKT expression, and Nrf2 nuclear translocation and the expression of downstream target genes (NQO1 and HO-1) in senescent CD4+ T cells. Furthermore, in vitro studies uncovered that hPMSC-Exo attenuated CD4+ T cell senescence by improving the PTEN/PI3K-Nrf2 axis by using the PTEN inhibitor bpV (HOpic). We also validated that PTEN was a target of miR-21 by using a luciferase reporter assay. Collectively, the obtained results suggested that hPMSC-Exo attenuates CD4+ T cells senescence via carrying miRNA-21 and activating PTEN/PI3K-Nrf2 axis mediated exogenous antioxidant defenses.

Highlights

Immunosenescence is accompanied by the dysfunction of T cells, leading to age-related immune dysfunction and increases the susceptibility to infectious and cancer diseases [1, 2]
We found that miR-21 is expressed at a significantly higher level in have found that placenta-derived mesenchymal stromal cells (hPMSCs)-Exo than in hPMSCs themselves, suggesting that Mesenchymal stem cells (MSCs) package the majority of the miR-21 produced in exosomes (Figure 4A)
Our current study shows that hPMSC-Exo carrying miR-21 could upregulate the expression of PTEN/PI3K-nuclear factor erythroid-2related factor 2 (Nrf2) signaling pathway in senescent CD4+ T cells, improve the antioxidant capacity of CD4+ T cells, and alleviate agerelated immune dysfunction

Summary

Introduction

Immunosenescence is accompanied by the dysfunction of T cells, leading to age-related immune dysfunction and increases the susceptibility to infectious and cancer diseases [1, 2]. The role of mesenchymal stem cells (MSCs) in aging progression has aroused widespread attention. Our laboratory have found that placenta-derived mesenchymal stromal cells (hPMSCs) attenuate D-gal induced CD4+ T cell senescence by targeting nuclear factor erythroid-2related factor 2 (Nrf2)-mediated antioxidant defenses [5]. The direct link between hPMSCs intervention and activation of the Nrf pathway in senescent CD4+ T cells remains to be elucidated. Han et al have demonstrated that MSC derived exosomes prevent aging-related vascular dysfunction in mouse hindlimb [9]. Whether MSC-derived exosomes contribute to the protection of the CD4+ T cell senescence needs to be further explored

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