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人牙髓间充质干细胞来源的外泌体 miRNA-21 通过靶向 PTEN/PI3K-Nrf2 轴保护 CD4 T 细胞免受衰老相关氧化损伤。

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

机构信息

Department of Anatomy, School of Basic Medicine, Binzhou Medical University, Yantai, China.

Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China.

出版信息

Front Immunol. 2021 Nov 23;12:780897. doi: 10.3389/fimmu.2021.780897. eCollection 2021.

DOI:10.3389/fimmu.2021.780897
PMID:34887868
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8649962/
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, 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 carrying miRNA-21 and activating PTEN/PI3K-Nrf2 axis mediated exogenous antioxidant defenses.

摘要

间充质干细胞（MSCs）衍生的外泌体被认为是许多与衰老相关疾病的新的治疗方法。本研究旨在使用 D-半乳糖诱导的小鼠衰老模型阐明人胎盘间充质干细胞衍生的外泌体（hPMSC-Exo）在与衰老相关的 CD4 T 细胞衰老中的保护作用，并确定其潜在机制。通过 SA-β-半乳糖染色检测衰老 T 细胞。通过检测 8-OH-dG 水平来评估 DNA 损伤程度。测量超氧化物歧化酶（SOD）和总抗氧化能力（T-AOC）的活性。通过 Western blot 和 RT-PCR 检测衰老相关蛋白和衰老相关分泌表型（SASP）的表达。我们发现，hPMSC-Exo 处理可显著降低衰老 CD4 T 细胞中的氧化应激损伤（ROS 和 8-OH-dG）、SA-β-半乳糖阳性细胞数、衰老相关蛋白表达（p53 和 γ-H2AX）和 SASP 表达（IL-6 和 OPN）。此外，hPMSC-Exo 含有 miR-21，可有效下调 PTEN 的表达，增加 p-PI3K 和 p-AKT 的表达，并使 Nrf2 核易位及其下游靶基因（NQO1 和 HO-1）的表达。此外，通过使用 PTEN 抑制剂 bpV（HOpic），研究表明 hPMSC-Exo 通过改善 PTEN/PI3K-Nrf2 轴来减轻 CD4 T 细胞衰老。我们还通过荧光素酶报告基因检测验证了 PTEN 是 miR-21 的靶基因。总之，研究结果表明，hPMSC-Exo 通过携带 miR-21 并激活 PTEN/PI3K-Nrf2 轴介导外源性抗氧化防御来减轻 CD4 T 细胞衰老。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/3e9d0d909309/fimmu-12-780897-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/e80bd93e587b/fimmu-12-780897-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/e23e9801d762/fimmu-12-780897-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/57146ddb8ad0/fimmu-12-780897-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/1a70bb45a1ea/fimmu-12-780897-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/eb0b83c54e82/fimmu-12-780897-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/d7acf0f829ec/fimmu-12-780897-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/3c79db83e016/fimmu-12-780897-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/3e9d0d909309/fimmu-12-780897-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/e80bd93e587b/fimmu-12-780897-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/e23e9801d762/fimmu-12-780897-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/57146ddb8ad0/fimmu-12-780897-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/1a70bb45a1ea/fimmu-12-780897-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/eb0b83c54e82/fimmu-12-780897-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/d7acf0f829ec/fimmu-12-780897-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/3c79db83e016/fimmu-12-780897-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a20a/8649962/3e9d0d909309/fimmu-12-780897-g008.jpg

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本文引用的文献

[1]
hPMSCs protects against D-galactose-induced oxidative damage of CD4 T cells through activating Akt-mediated Nrf2 antioxidant signaling.

Stem Cell Res Ther. 2020-11-4

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Biomed Pharmacother. 2020-12

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miRNA-29a reverses P-glycoprotein-mediated drug resistance and inhibits proliferation via up-regulation of PTEN in colon cancer cells.

Eur J Pharmacol. 2020-8-5

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Biogerontology. 2020-6

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