Transplantation of miR-193b-3p-Transfected BMSCs Improves Neurological Impairment after Traumatic Brain Injury through S1PR3-Mediated Regulation of the PI3K/AKT/mTOR Signaling Pathway

IF 1.5 4区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Critical Reviews in Eukaryotic Gene Expression Pub Date : 2024-01-01 DOI:10.1615/critreveukaryotgeneexpr.2024053225
Yinghong He, Yuanmou Li, Yan Zhang, Lixia Chen, Juan Luo, Liqiao Bi, Limei Liu, Xuelian Wang, Meifen Lv
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Abstract

The aim of the present study was to explore the molecular mechanisms by which miR-193b-3p-trans-fected bone marrow mesenchymal stem cells (BMSCs) transplantation improves neurological impairment after traumatic brain injury (TBI) through sphingosine-1-phosphate receptor 3 (S1PR3)-mediated regulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway at the cellular and animal levels. BMSCs were transfected with miR-193b-3p. A TBI cell model was established by oxygen−glucose deprivation (OGD)-induced HT22 cells, and a TBI animal model was established by controlled cortical impact (CCI). Cell apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL), and cell activity was detected by a cell counting kit 8 (CCK-8) assay. Western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of related proteins and genes. In this study, transfection of miR-193b-3p into BMSCs significantly enhanced BMSCs proliferation and differentiation. Transfection of miR-193b-3p reduced the levels of the interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha (TNF-α) inflammatory factors in cells and mouse models, and it inhibited neuronal apoptosis, which alleviated OGD-induced HT22 cell damage and neural function damage in TBI mice. Downstream experiments showed that miR-193b-3p targeting negatively regulated the expression of S1PR3, promoted the activation of the PI3K/AKT/mTOR signaling pathway, and inhibited the levels of apoptosis and inflammatory factors, which subsequently improved OGD-induced neuronal cell damage and nerve function damage in TBI mice. However, S1PR3 overexpression or inhibition of the PI3K/AKT/mTOR signaling pathway using the IN-2 inhibitor weakened the protective effect of miR-193b-3p-transfected BMSCs on HT22 cells. Transplantation of miR-193b-3p-transfected BMSCs inhibits neurological injury and improves the progression of TBI in mice through S1PR3-mediated regulation of the PI3K/AKT/mTOR pathway.
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转染 miR-193b-3p 的 BMSCs 移植通过 S1PR3 介导的 PI3K/AKT/mTOR 信号通路调节改善创伤性脑损伤后的神经功能损伤
本研究旨在探讨经miR-193b-3p转染的骨髓间充质干细胞(BMSCs)移植改善创伤性脑损伤(TBI)后神经功能损伤的分子机制。1-磷酸鞘氨醇受体3(S1PR3)在细胞和动物水平上介导的磷脂酰肌醇3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶标(PI3K/AKT/mTOR)通路调节,改善创伤性脑损伤(TBI)后的神经损伤。用 miR-193b-3p 转染 BMSCs。通过氧-葡萄糖剥夺(OGD)诱导的 HT22 细胞建立了创伤性脑损伤细胞模型,通过可控皮质冲击(CCI)建立了创伤性脑损伤动物模型。细胞凋亡通过末端脱氧核苷酸转移酶(TdT)介导的 dUTP缺口末端标记(TUNEL)检测,细胞活性通过细胞计数试剂盒 8(CCK-8)检测。Western 印迹分析和定量实时聚合酶链反应(qRT-PCR)用于检测相关蛋白和基因的表达。在这项研究中,转染 miR-193b-3p 到 BMSCs 能显著增强 BMSCs 的增殖和分化。转染 miR-193b-3p 能降低细胞和小鼠模型中白细胞介素-6(IL-6)、IL-1β 和肿瘤坏死因子-α(TNF-α)等炎症因子的水平,抑制神经细胞凋亡,从而减轻 OGD 诱导的 HT22 细胞损伤和 TBI 小鼠的神经功能损伤。下游实验表明,miR-193b-3p靶向负调控S1PR3的表达,促进PI3K/AKT/mTOR信号通路的激活,抑制细胞凋亡和炎症因子的水平,从而改善OGD诱导的TBI小鼠神经细胞损伤和神经功能损伤。然而,S1PR3过表达或使用IN-2抑制剂抑制PI3K/AKT/mTOR信号通路会削弱miR-193b-3p转染BMSCs对HT22细胞的保护作用。通过 S1PR3 介导的 PI3K/AKT/mTOR 通路调节,移植 miR-193b-3p 转染的 BMSCs 可抑制神经损伤并改善小鼠创伤性脑损伤的进展。
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来源期刊
Critical Reviews in Eukaryotic Gene Expression
Critical Reviews in Eukaryotic Gene Expression 生物-生物工程与应用微生物
CiteScore
2.70
自引率
0.00%
发文量
67
审稿时长
1 months
期刊介绍: Critical ReviewsTM in Eukaryotic Gene Expression presents timely concepts and experimental approaches that are contributing to rapid advances in our mechanistic understanding of gene regulation, organization, and structure within the contexts of biological control and the diagnosis/treatment of disease. The journal provides in-depth critical reviews, on well-defined topics of immediate interest, written by recognized specialists in the field. Extensive literature citations provide a comprehensive information resource. Reviews are developed from an historical perspective and suggest directions that can be anticipated. Strengths as well as limitations of methodologies and experimental strategies are considered.
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