The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
Department of Interventional Radiology and Vascular Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
Stem Cell Res Ther. 2022 Oct 4;13(1):491. doi: 10.1186/s13287-022-03178-3.
Mesenchymal stem/stromal cells (MSCs) acquire immunosuppressive capacity only in an inflammatory microenvironment. This can be recapitulated in vitro by treating MSCs with inflammatory cytokines TNFα and IFNγ, which induce indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene-6 (TSG-6). However, the signaling pathways downstream of the cytokines remain to be elucidated.
Inflammatory bowel disease (IBD) mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. Human UC-MSCs were pretreated with TNF-α and IFN-γ for 24 h and were then infused intravenously at day 2 of DSS administration. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay. Real-time PCR and Western blot were used to examine the mRNA level and protein expression. MSCs overexpressing constitutive active AKT or dominant negative AKT were generated and were analyzed. The glycolysis level of the MSCs was measured using Extracellular Flux Analyzer. 2-NBDG was used to monitor the uptake of glucose by MSCs.
TNFα and IFNγ treatment led to rapid consumption of glucose and metabolic skewing toward glycolysis in MSCs, which was required for the therapeutic efficacy of MSCs on IBD. Blockade of glycolysis in MSCs inhibited the expression of immunomodulatory molecules, IDO and TSG-6, as well as the therapeutic effect on IBD. Moreover, PI3K-AKT signaling axis was rapidly activated and was required for the skewing toward glycolysis induced by TNFα and IFNγ. MSCs expressing dominant negative AKT were compromised in their therapeutic efficacy on IBD.
The glycolysis-dependent anti-inflammatory property of MSCs conferred by inflammatory cytokines is mediated by PI3K-AKT signaling pathway.
间充质干细胞（MSCs）仅在炎症微环境中获得免疫抑制能力。通过用炎症细胞因子 TNFα 和 IFNγ 处理 MSCs 可以在体外重现这种情况，这会诱导吲哚胺 2,3-双加氧酶（IDO）和 TNF 刺激基因-6（TSG-6）的表达。然而，细胞因子下游的信号通路仍有待阐明。
通过在饮用水中添加葡聚糖硫酸钠（DSS）使小鼠建立炎症性肠病（IBD）模型 7 天。用 TNF-α 和 IFN-γ 预处理人 UC-MSCs 24 小时，然后在 DSS 给药的第 2 天静脉内输注。收集结肠组织进行长度测量和组织病理学检查。通过酶联免疫吸附试验测量小鼠血清中 IL-6 的水平。使用实时 PCR 和 Western blot 检测 mRNA 水平和蛋白表达。生成并分析过表达组成型激活 AKT 或显性负性 AKT 的 MSCs。使用细胞外通量分析仪测量 MSCs 的糖酵解水平。使用 2-NBDG 监测 MSCs 对葡萄糖的摄取。
TNFα 和 IFNγ 处理导致 MSCs 快速消耗葡萄糖并向糖酵解代谢转变，这是 MSCs 治疗 IBD 的疗效所必需的。在 MSCs 中阻断糖酵解会抑制免疫调节分子 IDO 和 TSG-6 的表达以及对 IBD 的治疗作用。此外，PI3K-AKT 信号轴被迅速激活，并且是 TNFα 和 IFNγ 诱导的糖酵解偏向所必需的。表达显性负性 AKT 的 MSCs 在治疗 IBD 方面的疗效受损。
炎症细胞因子赋予 MSCs 的依赖糖酵解的抗炎特性是由 PI3K-AKT 信号通路介导的。
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