Bone Marrow Mesenchymal Stem Cells Exert Protective Effects After Ischemic Stroke Through Upregulation of Glutathione,Stem Cell Reviews and Reports

当前位置： X-MOL 学术 › Stem Cell Rev and Rep. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Bone Marrow Mesenchymal Stem Cells Exert Protective Effects After Ischemic Stroke Through Upregulation of Glutathione
Stem Cell Reviews and Reports ( IF 4.5 ) Pub Date : 2021-08-27 , DOI: 10.1007/s12015-021-10178-y
Xiao-Yan Lan ₁ , Zheng-Wu Sun ₂ , Gui-Lian Xu ₃ , Cheng-Yan Chu ₁ , Hua-Min Qin ₄ , Shen Li ₅ , Xin Geng ₃ , Peng Gao ₆ , Johannes Boltze ₇ , Shen Li ₁

Affiliation

Bone marrow mesenchymal stem cells (BMSCs) have been shown to promote stroke recovery, however, the underlying mechanisms are not well understood. In this study naïve rats were intravenously injected with syngeneic BMSCs to screen for potential differences in brain metabolite spectrum versus vehicle-treated controls by capillary electrophoresis-mass spectrometry. A total of 65 metabolites were significantly changed after BMSC treatment. Among them, 5-oxoproline, an intermediate in the biosynthesis of the endogenous glutathione (GSH), was increased. To confirm the obtained results and investigate the metabolic pathways, BMSCs were injected into rats 24 h after middle cerebral artery occlusion (MCAO). Rats receiving vehicle solution and sham-operated animals served as controls. High performance liquid chromatography, reverse transcription-quantitative polymerase chain reaction, and Western blotting revealed that intravenous BMSC application increased the levels of 5-oxoproline and GSH in MCAO rats, as well as the expression of key enzymes involved in GSH synthesis including, gamma-glutamylcyclotransferase and gamma-glutamylcysteine ligase. Subsequent clinical investigation confirmed that acute ischemic stroke patients had higher plasma 5-oxoproline and GSH levels than age- and sex-matched non-stroke controls. The optimal cutoff value for 5-oxoproline diagnosing acute ischemic stroke (≤ 7d) was 3.127 µg/mL (sensitivity, 63.4 %; specificity, 81.2 %) determined by receiver characteristic operator curve. The area under the curve was 0.782 (95 % confidence interval: 0.718–0.845). Our findings indicate that BMSCs play a protective role in ischemic stroke through upregulation of GSH and 5-oxoproline is a potential biomarker for acute ischemic stroke.

Graphical Abstract

Ischemic stroke causes oxidative stress and induction of endogenous, glutathione-dependent anti-oxidative mechanisms. 5-oxoproline, an important metabolite in glutathione biosynthesis, could serve as a biomarker of acute ischemic stroke. Moreover, intravenous bone marrow mesenchymal stem cell (BMSC) treatment after experimental stroke upregulates the expression of key enzymes involved in glutathione synthesis, which results in better antioxidative defense and improved stroke outcome.

中文翻译：

骨髓间充质干细胞通过上调谷胱甘肽在缺血性中风后发挥保护作用

骨髓间充质干细胞 (BMSCs) 已被证明可促进中风恢复，但其潜在机制尚不清楚。在这项研究中，幼稚大鼠被静脉注射同系 BMSC，以通过毛细管电泳-质谱法筛选脑代谢物谱与载体处理对照的潜在差异。在 BMSC 处理后，共有 65 种代谢物发生了显着变化。其中，内源性谷胱甘肽（GSH）生物合成的中间体5-氧代脯氨酸有所增加。为了证实获得的结果并研究代谢途径，在大脑中动脉闭塞 (MCAO) 后 24 小时将 BMSCs 注射到大鼠体内。接受载体溶液的大鼠和假手术动物作为对照。高效液相色谱，逆转录-定量聚合酶链反应和蛋白质印迹显示，静脉内 BMSC 应用增加了 MCAO 大鼠的 5-oxoproline 和 GSH 水平，以及参与 GSH 合成的关键酶的表达，包括 γ-谷氨酰环转移酶和 γ-谷氨酰半胱氨酸连接酶。随后的临床研究证实，急性缺血性卒中患者的血浆 5-氧脯氨酸和 GSH 水平高于年龄和性别匹配的非卒中对照组。由受试者特征操作曲线确定的 5-氧代脯氨酸诊断急性缺血性卒中（≤ 7 天）的最佳截止值为 3.127 µg/mL（敏感性为 63.4 %；特异性为 81.2 %）。曲线下面积为 0.782（95% 置信区间：0.718–0.845）。