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Bone marrow mesenchymal stem cells exert protective effects after ischemic stroke through upregulation of glutathione

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Lan, Xiao-Yan, Sun, Zheng-Wu, Xu, Gui-Lian, Chu, Cheng-Yan, Qin, Hua-Min, Li, Shen, Geng, Xin, Gao, Peng, Boltze, Johannes and Li, Shen (2021) Bone marrow mesenchymal stem cells exert protective effects after ischemic stroke through upregulation of glutathione. Stem Cell Reviews and Reports . doi:10.1007/s12015-021-10178-y (In Press)

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Official URL: https://doi.org/10.1007/s12015-021-10178-y

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Abstract

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. 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.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RB Pathology
R Medicine > RC Internal medicine
Divisions: Faculty of Science > Life Sciences (2010- )
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Cerebrovascular disease, Glutathione, Mesenchymal stem cells, Bone marrow cells, Metabolites, Oxidative stress
Journal or Publication Title: Stem Cell Reviews and Reports
Publisher: Springer
ISSN: 2629-3277
Official Date: 27 August 2021
Dates:
DateEvent
27 August 2021Published
28 April 2021Accepted
DOI: 10.1007/s12015-021-10178-y
Status: Peer Reviewed
Publication Status: In Press
Publisher Statement: This is a post-peer-review, pre-copyedit version of an article published in Stem Cell Reviews and Reports. The final authenticated version is available online at: http://dx.doi.org/10.1007/s12015-021-10178-y
Access rights to Published version: Restricted or Subscription Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
2019-MS-075Natural Science Foundation of Liaoning Provincehttp://dx.doi.org/10.13039/501100005047
XLYC1807124Program for Liaoning Innovative Talents in Universityhttp://dx.doi.org/10.13039/501100012591
2019J13SN109Dalian Medical Universityhttp://dx.doi.org/10.13039/501100012465
1811014Dalian Shi (China)http://viaf.org/viaf/159638351

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