Blood glutamate EAAT2-cell grabbing therapy in cerebral ischemia
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Title: | Blood glutamate EAAT2-cell grabbing therapy in cerebral ischemia |
Author: | Pérez Mato, María Iglesias Rey, Ramón Vieites Prado, Alba Dopico López, Antonio Argibay González, Bárbara Fernández Susavila, Héctor Silva Candal, Andrés da Pérez Díaz, Amparo Correa Paz, Clara Günther, Anne Ávila Gómez, Paulo Loza García, María Isabel Baumann, Arnd Castillo Sánchez, José Antonio Sobrino Moreiras, Tomás Campos Pérez, Francisco |
Affiliation: | Universidade de Santiago de Compostela. Departamento de Farmacia e Tecnoloxía Farmacéutica Universidade de Santiago de Compostela. Departamento de Bioquímica e Bioloxía Molecular Universidade de Santiago de Compostela. Departamento de Química Física |
Subject: | Cell therapy | Cell therapyCerebral ischemia | Excitatory amino acid transporter 2 | Excitotoxic injury | Excitotoxic protection | Glutamate | Mesenchymal stem cells | |
Date of Issue: | 2019-01 |
Publisher: | Elsevier |
Citation: | Pérez-Mato, M., Iglesias-Rey, R., Vieites-Prado, A., Dopico-López, A., Argibay, B., Fernández-Susavila, H., da Silva-Candal, A., Pérez-Díaz, A., Correa-Paz, C., Günther, A., Ávila-Gómez, P., Isabel Loza, M., Baumann, A., Castillo, J., Sobrino, T., & Campos, F. (2019). Blood glutamate EAAT2-cell grabbing therapy in cerebral ischemia. EBioMedicine, 39, 118-131. https://doi.org/10.1016/j.ebiom.2018.11.024 |
Abstract: | Background Excitatory amino acid transporter 2 (EAAT2) plays a pivotal role in glutamate clearance in the adult brain, thereby preventing excitotoxic effects. Considering the high efficacy of EAAT2 for glutamate uptake, we hypothesized that the expression of this transporter in mesenchymal stem cells (MSCs) for systemic administration could yield a cell-based glutamate-grabbing therapy, combining the intrinsic properties of these cells with excitotoxic protection. Methods To address this hypothesis, EAAT2-encoding cDNA was introduced into MSCs and human embryonic kidney 293 cells (HEK cells) as the control cell line. EAAT2 expression and functionality were evaluated by in vitro assays. Blood glutamate-grabbing activity was tested in healthy and ischemic rat models treated with 3 × 106 and 9 × 106 cells/animal. Findings The expression of EAAT2 in both cell types conferred the expected glutamate-grabbing activity in in vitro and in vivo studies. The functional improvement observed in ischemic rats treated with EAAT2–HEK at low dose, confirmed that this effect was indeed mediated by the glutamate-grabbing activity associated with EAAT2 functionality. Unexpectedly, both cell doses of non-transfected MSCs induced higher protection than transfected EAAT2–MSCs by another mechanism independent of the glutamate-grabbing capacity. Interpretation Although the transfection procedure most likely interferes with some of the intrinsic protective mechanisms of mesenchymal cells, the results show that the induced expression of EAAT2 in cells represents a novel alternative to mitigate the excitotoxic effects of glutamate and paves the way to combine this strategy with current cell therapies for cerebral ischemia. |
Publisher version: | https://doi.org/10.1016/j.ebiom.2018.11.024 |
URI: | http://hdl.handle.net/10347/21593 |
DOI: | 10.1016/j.ebiom.2018.11.024 |
ISSN: | 2352-3964 |
Rights: | © 2018 The Authors. Published by Elsevier B.V. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed. For commercial reuse, permission must be requested below. |
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Except where otherwise noted, this item's license is described as © 2018 The Authors. Published by Elsevier B.V. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed. For commercial reuse, permission must be requested below.