Blood glutamate EAAT 2 -cell grabbing therapy in cerebral ischemia

Excitatory amino acid transporter 2 (EAAT ) plays a pivotal role in glutamate clearance in the adult brain, thereby preventing excitotoxic effects. Considering the high efficacy of EAAT for glutamate uptake, we hypothesized that the expression of this transporter in mesenchymal stem cells (MSCs) for...

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Published inEBioMedicine Vol. 39; p. 118
Main Authors Pérez-Mato, María, Iglesias-Rey, Ramón, Vieites-Prado, Alba, Dopico-López, Antonio, Argibay, Bárbara, Fernández-Susavila, Héctor, da Silva-Candal, Andrés, Pérez-Díaz, Amparo, Correa-Paz, Clara, Günther, Anne, Ávila-Gómez, Paulo, Isabel Loza, M, Baumann, Arnd, Castillo, José, Sobrino, Tomás, Campos, Francisco
Format Journal Article
LanguageEnglish
Published Netherlands 01.01.2019
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Abstract Excitatory amino acid transporter 2 (EAAT ) plays a pivotal role in glutamate clearance in the adult brain, thereby preventing excitotoxic effects. Considering the high efficacy of EAAT 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. To address this hypothesis, EAAT -encoding cDNA was introduced into MSCs and human embryonic kidney 293 cells (HEK cells) as the control cell line. EAAT expression and functionality were evaluated by in vitro assays. Blood glutamate-grabbing activity was tested in healthy and ischemic rat models treated with 3 × 10 and 9 × 10 cells/animal. The expression of EAAT 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 EAAT -HEK at low dose, confirmed that this effect was indeed mediated by the glutamate-grabbing activity associated with EAAT functionality. Unexpectedly, both cell doses of non-transfected MSCs induced higher protection than transfected EAAT -MSCs by another mechanism independent of the glutamate-grabbing capacity. 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 EAAT 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.
AbstractList Excitatory amino acid transporter 2 (EAAT ) plays a pivotal role in glutamate clearance in the adult brain, thereby preventing excitotoxic effects. Considering the high efficacy of EAAT 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. To address this hypothesis, EAAT -encoding cDNA was introduced into MSCs and human embryonic kidney 293 cells (HEK cells) as the control cell line. EAAT expression and functionality were evaluated by in vitro assays. Blood glutamate-grabbing activity was tested in healthy and ischemic rat models treated with 3 × 10 and 9 × 10 cells/animal. The expression of EAAT 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 EAAT -HEK at low dose, confirmed that this effect was indeed mediated by the glutamate-grabbing activity associated with EAAT functionality. Unexpectedly, both cell doses of non-transfected MSCs induced higher protection than transfected EAAT -MSCs by another mechanism independent of the glutamate-grabbing capacity. 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 EAAT 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.
Author da Silva-Candal, Andrés
Pérez-Mato, María
Fernández-Susavila, Héctor
Argibay, Bárbara
Pérez-Díaz, Amparo
Sobrino, Tomás
Correa-Paz, Clara
Vieites-Prado, Alba
Ávila-Gómez, Paulo
Günther, Anne
Iglesias-Rey, Ramón
Baumann, Arnd
Dopico-López, Antonio
Campos, Francisco
Isabel Loza, M
Castillo, José
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  email: francisco.campos.perez@sergas.es
  organization: Clinical Neurosciences Research Laboratory (LINC), Department of Neurology, Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital, Santiago de Compostela, Spain. Electronic address: francisco.campos.perez@sergas.es
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Keywords Cerebral ischemia
Excitotoxic protection
Cell therapy
Excitatory amino acid transporter 2
Excitotoxic injury
Glutamate
Mesenchymal stem cells
Language English
License Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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Title Blood glutamate EAAT 2 -cell grabbing therapy in cerebral ischemia
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