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Blood glutamate EAAT 2 -cell grabbing therapy in cerebral ischemia.

Authors :: 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
Source :: EBioMedicine [EBioMedicine] 2019 Jan; Vol. 39, pp. 118-131. Date of Electronic Publication: 2018 Dec 13.
Publication Year :: 2019
Abstract: Background: Excitatory amino acid transporter 2 (EAAT <subscript>2</subscript> ) plays a pivotal role in glutamate clearance in the adult brain, thereby preventing excitotoxic effects. Considering the high efficacy of EAAT <subscript>2</subscript> 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.<br />Methods: To address this hypothesis, EAAT <subscript>2</subscript> -encoding cDNA was introduced into MSCs and human embryonic kidney 293 cells (HEK cells) as the control cell line. EAAT <subscript>2</subscript> 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 <superscript>6</superscript> and 9 × 10 <superscript>6</superscript> cells/animal.<br />Findings: The expression of EAAT <subscript>2</subscript> 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 <subscript>2</subscript> -HEK at low dose, confirmed that this effect was indeed mediated by the glutamate-grabbing activity associated with EAAT <subscript>2</subscript> functionality. Unexpectedly, both cell doses of non-transfected MSCs induced higher protection than transfected EAAT <subscript>2</subscript> -MSCs by another mechanism independent of the glutamate-grabbing capacity.<br />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 EAAT <subscript>2</subscript> 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.<br /> (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)