RT Journal Article
T1 Blood glutamate EAAT2-cell grabbing therapy in cerebral ischemia
A1 Pérez Mato, María
A1 Iglesias Rey, Ramón
A1 Vieites Prado, Alba
A1 Dopico López, Antonio
A1 Argibay González, Bárbara
A1 Fernández Susavila, Héctor
A1 Silva Candal, Andrés da
A1 Pérez Díaz, Amparo
A1 Correa Paz, Clara
A1 Günther, Anne
A1 Ávila Gómez, Paulo
A1 Loza García, María Isabel
A1 Baumann, Arnd
A1 Castillo Sánchez, José Antonio
A1 Sobrino Moreiras, Tomás
A1 Campos Pérez, Francisco
K1 Cell therapy
K1 Cell therapyCerebral ischemia
K1 Excitatory amino acid transporter 2
K1 Excitotoxic injury
K1 Excitotoxic protection
K1 Glutamate
K1 Mesenchymal stem cells
AB BackgroundExcitatory 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.MethodsTo 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.FindingsThe 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.InterpretationAlthough 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.
PB Elsevier
SN 2352-3964
YR 2019
FD 2019-01
LK http://hdl.handle.net/10347/21593
UL http://hdl.handle.net/10347/21593
LA eng
NO 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
NO This study was partially supported by grants from Instituto de Salud Carlos III (PI13/00292 and PI17/0054), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS (RD12/0014), Fundación Mutua Madrileña; the Ministry of Economy and Competitiveness of Spain (SAF2014-56336-R), Xunta de Galicia (Programa de Desarrollo Precomercial de los resultados de investigación del Sistema Público de Salud de Galicia_ PRIS); and the European Union program FEDER. Furthermore, F. Campos (CP14/00154) and T. Sobrino (CP12/03121 and CPII17/00027) are recipients of a research contract from Miguel Servet Program of Instituto de Salud Carlos III
DS Minerva
RD 23 abr 2026