title: Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes.
abstract: Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST. Concurrently, NPC-treated mice displayed a reduced CST degeneration, increased axonal rewiring, and augmented dendritic arborization, resulting in long-term functional amelioration persisting up to 60 d after ischemia. The enhanced functional and structural plasticity relied on the capacity of transplanted NPCs to localize in the peri-ischemic and ischemic area, to promote the upregulation of the glial glutamate transporter 1 (GLT-1) on astrocytes and to reduce peri-ischemic extracellular glutamate. The upregulation of GLT-1 induced by transplanted NPCs was found to rely on the secretion of VEGF by NPCs. Blocking VEGF during the first week after stroke reduced GLT-1 upregulation as well as long-term behavioral recovery in NPC-treated mice. Our results show that NPC transplantation, by modulating the excitatory-inhibitory balance and stroke microenvironment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke.
  
  
  
  Tissue damage and loss of function occurring after stroke can be constrained by fostering plasticity processes of the brain. Over the past years, stem cell transplantation for repair of the CNS has received increasing interest, although underlying mechanism remain elusive. We here show that neural stem/precursor cell transplantation after ischemic stroke is able to foster axonal rewiring and dendritic plasticity and to induce long-term functional recovery. The observed therapeutic effect of neural precursor cells seems to underlie their capacity to upregulate the glial glutamate transporter on astrocytes through the vascular endothelial growth factor inducing favorable changes in the electrical and molecular stroke microenvironment. Cell-based approaches able to influence plasticity seem particularly suited to favor poststroke recovery.
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and martino.gianvito@hsr.it bacigaluppi.marco@hsr.it.
authors.forename: Marco
authors.identifier: 0000-0002-0213-2328
authors.initials: M
authors.lastname: Bacigaluppi
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Gianluca Luigi
authors.identifier: 0000-0002-4286-825X
authors.initials: GL
authors.lastname: Russo
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Luca
authors.identifier: 0000-0002-9396-5607
authors.initials: L
authors.lastname: Peruzzotti-Jametti
authors.affiliation: Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sandrone
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Erica
authors.initials: E
authors.lastname: Butti
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Roberta
authors.identifier: 0000-0001-6264-677X
authors.initials: R
authors.lastname: De Ceglia
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Andrea
authors.identifier: 0000-0001-9010-2577
authors.initials: A
authors.lastname: Bergamaschi
authors.affiliation: Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy.
authors.forename: Caterina
authors.identifier: 0000-0001-6734-6979
authors.initials: C
authors.lastname: Motta
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Mattia
authors.identifier: 0000-0001-9245-914X
authors.initials: M
authors.lastname: Gallizioli
authors.affiliation: Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy.
authors.forename: Valeria
authors.identifier: 0000-0003-2529-7640
authors.initials: V
authors.lastname: Studer
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Colombo
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Cinthia
authors.initials: C
authors.lastname: Farina
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Neuroradiology Unit, Division of Neuroscience, San Raffaele Scientific Institute and Vita Salute San Raffaele University, 20132 Milan, Italy.
authors.forename: Letterio Salvatore
authors.identifier: 0000-0002-6190-6688
authors.initials: LS
authors.lastname: Politi
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and.
authors.forename: Luca
authors.initials: L
authors.lastname: Muzio
authors.affiliation: Neurochemistry and Behavior, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," 20156 Milan, Italy.
authors.forename: Claudia
authors.identifier: 0000-0001-6334-9013
authors.initials: C
authors.lastname: Villani
authors.affiliation: Neurochemistry and Behavior, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," 20156 Milan, Italy.
authors.forename: Roberto William
authors.identifier: 0000-0002-6017-9781
authors.initials: RW
authors.lastname: Invernizzi
authors.affiliation: Department of Neurology, University Hospital, D-45122 Essen, Germany, and.
authors.forename: Dirk Matthias
authors.initials: DM
authors.lastname: Hermann
authors.affiliation: Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy, Unit of Neurology and of Neurorehabilitation, IRCCS Neuromed, 86077 Pozzilli (IS), Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology and martino.gianvito@hsr.it bacigaluppi.marco@hsr.it.
authors.forename: Gianvito
authors.identifier: 0000-0003-1295-9131
authors.initials: G
authors.lastname: Martino
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal; D002545:Brain Ischemia / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000637:transplantation*; D009473:Neuronal Plasticity; D018408:Patch-Clamp Techniques; D020127:Recovery of Function; D033581:Stem Cell Transplantation / Q000379:methods*; D020521:Stroke / Q000473:pathology / Q000523:psychology / Q000628:therapy*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C493396:Slc1a2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D018698:Glutamic Acid
keywords: ischemia; neurophysiology; plasticity; recovery; stem cell; transplantation