Neural stem cell transplantation induces stroke recovery by upregulating glutamate transporter GLT-1 in astrocytes

Marco Bacigaluppi, Gianluca Luigi Russo, Luca Peruzzotti-Jametti, Silvia Rossi, Stefano Sandrone, Erica Butti, Roberta de Ceglia, Andrea Bergamaschi, Caterina Motta, Mattia Gallizioli, Valeria Studer, Emanuela Colombo, Cinthia Farina, Giancarlo Comi, Letterio Salvatore Politi, Luca Muzio, Claudia Villani, Roberto William Invernizzi, Dirk M. Hermann, Diego CentonzeGianvito Martino

Research output: Contribution to journalArticle

Abstract

Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Rescovery 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 microenvi-ronment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke.

Original languageEnglish
Pages (from-to)10529-10544
Number of pages16
JournalJournal of Neuroscience
Volume36
Issue number41
DOIs
Publication statusPublished - Oct 12 2016

Fingerprint

Amino Acid Transport System X-AG
Neural Stem Cells
Stem Cell Transplantation
Astrocytes
Stroke
Pyramidal Tracts
Up-Regulation
Cell Transplantation
Vascular Endothelial Growth Factor A
Glutamic Acid
Neuronal Plasticity
N-Methylaspartate
Therapeutics
Neuroglia
Ischemia

Keywords

  • Ischemia
  • Neurophysiology
  • Plasticity
  • Recovery
  • Stem cell
  • Transplantation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Neural stem cell transplantation induces stroke recovery by upregulating glutamate transporter GLT-1 in astrocytes. / Bacigaluppi, Marco; Russo, Gianluca Luigi; Peruzzotti-Jametti, Luca; Rossi, Silvia; Sandrone, Stefano; Butti, Erica; de Ceglia, Roberta; Bergamaschi, Andrea; Motta, Caterina; Gallizioli, Mattia; Studer, Valeria; Colombo, Emanuela; Farina, Cinthia; Comi, Giancarlo; Politi, Letterio Salvatore; Muzio, Luca; Villani, Claudia; Invernizzi, Roberto William; Hermann, Dirk M.; Centonze, Diego; Martino, Gianvito.

In: Journal of Neuroscience, Vol. 36, No. 41, 12.10.2016, p. 10529-10544.

Research output: Contribution to journalArticle

Bacigaluppi, Marco ; Russo, Gianluca Luigi ; Peruzzotti-Jametti, Luca ; Rossi, Silvia ; Sandrone, Stefano ; Butti, Erica ; de Ceglia, Roberta ; Bergamaschi, Andrea ; Motta, Caterina ; Gallizioli, Mattia ; Studer, Valeria ; Colombo, Emanuela ; Farina, Cinthia ; Comi, Giancarlo ; Politi, Letterio Salvatore ; Muzio, Luca ; Villani, Claudia ; Invernizzi, Roberto William ; Hermann, Dirk M. ; Centonze, Diego ; Martino, Gianvito. / Neural stem cell transplantation induces stroke recovery by upregulating glutamate transporter GLT-1 in astrocytes. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 41. pp. 10529-10544.
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AU - Bacigaluppi, Marco

AU - Russo, Gianluca Luigi

AU - Peruzzotti-Jametti, Luca

AU - Rossi, Silvia

AU - Sandrone, Stefano

AU - Butti, Erica

AU - de Ceglia, Roberta

AU - Bergamaschi, Andrea

AU - Motta, Caterina

AU - Gallizioli, Mattia

AU - Studer, Valeria

AU - Colombo, Emanuela

AU - Farina, Cinthia

AU - Comi, Giancarlo

AU - Politi, Letterio Salvatore

AU - Muzio, Luca

AU - Villani, Claudia

AU - Invernizzi, Roberto William

AU - Hermann, Dirk M.

AU - Centonze, Diego

AU - Martino, Gianvito

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N2 - Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Rescovery 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 microenvi-ronment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke.

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