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Int. J. Mol. Sci. 2018, 19(3), 651; https://doi.org/10.3390/ijms19030651

Mesenchymal Stem Cell Protection of Neurons against Glutamate Excitotoxicity Involves Reduction of NMDA-Triggered Calcium Responses and Surface GluR1, and Is Partly Mediated by TNF

1
Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave., 11521 Athens, Greece
2
Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
3
Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave., 11521 Athens, Greece
*
Author to whom correspondence should be addressed.
Received: 5 February 2018 / Revised: 14 February 2018 / Accepted: 14 February 2018 / Published: 25 February 2018
(This article belongs to the Special Issue Tumor Necrosis Factor (TNF))
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Abstract

Mesenchymal stem cells (MSC) provide therapeutic effects in experimental CNS disease models and show promise as cell-based therapies for humans, but their modes of action are not well understood. We previously show that MSC protect rodent neurons against glutamate excitotoxicity in vitro, and in vivo in an epilepsy model. Neuroprotection is associated with reduced NMDA glutamate receptor (NMDAR) subunit expression and neuronal glutamate-induced calcium (Ca2+) responses, and increased expression of stem cell-associated genes. Here, to investigate whether MSC-secreted factors modulate neuronal AMPA glutamate receptors (AMPAR) and gene expression, we performed longitudinal studies of enriched mouse cortical neurons treated with MSC conditioned medium (CM). MSC CM did not alter total levels of GluR1 AMPAR subunit in neurons, but its distribution, reducing cell surface levels compared to non-treated neurons. Proportions of NeuN-positive neurons, and of GFAP- and NG2-positive glia, were equal in untreated and MSC CM-treated cultures over time suggesting that neurons, rather than differentially-expanded glia, account for the immature gene profile previously reported in MSC CM-treated cultures. Lastly, MSC CM contained measurable amounts of tumor necrosis factor (TNF) bioactivity and pre-treatment of MSC CM with the TNF inhibitor etanercept reduced its ability to protect neurons. Together these results indicate that MSC-mediated neuroprotection against glutamate excitotoxicity involves reduced NMDAR and GluR1-containing AMPAR function, and TNF-mediated neuroprotection. View Full-Text
Keywords: neurodegeneration; neuroprotection; neuronal Ca2+ signaling; glutamate receptors; NMDA; AMPA receptors; TNF; multiple sclerosis neurodegeneration; neuroprotection; neuronal Ca2+ signaling; glutamate receptors; NMDA; AMPA receptors; TNF; multiple sclerosis
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Papazian, I.; Kyrargyri, V.; Evangelidou, M.; Voulgari-Kokota, A.; Probert, L. Mesenchymal Stem Cell Protection of Neurons against Glutamate Excitotoxicity Involves Reduction of NMDA-Triggered Calcium Responses and Surface GluR1, and Is Partly Mediated by TNF. Int. J. Mol. Sci. 2018, 19, 651.

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