Therapeutic Effect of Astroglia-like Mesenchymal Stem Cells Expressing Glutamate Transporter in a Genetic Rat Model of Depression
| Autor: | Hae Kyung Lee, Gila Kazimirsky, Susan Finniss, Rachela Popovtzer, Simona Cazacu, Gal Yadid, Menachem Motiei, Amit Shwartz, Shani Yael Dagan, Noam Kronfeld, Oshra Betzer, Chaya Brodie |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Amino Acid Transport System X-AG Gene Expression Medicine (miscellaneous) Hippocampus Pharmacology Neurotransmission Mesenchymal Stem Cell Transplantation 03 medical and health sciences Glutamatergic 0302 clinical medicine Neurotrophic factors Genetic model Animals Humans Longitudinal Studies Pharmacology Toxicology and Pharmaceutics (miscellaneous) Behavior Animal Depression Chemistry Dentate gyrus Mesenchymal stem cell Mesenchymal Stem Cells Rats Cell biology Disease Models Animal 030104 developmental biology Dentate Gyrus Excitatory postsynaptic potential Therapeutic Uses 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.18914 |
| Popis: | Recent studies have proposed that abnormal glutamatergic neurotransmission and glial pathology play an important role in the etiology and manifestation of depression. It was postulated that restoration of normal glutamatergic transmission, by enhancing glutamate uptake, may have a beneficial effect on depression. We examined this hypothesis using unique human glial-like mesenchymal stem cells (MSCs), which in addition to inherent properties of migration to regions of injury and secretion of neurotrophic factors, were differentiated to express high levels of functional glutamate transporters (excitatory amino acid transporters; EAAT). Additionally, gold nanoparticles (GNPs), which serve as contrast agents for CT imaging, were loaded into the cells for non-invasive, real-time imaging and tracking of MSC migration and final location within the brain. MSC-EAAT (2×105; 10 μl) were administered (i.c.v.) to Flinder Sensitive Line rats (FSLs), a genetic model for depression, and longitudinal behavioral and molecular changes were monitored. FSL rats treated with MSC-EAAT showed attenuated depressive-like behaviors (measured by the forced swim test, novelty exploration test and sucrose self-administration paradigm), as compared to controls. CT imaging, Flame Atomic Absorption Spectroscopy analysis and immunohistochemistry showed that the majority of MSCs homed specifically to the dentate gyrus of the hippocampus, a region showing structural brain changes in depression, including loss of glial cells. mRNA and protein levels of EAAT1 and BDNF were significantly elevated in the hippocampus of MSC-EAAT-treated FSLs. Our findings indicate that MSC-EAATs effectively improve depressive-like manifestations, possibly in part by increasing both glutamate uptake and neurotropic factor secretion in the hippocampus. |
| Databáze: | OpenAIRE |
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