title: Mesenchymal stem cells enhance GABAergic transmission in co-cultured hippocampal neurons.
abstract: Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent stem cells endowed with neurotrophic potential combined with immunological properties, making them a promising therapeutic tool for neurodegenerative disorders. However, the mechanisms through which MSCs promote the neurological recovery following injury or inflammation are still largely unknown, although cell replacement and paracrine mechanisms have been hypothesized. In order to find out what are the mechanisms of the trophic action of MSCs, as compared to glial cells, on CNS neurons, we set up a co-culture system where rat MSCs (or cortical astrocytes) were used as a feeding layer for hippocampal neurons without any direct contact between the two cell types. The analysis of hippocampal synaptogenesis, synaptic vesicle recycling and electrical activity show that MSCs were capable to support morphological and functional neuronal differentiation. The proliferation of hippocampal glial cells induced by the release of bioactive substance(s) from MSCs was necessary for neuronal survival. Furthermore, MSCs selectively increased hippocampal GABAergic pre-synapses. This effect was paralleled with a higher expression of the potassium/chloride KCC2 co-transporter and increased frequency and amplitude of mIPSCs and sIPSCs. The enhancement of GABA synapses was impaired by the treatment with K252a, a Trk/neurotrophin receptor blocker, and by TrkB receptor bodies hence suggesting the involvement of BDNF as a mediator of such effects. The results obtained here indicate that MSC-secreted factors induce glial-dependent neuronal survival and trigger an augmented GABAergic transmission in hippocampal cultures, highlighting a new effect by which MSCs could promote CNS repair. Our results suggest that MSCs may be useful in those neurological disorders characterized by an impairment of excitation versus inhibition balance.
authors.affiliation: Department of Experimental Medicine, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Mauri
authors.forename: Daniela
authors.initials: D
authors.lastname: Lentini
authors.forename: Marta
authors.initials: M
authors.lastname: Gravati
authors.forename: Dana
authors.initials: D
authors.lastname: Foudah
authors.forename: Gerardo
authors.initials: G
authors.lastname: Biella
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Mauro
authors.initials: M
authors.lastname: Toselli
authors.forename: Marco
authors.initials: M
authors.lastname: Parenti
authors.forename: Silvia
authors.initials: S
authors.lastname: Coco
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D061252:Feeder Cells; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005680:gamma-Aminobutyric Acid