title: Mesenchymal stem cells protect from sub-chronic phencyclidine insult in vivo and counteract changes in astrocyte gene expression in vitro.
abstract: Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine strategies in brain diseases. Experimental studies have shown that repeated administration of phencyclidine (PCP) leads to schizophrenia-like behavioral changes in mice. The aim of the present study was to explore the effectiveness of MSC transplantation into the hippocampus in attenuating PCP-induced social behavior deficits. PCP was administered subcutaneously to C57bl mice (10mg/kg daily) for 2 weeks. On the first day of PCP administration, adult human MSCs were transplanted into the hippocampus. A week after the last PCP dose, the mice underwent social preference testing. MSC transplantation was associated with a significant reduction in the adverse social behavior induced by PCP. Immunohistochemical analysis revealed that the stem cells survived in the mouse brain, and hippocampal Western blot analysis revealed a statistical trend towards a decrease in cleaved caspase 3 protein levels in the stem cell treated group. Upon in vitro co-culture of astrocytes and MSCs, the MSCs, in the presence of PCP, positively regulated astrocyte expression of genes involved in glutamate metabolism and antioxidant defenses. These findings suggest that MSC transplantation into the hippocampus may serve as a novel neuroprotective tool for the treatment of the PCP-induced schizophrenia-like social endophenotype. The mechanism underlying the beneficial behavioral effect may involve modulation of host astrocyte functioning, including glutamate processing and antioxidant capacity.
authors.affiliation: Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel; Research Unit at Geha Mental Health Center, Israel. Electronic address: barzilyr@post.tau.ac.il.
authors.forename: Ran
authors.initials: R
authors.lastname: Barzilay
authors.forename: Javier
authors.initials: J
authors.lastname: Ganz
authors.forename: Ofer
authors.initials: O
authors.lastname: Sadan
authors.forename: Tali
authors.initials: T
authors.lastname: Ben-Zur
authors.forename: Ziv
authors.initials: Z
authors.lastname: Bren
authors.forename: Noa
authors.initials: N
authors.lastname: Hinden
authors.forename: Michal
authors.initials: M
authors.lastname: Taler
authors.forename: Nirit
authors.initials: N
authors.lastname: Lev
authors.forename: Irit
authors.initials: I
authors.lastname: Gil-Ad
authors.forename: Abraham
authors.initials: A
authors.lastname: Weizman
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010622:Phencyclidine / Q000633:toxicity*; D012559:Schizophrenia / Q000139:chemically induced* / Q000473:pathology / Q000601:surgery*
chemical_list: D010622:Phencyclidine
keywords: Animal model; Phencyclidine; Regenerative medicine; Schizophrenia; Social behavior; Stem cells