Mesenchymal stem cells protect from sub-chronic phencyclidine insult in vivo and counteract changes in astrocyte gene expression in vitro |
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| Authors: | Ran Barzilay Javier Ganz Ofer Sadan Tali Ben-Zur Ziv Bren Noa Hinden Michal Taler Nirit Lev Irit Gil-Ad Abraham Weizman Daniel Offen |
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| Institution: | 1. Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel;2. Research Unit at Geha Mental Health Center, Israel;3. Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel;1. Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan 330-090, Republic of Korea;2. Division of Rheumatology, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Cheonan 330-090, Republic of Korea;3. Development of Ginseng and Medical Plants Research Institute, Rural Administration, Eumseong, Republic of Korea;4. Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan 330-090, Republic of Korea;5. Division of Child & Adolescent Psychiatry, Department of Psychiatry, Soonchunhyang University Cheonan Hospital, Cheonan 330-721, Republic of Korea;6. Department of Preventive Medicine, Soonchunhyang University, Cheonan 330-721, Republic of Korea;7. Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan 330-090, Republic of Korea;8. Department of Neuropsychiatry, School of Medicine, Kyunghee University, Seoul, Republic of Korea;1. Department of Physiology and Pharmacology, Federal University of Ceará, Cel Nunes de Melo-1127, Caixa Postal-3157, 60430–270 Fortaleza, CE, Brazil;2. Department of Organic and Inorganic Chemistry, Federal University of Ceara, Fortaleza, CE, Brazil;1. Laboratory of Molecular Psychiatry, INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil;2. Programa de Pós-Graduação em Medicina: Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil;3. Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806‐000 Criciúma, SC, Brazil;4. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil;5. Faculdade de Medicina Christus, Fortaleza, Ceará, Brazil;6. Laboratório de Neurofarmacologia, Departamento de Fisiologia e Farmacologia da Universidade Federal do Ceará, Fortaleza, Brazil;1. Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil;2. Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;3. Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil |
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| 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 (10 mg/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. |
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