title: In vitro characteristics of valproic acid and all-trans-retinoic acid and their combined use in promoting neuronal differentiation while suppressing astrocytic differentiation in neural stem cells.
abstract: Multipotent neural stem cells (NSCs) are currently under investigation as a candidate treatment for central nervous system (CNS) injury because of their potential to compensate for neuronal damage and to reconstruct disrupted neuronal connections. To maximize the regenerative effect of the derived neurons and to minimize the side effects of the derived astrocytes, it is necessary to regulate the fate determination of NSCs to produce more neurons and fewer astrocytes. Both valproic acid (VPA) and all-trans-retinoic acid (ATRA), two clinically established drugs, induce neuronal differentiation and facilitate neurite outgrowth at the expense of astrocytic differentiation in NSCs. However, the time-dependent activities and the long-term treatment effects of these drugs have not been explored in NSCs. More importantly, the efficacies of VPA and ATRA in neuronal promotion and astrocytic suppression remain unclear. In this study, we compare the time-dependent characteristics of VPA and ATRA in NSC differentiation and neurite outgrowth in vitro and, for the first time, demonstrate the improved efficacy of their combined application in neuronal induction and astrocytic suppression. These significant effects are closely coupled to the altered expression of a neurogenic transcription factor, a Wnt signaling component, a cell cycle regulator and a neural growth factor, indicating an underlying cross-talk between the mechanisms of action of ATRA and VPA. These findings indicate that a novel strategy combining these two therapeutic drugs may improve the restorative effect of NSC transplantation by altering the expression of their interconnected targets for fate determination.
authors.affiliation: Department of Orthopaedics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China. Electronic address: tiancichu2012@hotmail.com.
authors.forename: Tianci
authors.initials: T
authors.lastname: Chu
authors.affiliation: Department of Orthopaedics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China. Electronic address: kevin_zyfllxy@hotmail.com.
authors.forename: Hengxing
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China. Electronic address: tianyiwang121@yahoo.com.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China. Electronic address: lulumagic@126.com.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Orthopaedics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China. Electronic address: lifuyuanty@163.com.
authors.forename: Fuyuan
authors.initials: F
authors.lastname: Li
authors.affiliation: School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin 300071, PR China. Electronic address: liubin78@yahoo.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin 300071, PR China. Electronic address: kongxiaohong@yahoo.com.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Orthopaedics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China. Electronic address: shiqing.feng@yahoo.com.
authors.forename: Shiqing
authors.initials: S
authors.lastname: Feng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004338:Drug Combinations; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016548:Prosencephalon / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D051176:beta Catenin; D014212:Tretinoin; D014635:Valproic Acid
keywords: All-trans-retinoic acid; Cell fate determination; Cross-talk; Neural stem cell; Time-dependent; Valproic acid