title: Electric signals regulate directional migration of ventral midbrain derived dopaminergic neural progenitor cells via Wnt/GSK3β signaling.
abstract: Neural progenitor cell (NPC) replacement therapy is a promising treatment for neurodegenerative disorders including Parkinson's disease (PD). It requires a controlled directional migration and integration of NPCs, for example dopaminergic (DA) progenitor cells, into the damaged host brain tissue. There is, however, only limited understanding of how to regulate the directed migration of NPCs to the diseased or damaged brain tissues for repair and regeneration. The aims of this study are to explore the possibility of using a physiological level of electrical stimulation to regulate the directed migration of ventral midbrain NPCs (NPCs(vm)), and to investigate their potential regulation via GSK3β and associated downstream effectors. We tested the effects of direct-current (DC) electric fields (EFs) on the migration behavior of the NPCs(vm). A DC EF induced directional cell migration toward the cathode, namely electrotaxis. Reversal of the EF polarity triggered a sharp reversal of the NPC(vm) electrotaxis. The electrotactic response was both time and EF voltage dependent. Pharmacologically inhibiting the canonical Wnt/GSK3β pathway significantly reduced the electrotactic response of NPCs(vm), which is associated with the down-regulation of GSK3β phosphorylation, β-catenin activation and CLASP2 expression. This was further proved by RNA interference of GSK3β, which also showed a significantly reduced electrotactic response in association with reduced β-catenin activation and CLASP2 expression. In comparison, RNA interference of β-catenin slightly reduced electrotactic response and CLASP2 expression. Both pharmacological inhibition of Wnt/GSK3β and RNA interference of GSK3β/β-catenin clearly reduced the asymmetric redistribution of CLASP2 and its co-localization with α-tubulin. These results suggest that Wnt/GSK3β signaling contributes to the electrotactic response of NPCs(vm) through the coordination of GSK3β phosphorylation, β-catenin activation, CLASP2 expression and asymmetric redistribution to the leading edge of the migrating cells.
authors.affiliation: Laboratory Animal Center, China Medical University, Shenyang, 110001, China; School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF14 4XY, UK.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF14 4XY, UK.
authors.forename: Bangfu
authors.initials: B
authors.lastname: Zhu
authors.affiliation: School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF14 4XY, UK.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Institute of Neurosciences, Fourth Military Medical University, 169 West Changle Road, Xi'an 710032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Bio-X Center, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Tian
authors.affiliation: Institute of Neurosciences, Fourth Military Medical University, 169 West Changle Road, Xi'an 710032, China.
authors.forename: Gong
authors.initials: G
authors.lastname: Ju
authors.affiliation: School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF14 4XY, UK.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wei
authors.affiliation: School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF14 4XY, UK; Department of Dermatology, China Medical University, Shenyang, 110001, China. Electronic address: SongB3@cardiff.ac.uk.
authors.forename: Bing
authors.initials: B
authors.lastname: Song
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism; D004574:Electromagnetic Fields; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C577861:CLASP2 protein, rat; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: Dopaminergic neurons; Electric fields; Migration; Neural progenitor cell; Ventral midbrain; Wnt/GSK3β signaling pathway