title: Valproic acid enhances neuronal differentiation of sympathoadrenal progenitor cells.
abstract: The antiepileptic drug valproic acid (VPA) has been shown to influence the neural differentiation and neurite outgrowth of neural stem cells. Sympathoadrenal progenitor cells share properties with neural stem cells and are considered a potential cell source in the treatment of neurodegenerative diseases. The present study therefore aims at modulating the neural differentiation potential of these cells by treatment with the histone deacetylase inhibitor VPA. We studied the epigenetic effects of VPA in two culture conditions: suspension conditions aimed to expand adrenomedullary sympathoadrenal progenitors within free-floating chromospheres and adherent cell cultures optimized to derive neurons. Treatment of chromospheres with VPA may launch neuronal differentiation mechanisms and improve their neurogenic potential upon transplantation. However, also transplantation of differentiated functional neurons could be beneficial. Treating chromospheres for 7 days with clinically relevant concentrations of VPA (2 mm) revealed a decrease of neural progenitor markers Nestin, Notch2 and Sox10. Furthermore, VPA initiated catecholaminergic neuronal differentiation indicated by upregulation of the neuronal marker β-III-tubulin, the dopaminergic transcription factor Pitx3 and the catecholaminergic enzymes TH and GTPCH. In adherent neural differentiation conditions, VPA treatment improved the differentiation of sympathoadrenal progenitor cells into catecholaminergic neurons with significantly elevated levels of nor- and epinephrine. In conclusion, similar to neural stem cells, VPA launches differentiation mechanisms in sympathoadrenal progenitor cells that result in increased generation of functional neurons. Thus, data from this study will be relevant to the potential use of chromaffin progenitors in transplantation therapies of neurodegenerative diseases.
authors.affiliation: Division of Molecular Endocrinology, Medical Clinic III, Carl Gustav Carus University Clinic, Technische Universität Dresden, Dresden, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Vukićević
authors.affiliation: Departments of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Qin
authors.affiliation: Division of Molecular Endocrinology, Medical Clinic III, Carl Gustav Carus University Clinic, Technische Universität Dresden, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Balyura
authors.affiliation: 1] Departments of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany [2] Medical Clinic III, Carl Gustav Carus University Clinic, Technische Universität Dresden, Dresden, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Eisenhofer
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute, and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Wong
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute, and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Licinio
authors.affiliation: 1] Medical Clinic III, Carl Gustav Carus University Clinic, Technische Universität Dresden, Dresden, Germany [2] Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
authors.forename: S R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: 1] Division of Molecular Endocrinology, Medical Clinic III, Carl Gustav Carus University Clinic, Technische Universität Dresden, Dresden, Germany [2] Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ehrhart-Bornstein
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016196:S Phase / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D002395:Catecholamines; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014404:Tubulin; D014635:Valproic Acid; D006655:Histone Deacetylases