title: Valproic acid, a histone deacetylase inhibitor, decreases proliferation of and induces specific neurogenic differentiation of canine adipose tissue-derived stem cells.
abstract: Adipose tissue-derived stem cells (ADSCs) isolated from adult tissue have pluripotent differentiation and self-renewal capability. The tissue source of ADSCs can be obtained in large quantities and with low risks, thus highlighting the advantages of ADSCs in clinical applications. Valproic acid (VPA) is a widely used antiepileptic drug, which has recently been reported to affect ADSC differentiation in mice and rats; however, few studies have been performed on dogs. We aimed to examine the in vitro effect of VPA on canine ADSCs. Three days of pretreatment with VPA decreased the proliferation of ADSCs in a dose-dependent manner; VPA concentrations of 4 mM and above inhibited the proliferation of ADSCs. In parallel, VPA increased p16 and p21 mRNA expression, suggesting that VPA attenuated the proliferative activity of ADSCs by activating p16 and p21. Furthermore, the effects of VPA on adipogenic, osteogenic or neurogenic differentiation were investigated morphologically. VPA pretreatment markedly promoted neurogenic differentiation, but suppressed the accumulation of lipid droplets and calcium depositions. These modifications of ADSCs by VPA were associated with a particular gene expression profile, viz., an increase in neuronal markers, that is, NSE, TUBB3 and MAP2, a decrease in the adipogenic marker, LPL, but no changes in osteogenic markers, as estimated by reverse transcription-PCR analysis. These results suggested that VPA is a specific inducer of neurogenic differentiation of canine ADSCs and is a useful tool for studying the interaction between chromatin structure and cell fate determination.
authors.affiliation: Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252-5201, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kurihara
authors.forename: Takehito
authors.initials: T
authors.lastname: Suzuki
authors.forename: Motoharu
authors.initials: M
authors.lastname: Sakaue
authors.forename: Ohoshi
authors.initials: O
authors.lastname: Murayama
authors.forename: Yoko
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Onuki
authors.forename: Takuma
authors.initials: T
authors.lastname: Aoki
authors.forename: Miyoko
authors.initials: M
authors.lastname: Saito
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fujii
authors.forename: Masaharu
authors.initials: M
authors.lastname: Hisasue
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takizawa
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology; D004285:Dogs / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000502:physiology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000662:veterinary; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014404:Tubulin / Q000235:genetics / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000502:physiology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D056572:Histone Deacetylase Inhibitors; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D014635:Valproic Acid; D012313:RNA; D054462:p21-Activated Kinases; D010751:Phosphopyruvate Hydratase