title: Differentiation of rat adipose tissue-derived stem cells into neuron-like cells by valproic acid, a histone deacetylase inhibitor.
abstract: Valproic acid (VPA) is a widely used antiepileptic drug, which has recently been reported to modulate the neuronal differentiation of adipose tissue-derived stem cells (ASCs) in humans and dogs. However, controversy exists as to whether VPA really acts as an inducer of neuronal differentiation of ASCs. The present study aimed to elucidate the effect of VPA in neuronal differentiation of rat ASCs. One or three days of pretreatment with VPA (2 mM) followed by neuronal induction enhanced the ratio of immature neuron marker βIII-tubulin-positive cells in a time-dependent manner, where the majority of cells also had a positive signal for neurofilament medium polypeptide (NEFM), a mature neuron marker. RT-PCR analysis revealed increases in the mRNA expression of microtubule-associated protein 2 (MAP2) and NEFM mature neuron markers, even without neuronal induction. Three-days pretreatment of VPA increased acetylation of histone H3 of ASCs as revealed by immunofluorescence staining. Chromatin immunoprecipitation assay also showed that the status of histone acetylation at H3K9 correlated with the gene expression of TUBB3 in ASCs by VPA. These results indicate that VPA significantly promotes the differentiation of rat ASCs into neuron-like cells through acetylation of histone H3, which suggests that VPA may serve as a useful tool for producing transplantable cells for future applications in clinical treatments.
authors.affiliation: Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Okubo
authors.forename: Daiki
authors.initials: D
authors.lastname: Hayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yaguchi
authors.forename: Yudai
authors.initials: Y
authors.lastname: Fujita
authors.forename: Motoharu
authors.initials: M
authors.lastname: Sakaue
authors.forename: Takehito
authors.initials: T
authors.lastname: Suzuki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tsukamoto
authors.forename: Ohoshi
authors.initials: O
authors.lastname: Murayama
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lynch
authors.forename: Yoko
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takizawa
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D017208:Rats, Wistar; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013268:Stimulation, Chemical; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; C488416:Tubb3 protein, rat; D014404:Tubulin; C061195:neurofilament protein M; D014635:Valproic Acid