Valproic Acid, a Histone Deacetylase Inhibitor, Decreases Proliferation of          and Induces Specific Neurogenic Differentiation of Canine Adipose Tissue-Derived Stem          Cells

Yasuhiro KURIHARA; Takehito SUZUKI; Motoharu SAKAUE; Ohoshi MURAYAMA; Yoko MIYAZAKI; Atsushi ONUKI; Takuma AOKI; Miyoko SAITO; Yoko FUJII; Masaharu HISASUE; Kazuaki TANAKA; Tatsuya TAKIZAWA

doi:10.1292/jvms.13-0219

Surgery

Valproic Acid, a Histone Deacetylase Inhibitor, Decreases Proliferation of and Induces Specific Neurogenic Differentiation of Canine Adipose Tissue-Derived Stem Cells

Yasuhiro KURIHARA, Takehito SUZUKI, Motoharu SAKAUE, Ohoshi MURAYAMA, Yoko MIYAZAKI, Atsushi ONUKI, Takuma AOKI, Miyoko SAITO, Yoko FUJII, Masaharu HISASUE, Kazuaki TANAKA, Tatsuya TAKIZAWA

Author information

Yasuhiro KURIHARA
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Takehito SUZUKI
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Motoharu SAKAUE
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Ohoshi MURAYAMA
School of Life and Environmental Science, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Yoko MIYAZAKI
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Atsushi ONUKI
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Takuma AOKI
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Miyoko SAITO
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Yoko FUJII
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Masaharu HISASUE
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Kazuaki TANAKA
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan
Tatsuya TAKIZAWA
Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara 252–5201, Japan

Keywords: adipose tissue-derived stem cell, cell proliferation, histone deacetylase inhibitor, pluripotency, valproic acid

JOURNAL FREE ACCESS

2014 Volume 76 Issue 1 Pages 15-23

DOI https://doi.org/10.1292/jvms.13-0219

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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.

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