Valproic acid promotes mature neuronal differentiation of adipose tissue-derived stem cells through iNOS–NO–cGMP signaling pathway

Publication date: Available online 1 September 2019Source: Nitric OxideAuthor(s): Takumi Okubo, Shinri Fujimoto, Daiki Hayashi, Takehito Suzuki, Motoharu Sakaue, Yoko Miyazaki, Kazuaki Tanaka, Makoto Usami, Tatsuya TakizawaAbstractValproic acid (VPA) remarkably promotes the differentiation of adipose tissue-derived stem cells (ASCs) to mature neuronal cells, enabling neuronal induction within only three days. Here, we investigated the involvement of NO-signaling in the VPA-promoted neuronal differentiation of ASCs as a possible mechanism. Cultured rat ASCs were differentiated to matured neuronal cells rich in dendrites and expressing βIII-tubulin protein, a neuronal marker, by treatments with VPA at 2 mM for 3 days and subsequently with the neuronal induction medium (NIM) containing cAMP-elevating agents for 2 h. Increased intracellular NO was detected in neuronal cells differentiated from ASCs treated with VPA by a fluorescence NO-specific probe, diaminofluorescein-FM diacetate. However, a NO donor (NOC18) increased the incidence of neuronal cells only to a lesser extent than VPA, indicating the insufficiency of exogenous NO. RT-PCR analysis of ASCs treated with VPA showed increased mRNA expression of inducible nitric oxide synthase (iNOS) with the acetylation of its associated histone H3K9. iNOS inhibitors (1400 W and dexamethasone) or a soluble guanylate cyclase inhibitor (ODQ) decreased the incidence of neuronal cells differentiated from ASCs treated with VPA. Thes...
Source: Nitric Oxide - Category: Chemistry Source Type: research