title: Histone deacetylase inhibitor valproic acid promotes the differentiation of human induced pluripotent stem cells into hepatocyte-like cells.
abstract: In this study, we aimed to elucidate the effects and mechanism of action of valproic acid on hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells. Human induced pluripotent stem cells were differentiated into endodermal cells in the presence of activin A and then into hepatic progenitor cells using dimethyl sulfoxide. Hepatic progenitor cells were matured in the presence of hepatocyte growth factor, oncostatin M, and dexamethasone with valproic acid that was added during the maturation process. After 25 days of differentiation, cells expressed hepatic marker genes and drug-metabolizing enzymes and exhibited drug-metabolizing enzyme activities. These expression levels and activities were increased by treatment with valproic acid, the timing and duration of which were important parameters to promote differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells into hepatocytes. Valproic acid inhibited histone deacetylase activity during differentiation of human induced pluripotent stem cells, and other histone deacetylase inhibitors also enhanced differentiation into hepatocytes. In conclusion, histone deacetylase inhibitors such as valproic acid can be used to promote hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells.
authors.affiliation: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan; Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwao
authors.affiliation: Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Sachimi
authors.initials: S
authors.lastname: Yoshihashi
authors.affiliation: Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Mimori
authors.affiliation: Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Ruri
authors.initials: R
authors.lastname: Ogihara
authors.affiliation: Department of Environmental and Health Science, Tohoku Pharmaceutical University, Sendai, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nagata
authors.affiliation: Department of Food Science and Technology, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology, Tokyo, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kurose
authors.affiliation: DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Toda, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Saito
authors.affiliation: DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Toda, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.affiliation: Department of Biochemical Pharmacology and Toxicology, Shinshu University, Matsumoto, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohmori
authors.affiliation: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan; Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan; Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Tamihide
authors.initials: T
authors.lastname: Matsunaga
mesh_terms: D000328:Adult; D000368:Aged; D000418:Albumins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D013194:Staining and Labeling; D013379:Substrate Specificity / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000418:Albumins; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D014635:Valproic Acid; D051544:Cytochrome P-450 CYP3A
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