Histone deacetylase inhibitor valproic acid promotes the differentiation of human induced pluripotent stem cells into hepatocyte-like cells

PLoS One. 2014 Aug 1;9(8):e104010. doi: 10.1371/journal.pone.0104010. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Albumins / metabolism
  • Biomarkers / metabolism
  • Cell Differentiation / drug effects*
  • Cell Line
  • Cell Shape / drug effects
  • Cytochrome P-450 CYP3A / biosynthesis
  • Cytochrome P-450 CYP3A / genetics
  • Enzyme Induction / drug effects
  • Fluorescent Antibody Technique
  • Hepatocytes / cytology*
  • Hepatocytes / drug effects
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Inactivation, Metabolic / drug effects
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / enzymology
  • Middle Aged
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Small Molecule Libraries / pharmacology
  • Staining and Labeling
  • Substrate Specificity / drug effects
  • Valproic Acid / pharmacology*

Substances

  • Albumins
  • Biomarkers
  • Histone Deacetylase Inhibitors
  • RNA, Messenger
  • Small Molecule Libraries
  • Valproic Acid
  • Cytochrome P-450 CYP3A

Grant support

This work was supported, in part, by Grants-in-Aid from the Japan Society for the Promotion of Science (23390036, 22390028 and 25460193), by Research on Publicly Essential Drugs and Medical Devices from Japan Health Sciences Foundation (KHB1011 and KHB1208), and by a National Grant-in-Aid from Japanese Ministry of Health, Labor, and Welfare (H22-003). Mitsubishi Tanabe Pharma Corporation provided support in the form of salaries for authors MS & TN, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.