Phthalazinone Pyrazole Enhances the Hepatic Functions of Human Embryonic Stem Cell-Derived Hepatocyte-Like Cells via Suppression of the Epithelial-Mesenchymal Transition

Young Jun Choi, Hyemin Kim, Ji Woo Kim, Chang Woo Song, Dae-Sung Kim, Seokjoo Yoon, Han Jin Park

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Abstract

During liver development, nonpolarized hepatic progenitor cells differentiate into mature hepatocytes with distinct polarity. This polarity is essential for maintaining the intrinsic properties of hepatocytes. The balance between the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) plays a decisive role in differentiation of polarized hepatocytes. In this study, we found that phthalazinone pyrazole (PP), a selective inhibitor of Aurora-A kinase (Aurora-A), suppressed the EMT during the differentiation of hepatocyte-like cells (HLCs) from human embryonic stem cells. The differentiated HLCs treated with PP at the hepatoblast stage showed enhanced hepatic morphology and functions, particularly with regard to the expression of drug metabolizing enzymes. Moreover, we found that these effects were mediated though suppression of the AKT pathway, which is involved in induction of the EMT, and upregulation of hepatocyte nuclear factor 4α expression rather than Aurora-A inhibition. In conclusion, these findings provided insights into the regulatory role of the EMT on in vitro hepatic maturation, suggesting that inhibition of the EMT may drive transformation of hepatoblast cells into mature and polarized HLCs.

Original languageEnglish
Pages (from-to)438-450
Number of pages13
JournalStem Cell Reviews and Reports
Volume14
Issue number3
DOIs
Publication statusPublished - 2018 Jun 1

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Keywords

  • Epithelial-mesenchymal transition
  • Hepatocyte-like cells
  • Mesenchymal-epithelial transition
  • Phthalazinone pyrazole
  • Polarity

ASJC Scopus subject areas

  • Cell Biology
  • Cancer Research

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