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

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...

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Bibliographic Details
Published in:Stem cell reviews and reports 2018-06, Vol.14 (3), p.438-450
Main Authors: Choi, Young-Jun, Kim, Hyemin, Kim, Ji-Woo, Song, Chang-Woo, Kim, Dae-Sung, Yoon, Seokjoo, Park, Han-Jin
Format: Article
Language:English
Subjects:
AKT protein
Cell Differentiation - drug effects
Cell Proliferation - drug effects
Cells, Cultured
Embryo cells
Embryos
Enzyme inhibitors
Epithelial-Mesenchymal Transition - drug effects
Genetic transformation
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Human Embryonic Stem Cells - drug effects
Human Embryonic Stem Cells - metabolism
Humans
Immunohistochemistry
Inhibition
Liver
Liver - cytology
Maturation
Mesenchyme
Polarity
Pyrazoles - pharmacology
Stem cells
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Summary: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.
ISSN:2629-3269
2629-3277
DOI:10.1007/s12015-017-9795-4