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Role of HGF and EGF signaling in transdifferentiation of hepatocytes to biliary epithelium in organoid cultures
Author(s) -
Limaye Pallavi B.,
Bowen William C.,
Luo Jianhua,
Michalopoulos George K.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a71-a
Subject(s) - hepatocyte growth factor , transdifferentiation , epidermal growth factor , organoid , microbiology and biotechnology , biology , western blot , protein kinase b , hepatocyte , cancer research , chemistry , signal transduction , cell culture , stem cell , receptor , in vitro , biochemistry , genetics , gene
We have previously demonstrated that hepatocytes transdifferentiate into biliary epithelium (BE) in vivo & in vitro . The present study was designed to investigate the mechanisms of hepatocyte transdifferentiation in vitro . Rat hepatocyte organoid cultures were stimulated with various growth factors (GF) including HGF, EGF, VEGF, PDGF, stem cell factor (SCF), microphage stimulating protein (MSP), FGF‐a, FGF‐b, and FGF‐8b. Only the cultures treated with HGF, EGF and their combination exhibited formation of true tissue with characteristic histologic architecture comprising hepatocytes and hepatocyte‐derived BE. AE1/AE3 immunohistochemistry was used to confirm presence of BE. While Western blot analysis revealed expression of receptors for all the GFs, none of the GFs tested other than HGF and EGF promoted hepatocyte to BE transdifferentiation. Microarray analysis of the organoid cultures identified upregulation of some important target genes of HGF and EGF such as osteopontin, CD44, CXC chemokine LIX, cyclin D1, and β‐catenin, which was confirmed with Western blot analysis. Further analysis indicated that AKT phosphorylation secondary to HGF and EGF‐mediated signaling was increased in cultures treated with HGF, EGF and the combination, but not by the other growth factors. These data indicate that HGF and EGF signaling with downstream AKT activation may be responsible for hepatocyte to BE transdifferentiation.