title: Hepatic biliary epithelial cells acquire epithelial integrity but lose plasticity to differentiate into hepatocytes in vitro during development.
abstract: In developing organs, epithelial tissue structures are mostly developed by the perinatal period. However, it is unknown whether epithelial cells are already functionally mature and whether they are fixed in their lineage. Here we show that epithelial cells alter their plasticity during postnatal development by examining the differentiation potential of epithelial cell adhesion molecule (EpCAM)(+) cholangiocytes (biliary epithelial cells) isolated from neonatal and adult mouse livers. We found that neonatal cholangiocytes isolated from 1-week-old liver converted into functional hepatocytes in the presence of oncostatin M and Matrigel®. In contrast, neither morphological changes nor expression of hepatocyte markers were induced in adult cholangiocytes. The transcription factors hepatocyte nuclear factor 4α and CCAAT/enhancer binding protein α (C/EBPα), which are necessary for hepatocytic differentiation, were induced in neonatal cholangiocytes but not in adult cells, whereas grainyhead-like 2 (Grhl2) and hairy-enhance of slit 1 (Hes1), which are implicated in cholangiocyte differentiation, were continuously expressed in adult cells. Overexpression of C/EBPα and Grhl2 promoted and inhibited hepatocytic differentiation, respectively. Furthermore, adult cholangiocytes formed a monolayer with higher barrier function than neonatal ones did, suggesting that cholangiocytes are still in the process of epithelial maturation even after forming tubular structures during the neonatal period. Taken together, these results suggest that cholangiocytes lose plasticity to convert into hepatocytes during epithelial maturation. They lose competency to upregulate hepatocytic transcription factors and downregulate cholagiocytic ones under conditions inducing hepatocytic differentiation. Our results suggest that a molecular machinery augmenting epithelial integrity limits lineage plasticity of epithelial cells.
authors.affiliation: Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanimizu
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ichinohe
authors.forename: Toru
authors.initials: T
authors.lastname: Mizuguchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Mitaka
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D001659:Biliary Tract / Q000166:cytology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000254:growth & development; D051379:Mice; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D051557:Hepatocyte Nuclear Factor 4; D014157:Transcription Factors; C552738:grainy head-like 2 protein, mouse
keywords: Bile duct; Cholangiocytes; Epithelial progenitors; Mature hepatocytes; Plasticity