title: Progressive induction of hepatocyte progenitor cells in chronically injured liver.
abstract: Differentiated epithelial cells show substantial lineage plasticity upon severe tissue injuries. In chronically injured mouse livers, part of hepatocytes become Sry-HMG box containing 9 (Sox9) (+) epithelial cell adhesion molecule (-) hepatocyte nuclear factor 4 α (+) biphenotypic hepatocytes. However, it is not clear whether all Sox9+hepatocytes uniformly possess cellular properties as hepatocyte progenitors. Here, we examined the microarray data comparing Sox9+hepatocytes with mature hepatocytes and identified CD24 as a novel marker for biphenotypic hepatocytes. Immunohistochemical analyses showed that part of Sox9+hepatocytes near expanded ductular structures expressed CD24 in the liver injured by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet and by bile duct ligation. Indeed, Sox9+hepatocytes could be separated into CD24-and CD24+cells by fluorescence activated cell sorting. The ratio of CD24+cells against CD24-ones in Sox9+hepatocytes gradually increased while DDC-injury progressed and colony-forming capability mostly attributed to CD24+cells. Although hepatocyte markers were remarkably downregulated in of Sox9+CD24+hepatocytes, they re-differentiated into mature hepatocytes in vitro and in vivo. Our current results demonstrate that the emergence of biphenotypic hepatocytes is a sequential event including the transition from CD24-and CD24+status, which may be a crucial step for hepatocytes to acquire progenitor properties.
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 060-8556, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanimizu
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 060-8556, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ichinohe
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, 1-1-1 Higashi 2 jou, Midorigaoka, Asahikawa 078-1580, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Orthopedics, Gifu University School of Medicine, Yanagido 1-1, Gifu 501-1194, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, 1-1-1 Higashi 2 jou, Midorigaoka, Asahikawa 078-1580, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishikawa
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 060-8556, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Mitaka
mesh_terms: D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000293:injuries* / Q000503:physiopathology*; D008107:Liver Diseases / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D055758:SOX9 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D051927:CD24 Antigen; C497890:Cd24a protein, mouse; D000071858:Epithelial Cell Adhesion Molecule; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse