title: Contributions of hepatocytes and bile ductular cells in ductular reactions and remodeling of the biliary system after chronic liver injury.
abstract: Mature hepatocytes are suggested to possess a capacity for bile ductular transdifferentiation, but whether and how hepatocytes contribute to ductular reaction in chronic liver diseases has not been elucidated. We examined whether mouse hepatocytes can transdifferentiate into bile ductular cells in vitro, using a three-dimensional collagen gel culture method, and in vivo, using a liver repopulation model in which β-galactosidase-positive hepatocytes from Alb-Cre × ROSA26R mice were transplanted into the liver of wild-type mice. We further examined the relative contribution of intrinsic hepatocytes in ductular reaction in a hepatocyte lineage-tracing model using Mx1-Cre × ROSA26R mice treated with polyinosinic-polycytidylic acid. Within collagen gels, hepatocytes exhibited branching morphogenesis associated with the emergence of bile duct-like phenotype. In the liver repopulation model, many β-galactosidase-positive, hepatocyte-derived bile ductular structures were identified; these markedly increased after liver injury. In Mx1-Cre × ROSA26R mice, relatively minor but significant contributions of hepatocyte-derived bile ductules were observed in both periportal and centrilobular ductular reaction. As the centrilobular ductular reaction progressed, the portal ducts or ductules migrated toward the injured area and joined with hepatocyte-derived ductules, leaving the portal tract without biliary structures. We conclude that hepatocytes and bile ducts or ductules are important sources of ductular reaction and that the intrahepatic biliary system undergoes remarkable remodeling in response to chronic liver injury.
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nagahama
authors.affiliation: Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sone
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Bing
authors.initials: B
authors.lastname: Xin
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Division of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Akita Red Cross Hospital, Akita, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Enomoto
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan. Electronic address: nishikwa@asahikawa-med.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishikawa
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology*; D001659:Biliary Tract / Q000473:pathology*; D019070:Cell Lineage; D054338:Cell Transdifferentiation / Q000502:physiology*; D022781:Hepatocytes / Q000473:pathology*; D008107:Liver Diseases / Q000473:pathology*; D051379:Mice