Differential expression of Lutheran/BCAM regulates biliary tissue remodeling in ductular reaction during liver regeneration
Yasushi Miura,
Satoshi Matsui,
Naoko Miyata,
Kenichi Harada,
Yamato Kikkawa,
Masaki Ohmuraya,
Kimi Araki,
Shinya Tsurusaki,
Hitoshi Okochi,
Nobuhito Goda,
Atsushi Miyajima,
Minoru Tanaka
Affiliations
Yasushi Miura
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
Satoshi Matsui
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
Naoko Miyata
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
Kenichi Harada
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
Yamato Kikkawa
Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
Masaki Ohmuraya
Department of Genetics, Hyogo College of Medicine, Hyogo, Japan
Kimi Araki
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
Shinya Tsurusaki
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Laboratory of Stem Cell Regulation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
Hitoshi Okochi
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
Nobuhito Goda
Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
Atsushi Miyajima
Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Laboratory of Stem Cell Regulation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
Under chronic or severe liver injury, liver progenitor cells (LPCs) of biliary origin are known to expand and contribute to the regeneration of hepatocytes and cholangiocytes. This regeneration process is called ductular reaction (DR), which is accompanied by dynamic remodeling of biliary tissue. Although the DR shows apparently distinct mode of biliary extension depending on the type of liver injury, the key regulatory mechanism remains poorly understood. Here, we show that Lutheran (Lu)/Basal cell adhesion molecule (BCAM) regulates the morphogenesis of DR depending on liver disease models. Lu+ and Lu- biliary cells isolated from injured liver exhibit opposite phenotypes in cell motility and duct formation capacities in vitro. By overexpression of Lu, Lu- biliary cells acquire the phenotype of Lu+ biliary cells. Lu-deficient mice showed severe defects in DR. Our findings reveal a critical role of Lu in the control of phenotypic heterogeneity of DR in distinct liver disease models.
