1. Developmental Biology
  2. Stem Cells and Regenerative Medicine
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Differential expression of Lutheran/BCAM regulates biliary tissue remodeling in ductular reaction during liver regeneration

  1. Yasushi Miura
  2. Satoshi Matsui
  3. Naoko Miyata
  4. Kenichi Harada
  5. Yamato Kikkawa
  6. Masaki Ohmuraya
  7. Kimi Araki
  8. Shinya Tsurusaki
  9. Hitoshi Okochi
  10. Nobuhito Goda
  11. Atsushi Miyajima
  12. Minoru Tanaka  Is a corresponding author
  1. National Center for Global Health and Medicine, Japan
  2. Kanazawa University, Japan
  3. Tokyo University of Pharmacy and Life Sciences, Japan
  4. Hyogo College of Medicine, Japan
  5. Kumamoto University, Japan
  6. Waseda University, Japan
  7. The University of Tokyo, Japan
Research Article
  • Cited 5
  • Views 1,244
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Cite this article as: eLife 2018;7:e36572 doi: 10.7554/eLife.36572

Abstract

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.

Article and author information

Author details

  1. Yasushi Miura

    Department of Regenerative Medicine, National Center for Global Health and Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Satoshi Matsui

    Department of Regenerative Medicine, National Center for Global Health and Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Naoko Miyata

    Department of Regenerative Medicine, National Center for Global Health and Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Kenichi Harada

    Department of Human Pathology, Kanazawa University, Kanazawa, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Yamato Kikkawa

    Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Masaki Ohmuraya

    Department of Genetics, Hyogo College of Medicine, Hyogo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Kimi Araki

    Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Shinya Tsurusaki

    Department of Regenerative Medicine, National Center for Global Health and Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Hitoshi Okochi

    Department of Regenerative Medicine, National Center for Global Health and Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Nobuhito Goda

    Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Atsushi Miyajima

    Laboratory of Cell Growth and Differentiation, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Minoru Tanaka

    Department of Regenerative Medicine, National Center for Global Health and Medicine, Tokyo, Japan
    For correspondence
    m-tanaka@ri.ncgm.go.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2500-7973

Funding

Japan Society for the Promotion of Science (26110007)

  • Minoru Tanaka

Japan Society for the Promotion of Science (26253023)

  • Atsushi Miyajima

Japan Society for the Promotion of Science (26110001)

  • Masaki Ohmuraya

Japan Agency for Medical Research and Development (JP17be0304201)

  • Minoru Tanaka

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed according to institutional guidelines and approved by the Animal Care and Use committee of the Institute of Molecular and Cellular Biosciences, The University of Tokyo (approval numbers 2501, 2501-1, 2609,2706 and 3004), Kumatomo University (approval number A27-092), Hyogo College of Medicine (approval number 16-043, 16-046), and National Center for Global Health and Medicine Research Institute (approval number 15080, 16023, 17086 and 18069). Every effort was made to minimize animal suffering and to reduce the number of animals used.

Human subjects: The study using human samples was approved by the Kanazawa University Ethics Committee (approval number 305-4), and all of the analyzed samples are derived from patients who provided informed written consent for the use of their tissue samples in research.

Reviewing Editor

  1. Frédéric Lemaigre, Université catholique de Louvain, Belgium

Publication history

  1. Received: March 11, 2018
  2. Accepted: July 28, 2018
  3. Accepted Manuscript published: July 30, 2018 (version 1)
  4. Version of Record published: August 23, 2018 (version 2)

Copyright

© 2018, Miura et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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