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.
- Minoru Tanaka
- Atsushi Miyajima
- Masaki Ohmuraya
- Minoru Tanaka
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Frédéric Lemaigre, Université catholique de Louvain, Belgium
© 2018, Miura et al.
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