Differential expression of Lutheran/BCAM regulates biliary tissue remodeling in ductular reaction during liver regeneration.

Yasushi Miura,Kenichi Harada,Shinya Tsurusaki,Hitoshi Okochi,Naoko Miyata,Yamato Kikkawa,Minoru Tanaka,Satoshi Matsui,Kimi Araki,Masaki Ohmuraya,Atsushi Miyajima,Nobuhito Goda

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.

Highlights

The liver is known to possess high capacity for regeneration upon injury
Because most known liver progenitor cells (LPCs) markers are uniformly expressed in both types of ductular reaction (DR), these molecules may not account for the heterogeneity of LPC
As reported by the previous paper that Lu is stained in hepatic arteries and portal vein of adult human liver (Parsons et al, 1995), co-staining of Lu and platelet endothelial cell adhesion molecule (PECAM), an endothelial marker, in the dihydrocollidine supplemented (DDC)-fed liver revealed that the Epithelial cell adhesion molecule (EpCAM)- duct with strong fluorescence is hepatic artery (Figure 1—figure supplement 2)

Summary

Introduction

The liver is known to possess high capacity for regeneration upon injury. In acutely injured or surgically resected livers, regeneration is usually achieved by proliferation and hypertrophy of residual hepatocytes (Fausto and Campbell, 2003; Miyaoka et al, 2012). Under chronic or severe liver injury that impairs the proliferation of hepatocytes, liver progenitor cell (LPC) has been postulated to contribute to liver regeneration by differentiating into hepatocytes and biliary epithelial cells (BECs), known as cholangiocytes (Thorgeirsson, 1996; Fausto, 2004; Miyajima et al, 2014). This response is known as ductular reaction (DR), in which LPC/biliary cell with BEC marker

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