Adaptive remodeling of the biliary architecture underlies liver homeostasis

Abstract

Serving as the center for metabolism and detoxification, the liver is inherently susceptible to a wide variety of damage imposed by toxins or chemicals. Induction of cell populations with biliary epithelial phenotypes, which include progenitor-like cells and are referred to as liver progenitor cells, is often observed in histopathological examination of various liver diseases in both human patients and animal models and has been implicated in regeneration. However, the tissue dynamics underlying this phenomenon remains largely unclear. We have developed a simple imaging technique to reveal the global and fine-scale architecture of the biliary tract spreading in the mouse liver. Using this novel method, we show that the emergence and expansion of liver progenitor cells actually reflect structural transformation of the intrahepatic biliary tree in mouse liver injury models. The biliary branches expanded their area gradually and contiguously along with the course of chronic injury. Relevant regulatory signals known to be involved in liver progenitor cell regulation, including fibroblast growth factor 7 and tumor necrosis factor-like weak inducer of apoptosis, can modulate the dynamics of the biliary epithelium in different ways. Importantly, the structural transformations of the biliary tree were diverse and corresponded well with the parenchymal injury patterns. That is, when chronic hepatocyte damage was induced in the pericentral area, the biliary branches exhibited an extended structure from the periportal area with apparent tropism toward the distant injured area. Conclusion: The hepatobiliary system possesses a unique and unprecedented structural flexibility and can remodel dynamically and adaptively in response to various injury conditions; this type of tissue plasticity should constitute an essential component to maintain liver homeostasis. (HEPATOLOGY 2015;61:2056-2066

Infliximab and Dexamethasone Attenuate the Ductular Reaction in Mice

“…S10). Our results confirm earlier data showing that in response to different injuries the plasticity of the biliary tree is remodelled accordingly2021, and suggest that the use of IFX and DEX may have an unprecedented impact on the flexibility of this hepatobiliary system. Contrarily to CDE, in DDC settings the remodeling of the biliary architecture was obvious and was therefore not quantified.…”

Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer

“…One possible function for oval cells could be restoration of the bile canaliculi network and liver polarity. Supporting these lines, inking the ductal tree has allowed visualization of its structure in different models of liver injury with oval cell expansion (Kaneko et al, 2015). Such studies show that oval cells are extensions of the pre-existing ductal tree, further challenging the view that oval cells are progenitor cells that seed the parenchyma to generate new hepatocytes.…”

Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish

“…Biliary epithelial cells (also called cholangiocytes) are the innermost epithelial cells forming the conduit of this 3D network. Various means to visualize the 3D structure of the biliary network have been developed (Kaneko et al, 2015;Sparks et al, 2010). However, there is as yet no method to quantify differences in 3D branching patterns of the entire network, and this has presented a significant barrier to our understanding of the formation of the intrahepatic biliary network and the pathogenesis of liver diseases.…”

“…In mammals, the apical membranes of two adjacent hepatocytes generate the bile canaliculus, which secretes bile into the intrahepatic biliary network; however, in zebrafish the bile canaliculi are unicellular structures and tubular invaginations of the hepatocyte apical membranes (Lorent et al, 2004;Sakaguchi et al, 2008). In zebrafish, the intrahepatic biliary network is formed by small-diameter ductular biliary epithelial cells, which might be analogous to small-diameter ductular biliary epithelial cells in the mammalian liver lobule that transport bile from the canalicular network to the intralobular bile ducts in the portral tract (Kaneko et al, 2015). Indeed, there is remarkable conservation of both genes and gene function across vertebrate biliary system development, and thus many candidate genes responsible for biliary system abnormalities in humans can be screened efficiently and rapidly in the zebrafish model Delous et al, 2012;Hand et al, 2009;Lorent et al, 2015Lorent et al, , 2010Lorent et al, , 2004Matthews et al, 2011Matthews et al, , 2005Sakaguchi et al, 2008;Schaub et al, 2012).…”