Cholestasis‐induced adaptive remodeling of interlobular bile ducts

Abstract

Cholestasis is a common complication in liver diseases that triggers a proliferative response of the biliary tree. Bile duct ligation (BDL) is a frequently used model of cholestasis in rodents. To determine which changes occur in the three‐dimensional (3D) architecture of the interlobular bile duct during cholestasis, we used 3D confocal imaging, surface reconstructions, and automated image quantification covering a period up to 28 days after BDL. We show a highly reproducible sequence of interlobular duct remodeling, where cholangiocyte proliferation initially causes corrugation of the luminal duct surface, leading to an approximately five‐fold increase in surface area. This is analogous to the function of villi in the intestine or sulci in the brain, where an expansion of area is achieved within a restricted volume. The increase in surface area is further enhanced by duct branching, branch elongation, and loop formation through self‐joining, whereby an initially relatively sparse mesh surrounding the portal vein becomes five‐fold denser through elongation, corrugation, and ramification. The number of connections between the bile duct and the lobular bile canalicular network by the canals of Hering decreases proportionally to the increase in bile duct length, suggesting that no novel connections are established. The diameter of the interlobular bile duct remains constant after BDL, a response that is qualitatively distinct from that of large bile ducts, which tend to enlarge their diameters. Therefore, volume enhancement is only due to net elongation of the ducts. Because curvature and tortuosity of the bile duct are unaltered, this enlargement of the biliary tree is caused by branching and not by convolution. Conclusion: BDL causes adaptive remodeling that aims at optimizing the intraluminal surface area by way of corrugation and branching. (Hepatology 2016;63:951–964)

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.…”

Model Prediction and Validation of an Order Mechanism Controlling the Spatiotemporal Phenotype of Early Hepatocellular Carcinoma

“…A limitation of the experimental validation presented here is that the analysis of images was performed in a two-dimensional manner. In the past, we have reported that threedimensional structures can easily be misinterpreted when only two-dimensional tissue slices are evaluated (Vartak et al 2016;Drasdo et al 2014a, b). For example, a column of initiated cells may appear as a single cell when the slice level is oriented perpendicular to the structure.…”

Highlight report: physiologically-based modeling of diseased liver tissue

“…Moreover, techniques of spatio-temporal tissue modeling have been established that allow simulations of how specific biological processes contribute to liver function (Hoehme et al 2017;Friebel et al 2015;Drasdo et al 2014a, b;Schliess et al 2014;Vartak et al 2016). Such techniques allow the in silico analysis of which degree of loss of tissue causes loss of function (or metabolic capacity) under the assumption of a proportional relationship.…”