A Predictive 3D Multi-Scale Model of Biliary Fluid Dynamics in the Liver Lobule

Abstract

Bile, the central metabolic product of the liver, is transported by the bile canaliculi network. The impairment of bile flow in cholestatic liver diseases has urged a demand for insights into its regulation. Here, we developed a predictive 3D multi-scale model that simulates fluid dynamic properties successively from the subcellular to the tissue level. The model integrates the structure of the bile canalicular network in the mouse liver lobule, as determined by high-resolution confocal and serial block-face scanning electron microscopy, with measurements of bile transport by intravital microscopy. The combined experiment-theory approach revealed spatial heterogeneities of biliary geometry and hepatocyte transport activity. Based on this, our model predicts gradients of bile velocity and pressure in the liver lobule. Validation of the model predictions by pharmacological inhibition of Rho kinase demonstrated a requirement of canaliculi contractility for bile flow in vivo. Our model can be applied to functionally characterize liver diseases and quantitatively estimate biliary transport upon drug-induced liver injury.

Hydrodynamics of bile flow

“…Using intravital microscopy and mice expressing a fluorescent fusion protein visualizing intracellular actin‐myosin filaments, the authors could confirm these earlier studies and show canalicular contractions with a frequency commensurate to measurements by Nathanson et al for vasopressin‐induced CV‐to‐PV intracellular cytosolic calcium waves . The importance of canalicular peristalsis for bile flow was confirmed in experiments showing that inhibiting the actin‐myosin contractions by a Rho‐kinase inhibitor caused dilatation of the canaliculus and delayed CF clearance …”

“…This is exactly what Meyer and coworkers did in a recent article (for overview, see Fig. A) . The authors used a combination of computational modeling and experimentation with a variety of imaging techniques to measure transmembrane transport and visualize the bile canaliculus.…”

“…Intravital imaging of the liver in anesthetized mice allows the reconstruction of a 3D model of the bile canaliculus and the design of a computational model of bile fluid dynamics. The study shows a multiscale approach going from the subcellular level (bile canaliculi) to the whole‐organ level . Determinants of bile flow are osmotic water influx and canalicular peristalsis.…”

Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration

“…Remarkably, YAP was not only cytoplasmic but also enriched at the apical region of the hepatocytes in vitro (Fig A, upper left), as observed during regeneration in vivo (see Figs E and ). To recapitulate more closely the state of hepatocytes in the regenerating liver, we added the BA deoxycholic acid (DCA) at 200 μM (Fig A, lower left), a concentration that is comparable to serum levels in mice after PH (Naugler, ). DCA was sufficient to stimulate YAP nuclear translocation (1.7‐fold increase as compared to DMSO control cells, Fig B), consistent with earlier observations (Anakk et al , ).…”

Site‐specific distribution of claudin‐based paracellular channels with roles in biological fluid flow and metabolism

“…Hepatocytes, a type of epithelial cell in the liver, join each other via adhesion apparatuses, including TJs, to form the bile canaliculi (BC), in which the cells’ apical surface faces the lumen . The BC form a tubular network throughout the liver lobule, which is a branching flow path for bile with blind (closed) ends around a central vein . Bile is generated in hepatocytes, secreted into the BC, and flows from the perivenous to the periportal area of the liver lobule (Fig.…”