A Predictive 3D Multi-Scale Model of Biliary Fluid Dynamics in the Liver Lobule.
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.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany.
Kirstin
K
Meyer
Center for Information Services and High Performance Computing, Technische Universität Dresden, Dresden, Saxony 01062, Germany; Center for Advancing Electronics Dresden, Technische Universität Dresden, Dresden, Saxony 01062, Germany.
Oleksandr
O
Ostrenko
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany; Faculty of Science, Technology and Communication, University of Luxembourg, 1359 Luxembourg, Luxembourg; Center for Advancing Electronics Dresden, Technische Universität Dresden, Dresden, Saxony 01062, Germany.
Georgios
G
Bourantas
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany.
Hernan
H
Morales-Navarrete
Intracellular Membrane Trafficking Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Natalie
N
Porat-Shliom
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany.
Fabian
F
Segovia-Miranda
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany.
Hidenori
H
Nonaka
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany.
Ali
A
Ghaemi
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany.
Jean-Marc
JM
Verbavatz
Center for Information Services and High Performance Computing, Technische Universität Dresden, Dresden, Saxony 01062, Germany; Center for Advancing Electronics Dresden, Technische Universität Dresden, Dresden, Saxony 01062, Germany.
Lutz
L
Brusch
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany; Faculty of Computer Science, Technische Universität Dresden, Dresden, Saxony 01187, Germany; Center for Advancing Electronics Dresden, Technische Universität Dresden, Dresden, Saxony 01062, Germany.
Ivo
I
Sbalzarini
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany; Faculty of Bioengineering and Bioinformatics, Moscow State University, 119991 Moscow, Russia.
Yannis
Y
Kalaidzidis
Intracellular Membrane Trafficking Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Roberto
R
Weigert
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany; Center for Advancing Electronics Dresden, Technische Universität Dresden, Dresden, Saxony 01062, Germany. Electronic address: zerial@mpi-cbg.de.
Marino
M
Zerial
D000818:Animals; D001646:Bile / Q000378:metabolism; D001648:Bile Canaliculi / Q000378:metabolism* / Q000502:physiology*; D001659:Biliary Tract / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D002779:Cholestasis / Q000378:metabolism; D003198:Computer Simulation; D005544:Forecasting; D022781:Hepatocytes / Q000378:metabolism; D057446:Hydrodynamics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
acetaminophen; actomyosin contractility; bile canaliculi; bile flow; cholestasis; computational fluid dynamics; drug-induced liver injury; mouse liver; multi-scale model; peristalsis