Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany.
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.
Cell Syst. 2017 Mar 22;4(3):277-290.e9. doi: 10.1016/j.cels.2017.02.008. Epub 2017 Mar 18.
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.
胆汁是肝脏的主要代谢产物，通过胆小管网络进行运输。在胆汁淤积性肝病中，胆汁流动受损促使人们需要深入了解其调节机制。在这里，我们开发了一种预测性的 3D 多尺度模型，该模型能够从亚细胞到组织水平依次模拟流体动力学特性。该模型整合了高分辨率共聚焦和连续块面扫描电子显微镜确定的小鼠肝小叶内胆小管网络的结构，以及活体显微镜测量的胆汁转运。联合实验理论方法揭示了胆道几何形状和肝细胞转运活性的空间异质性。基于这一点，我们的模型预测了肝小叶内胆汁速度和压力的梯度。通过药理学抑制 Rho 激酶对模型预测进行验证，表明胆小管收缩性对于体内胆汁流动是必需的。我们的模型可以用于对肝脏疾病进行功能特征描述，并在药物性肝损伤时定量估计胆汁转运。
