The mechanical basis of the dynamical structure of bile canaliculi in the liver

• Applicant: Dr. Pierre Haas
• Subject Area: Biophysics ; Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555830846

The physiological function of the liver relies on the robust formation of the network of bile canaliculi through which bile flows and its integrity under physiological and pathological changes. This project will elucidate how mechanics and bile pressure conspire to drive the genesis and maintenance of the bile canaliculi network. It will unravel the underlying biophysical principles by focusing on two recent experimental insights: First, structures termed "apical bulkheads" were discovered to form and retract dynamically inside the bile canaliculi. In previous work, we have shown that these membrane folds that protrude into the bile canaliculi increase the pressure that the canaliculi can hold. From existing experimental data by our collaborators, we will quantify the dynamics of apical bulkhead formation. Based on this quantification, we will develop models of folds in cylindrical membranes to determine the mechanical basis for the formation of apical bulkheads. Second, quantification, in unprecedented detail, of the dynamics of the bile canalicular network during development led to hypothesizing a novel mechanism of hepatocyte polarization that generates nascent bile canaliculi. To this interdisciplinary work, we have contributed a model of this polarization mechanism that reproduces coarse-grained features of the bile canalicular network quantitatively. Leveraging these existing experimental data and segmentations, we will quantify the detailed network distributions of the bile canaliculi during their development. This will allow us to test the new polarization mechanism by deriving a model that describes these distributions and couples this polarization mechanism to the pressure and the mechanics of the growing bile canaliculi and comparing its predictions to the experimental observations. This project will therefore yield not only fundamental physical insights into lumen formation and the dynamics of luminal networks. It will also provide key biophysical pieces of the large biological jigsaw that is liver development and hence indicate potential mechanisms for cholestatic liver diseases. By advancing biophysical understanding of the interplay between mechanics and cellular structures in the liver in this way, this research promises to contribute significantly to the broader field of organ development, function, and disease.

• DFG Programme: Research Grants