Intravital dynamic and correlative imaging reveals diffusion‐dominated canalicular and flow‐augmented ductular bile flux


Small‐molecule flux in tissue‐microdomains is essential for organ function, but knowledge of this process is scant due to the lack of suitable methods. We developed two independent techniques that allow the quantification of advection (flow) and diffusion in individual bile canaliculi and in interlobular bile ducts of intact livers in living mice, namely Fluorescence Loss After Photoactivation (FLAP) and Intravital Arbitrary Region Image Correlation Spectroscopy (IVARICS). The results challenge the prevailing ‘mechano‐osmotic’ theory of canalicular bile flow. After active transport across hepatocyte membranes bile acids are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts, diffusion is augmented by regulatable advection. Photoactivation of fluorescein bis‐(5‐carboxymethoxy‐2‐nitrobenzyl)‐ether (CMNB‐caged fluorescein) in entire lobules demonstrated the establishment of diffusive gradients in the bile canalicular network and the sink function of interlobular ducts. In contrast to the bile canalicular network, vectorial transport was detected and quantified in the mesh of interlobular bile ducts. In conclusion, the liver consists of a diffusion dominated canalicular domain, where hepatocytes secrete small molecules and generate a concentration gradient and a flow‐augmented ductular domain, where regulated water influx creates unidirectional advection that augments the diffusive flux.

Citation: Hepatology,hep.31422

Date Published: 19th Jun 2020

Registered Mode: by DOI

Authors: Nachiket Vartak, Georgia Guenther, Florian Joly, Amruta Damle‐Vartak, Gudrun Wibbelt, Jörns Fickel, Simone Jörs, Brigitte Begher‐Tibbe, Adrian Friebel, Kasimir Wansing, Ahmed Ghallab, Marie Rosselin, Noemie Boissier, Irene Vignon‐Clementel, Christian Hedberg, Fabian Geisler, Heribert Hofer, Peter Jansen, Stefan Hoehme, Dirk Drasdo, Jan G. Hengstler

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Vartak, N., Guenther, G., Joly, F., Damle‐Vartak, A., Wibbelt, G., Fickel, J., Jörs, S., Begher‐Tibbe, B., Friebel, A., Wansing, K., Ghallab, A., Rosselin, M., Boissier, N., Vignon‐Clementel, I., Hedberg, C., Geisler, F., Hofer, H., Jansen, P., Hoehme, S., … Hengstler, J. G. (2021). Intravital Dynamic and Correlative Imaging of Mouse Livers Reveals Diffusion‐Dominated Canalicular and Flow‐Augmented Ductular Bile Flux. In Hepatology (Vol. 73, Issue 4, pp. 1531–1550). Wiley.

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Created: 25th Aug 2020 at 08:13

Last updated: 25th Aug 2020 at 08:15

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