Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Carlotta Mayer - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Sophie Nehring - , University Hospital Carl Gustav Carus Dresden (Author)
  • Michael Kücken - , Department of Innovative Methods of Computing (IMC) (Author)
  • Urska Repnik - , Kiel University (Author)
  • Sarah Seifert - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Aleksandra Sljukic - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Julien Delpierre - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Hernán Morales-Navarrete - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Sebastian Hinz - , Rostock University Medical Centre (Author)
  • Mario Brosch - , Department of Internal Medicine I, Center for Regenerative Therapies Dresden, University Hospital Carl Gustav Carus Dresden (Author)
  • Brian Chung - , Oslo University Hospital Rikshospitalet (Author)
  • Tom Karlsen - , Oslo University Hospital Rikshospitalet (Author)
  • Meritxell Huch - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Yannis Kalaidzidis - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Lutz Brusch - , Department of Innovative Methods of Computing (IMC) (Author)
  • Jochen Hampe - , Department of Internal Medicine I, Center for Regenerative Therapies Dresden, University Hospital Carl Gustav Carus Dresden (Author)
  • Clemens Schafmayer - , Rostock University Medical Centre (Author)
  • Marino Zerial - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)

Abstract

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

Details

Original languageEnglish
Article numbere57181
Number of pages22
JournalEMBO reports
Volume24
Issue number9
Publication statusPublished - 6 Sept 2023
Peer-reviewedYes

External IDs

WOS 001039881900001
Scopus 85166430458
ORCID /0000-0003-0137-5106/work/142244266
ORCID /0000-0002-2421-6127/work/198593422

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • Apical bulkheads, Bile canaliculi, Hepatocyte, Hepatocyte rosettes, Hepatocytes, Primary sclerosing cholangitis, Animals, Liver, Mice, Liver Diseases, Bile, Bile Canaliculi

Library keywords