Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids

Fotios Sampaziotis, Alexander W Justin, Olivia C Tysoe, Stephen Sawiak, Edmund M Godfrey, Sara S Upponi, Richard L Gieseck, Miguel Cardoso de Brito, Natalie Lie Berntsen, María J Gómez-Vázquez, Daniel Ortmann, Loukia Yiangou, Alexander Ross, Johannes Bargehr, Alessandro Bertero, Mariëlle C F Zonneveld, Marianne T Pedersen, Matthias Pawlowski, Laura Valestrand, Pedro MadrigalNikitas Georgakopoulos, Negar Pirmadjid, Gregor M Skeldon, John Casey, Wenmiao Shu, Paulina M Materek, Kirsten E Snijders, Stephanie E Brown, Casey A Rimland, Ingrid Simonic, Susan E Davies, Kim B Jensen, Matthias Zilbauer, William T H Gelson, Graeme J Alexander, Sanjay Sinha, Nicholas R F Hannan, Thomas A Wynn, Tom H Karlsen, Espen Melum, Athina E Markaki, Kourosh Saeb-Parsy, Ludovic Vallier

Research output: Contribution to journalArticlepeer-review

Abstract

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.

Original languageEnglish
Pages (from-to)954-963
Number of pages10
JournalNature Medicine
Volume23
Issue number8
Early online date3 Jul 2017
DOIs
Publication statusPublished - Aug 2017

Keywords

  • Animals
  • Bile Ducts, Extrahepatic
  • Biliary Tract
  • Cell Transplantation
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Epithelial Cells
  • Gallbladder
  • Humans
  • In Vitro Techniques
  • Keratin-19
  • Keratin-7
  • Mice
  • Organoids
  • Regeneration
  • Secretin
  • Somatostatin
  • Tissue Engineering
  • Tissue Scaffolds
  • gamma-Glutamyltransferase
  • Journal Article
  • Video-Audio Media

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