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

Sampaziotis, Fotios and Justin, Alexander W and Tysoe, Olivia C and Sawiak, Stephen and Godfrey, Edmund M and Upponi, Sara S and Gieseck III, Richard L and de Brito, Miguel Cardoso and Berntsen, Natalie Lie and Gómez-Vázquez, María J and Ortmann, Daniel and Yiangou, Loukia and Ross, Alexander and Bargehr, Johannes and Bertero, Alessandro and Zonneveld, Mariëlle C F and Pedersen, Marianne T and Pawlowski, Matthias and Valestrand, Laura and Madrigal, Pedro and Georgakopoulos, Nikitas and Pirmadjid, Negar and Skeldon, Gregor M and Casey, John and Shu, Wenmiao and Materek, Paulina M and Snijders, Kirsten E and Brown, Stephanie E and Rimland, Casey A and Simonic, Ingrid and Davies, Susan E and Jensen, Kim B and Zilbauer, Matthias and Gelson, William T H and Alexander, Graeme J and Sinha, Sanjay and Hannan, Nicholas R F and Wynn, Thomas A and Karlsen, Tom H and Melum, Espen and Markaki, Athina E and Saeb-Parsy, Kourosh and Vallier, Ludovic (2017) Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. Nature Medicine, 23 (8). pp. 954-963. ISSN 1078-8956

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    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.