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

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

Abstract

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. 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.

Citation

Sampaziotis, F., Justin, A. W., Tysoe, O. C., Sawiak, S., Godfrey, E. M., Upponi, S. S., Gieseck, R. L., de Brito, M. C., Berntsen, N. L., Gómez-Vázquez, M. J., Ortmann, D., Yiangou, L., Ross, A., Bargehr, J., Bertero, A., Zonneveld, M. C., Pedersen, M. T., Pawlowski, M., Valestrand, L., Madrigal, P., …Vallier, L. (2017). Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. Nature Medicine, 23(8), 954-963. https://doi.org/10.1038/nm.4360

• Journal Article Type: Article
• Acceptance Date: May 24, 2017
• Online Publication Date: Jul 3, 2017
• Publication Date: Aug 1, 2017
• Deposit Date: Jul 4, 2017
• Publicly Available Date: Jul 4, 2017
• Journal: Nature Medicine
• Print ISSN: 1078-8956
• Electronic ISSN: 1546-170X
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 23
• Issue: 8
• Pages: 954-963
• DOI: https://doi.org/10.1038/nm.4360
• Keywords: Cholangiocytes, Bile duct, Bio-engineering, Tissue engineering, Organoids, Regenerative medicine, Cell-based therapy, Biliary atresia, PGA scaffold, Collagen scaffold, Densified collagen
• Public URL: https://nottingham-repository.worktribe.com/output/871037
• Publisher URL: http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4360.html
• Contract Date: Jul 4, 2017