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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; Gómez-Vázquez, María J.; Ortmann, Daniel; Yiangou, Loukia; Ross, Alexander; Bargehr, Johannes; Bertero, Alessandro; Zonneveld, Mariëlle 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

Authors

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 Madrigal

Nikitas Georgakopoulos

Negar Pirmadjid

Gregor M. Skeldon

John Casey

Wenmiao Shu

Paulina M. Materek

Kirsten Snijders

Stephanie Brown

Casey A. Rimland

Ingrid Simonic

Susan E. Davies

Kim B. Jensen

Matthias Zilbauer

William T.H. Gelson

Graeme J. Alexander

Sanjay Sinha

NICK HANNAN NICK.HANNAN@NOTTINGHAM.AC.UK
Assistant Professor in Translational Stem Cell Biology

Thomas A. Wynn

Tom H. Karlsen

Espen Melum

Athina E. Markaki

Kourosh Saeb-Parsy

Ludovic Vallier



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., …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 http://eprints.nottingham.ac.uk/id/eprint/43956
Publisher URL http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4360.html
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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