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

Fotios Sampaziotis^{1

2

3}, Alexander W Justin⁴, Olivia C Tysoe^{1

2}, Stephen Sawiak⁵, Edmund M Godfrey⁶, Sara S Upponi⁶, Richard L Gieseck 3rd⁷, Miguel Cardoso de Brito^{1

2}, Natalie Lie Berntsen⁸, María J Gómez-Vázquez⁹, Daniel Ortmann^{1

2}, Loukia Yiangou^{1

10

11}, Alexander Ross^{1

12

13}, Johannes Bargehr^{1

10

11

11}, Alessandro Bertero^{1

2}, Mariëlle C F Zonneveld¹, Marianne T Pedersen¹⁴, Matthias Pawlowski¹, Laura Valestrand⁸, Pedro Madrigal^{1

15}, Nikitas Georgakopoulos², Negar Pirmadjid², Gregor M Skeldon^{16

17}, John Casey¹⁸, Wenmiao Shu^{16

17}, Paulina M Materek¹⁹, Kirsten E Snijders¹, Stephanie E Brown^{1

2}, Casey A Rimland^{1

2

7

20}, Ingrid Simonic²¹, Susan E Davies²², Kim B Jensen¹³, Matthias Zilbauer^{1

11}, William T H Gelson³, Graeme J Alexander^{10

11}, Sanjay Sinha^{1

12}, Nicholas R F Hannan^{23

24}, Thomas A Wynn⁷, Tom H Karlsen⁸, Espen Melum⁸, Athina E Markaki⁴, Kourosh Saeb-Parsy², Ludovic Vallier^{1

2

15}

Affiliations

¹ Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK.
² Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
³ Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁴ Department of Engineering, University of Cambridge, Cambridge, UK.
⁵ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
⁶ Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁷ Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
⁸ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁹ Cambridge Genomic Services, Department of Pathology, University of Cambridge, Cambridge, UK.
¹⁰ Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
¹¹ Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
¹² University Department of Paediatrics, University of Cambridge, Cambridge, UK.
¹³ Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁴ Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
¹⁵ Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁶ School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK.
¹⁷ Department of Biomedical Engineering, University of Strathclyde, Glasgow, UK.
¹⁸ Department of Surgery, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, UK.
¹⁹ NIHR Cambridge Biomedical Centre (BRC) hIPSCs Core Facility, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
²⁰ University of North Carolina, Chapel Hill, School of Medicine, Chapel Hill, North Carolina, USA.
²¹ Medical Genetics Laboratories, Cambridge University Hospitals NHS Trust, Cambridge, UK.
²² Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
²³ Center for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
²⁴ Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.

PMID: 28671689
DOI: 10.1038/nm.4360

Free article

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

Fotios Sampaziotis et al. Nat Med. 2017 Aug.

Free article

. 2017 Aug;23(8):954-963.

doi: 10.1038/nm.4360. Epub 2017 Jul 3.

Authors

Affiliations

¹ Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK.
² Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
³ Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁴ Department of Engineering, University of Cambridge, Cambridge, UK.
⁵ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
⁶ Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁷ Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
⁸ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁹ Cambridge Genomic Services, Department of Pathology, University of Cambridge, Cambridge, UK.
¹⁰ Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
¹¹ Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
¹² University Department of Paediatrics, University of Cambridge, Cambridge, UK.
¹³ Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁴ Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
¹⁵ Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁶ School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK.
¹⁷ Department of Biomedical Engineering, University of Strathclyde, Glasgow, UK.
¹⁸ Department of Surgery, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, UK.
¹⁹ NIHR Cambridge Biomedical Centre (BRC) hIPSCs Core Facility, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
²⁰ University of North Carolina, Chapel Hill, School of Medicine, Chapel Hill, North Carolina, USA.
²¹ Medical Genetics Laboratories, Cambridge University Hospitals NHS Trust, Cambridge, UK.
²² Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
²³ Center for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
²⁴ Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.

PMID: 28671689
DOI: 10.1038/nm.4360

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.

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Comment in

Regenerative medicine: Bioengineering the common bile duct.
Thomas H. Thomas H. Nat Rev Gastroenterol Hepatol. 2017 Sep;14(9):504-505. doi: 10.1038/nrgastro.2017.99. Epub 2017 Jul 12. Nat Rev Gastroenterol Hepatol. 2017. PMID: 28698664 No abstract available.
Bioengineering: Bile ducts regenerated.
Zhang L, Hui L. Zhang L, et al. Nature. 2017 Jul 12;547(7662):171-172. doi: 10.1038/547171a. Nature. 2017. PMID: 28703183 No abstract available.

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

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

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