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

Nature Medicine volume 23, pages 954–963 (2017)Cite this article

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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.

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Figure 1: Derivation and characterization of ECOs.
Figure 2: Functional characterization of ECOs.
Figure 3: ECOs dissociated to single cells can populate biodegradable PGA scaffolds.
Figure 4: Biliary reconstruction in a mouse model of EHBI using ECOs.
Figure 5: ECOs can populate tubular densified collagen scaffolds.
Figure 6: Bile duct replacement using ECO-populated densified collagen tubes.

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Article 01 December 2022

Zixuan Zhao, Xinyi Chen, … Hanry Yu

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Acknowledgements

The authors would like to thank J. Skepper, L. Carter and the University of Cambridge Advanced Imaging Centre for their help with electron microscopy; E. Farnell and the University of Cambridge, Cambridge Genomic Services for their help with microarray data processing and analysis; A. Petrunkina and the NIHR Cambridge BRC Cell Phenotyping Hub for their help with cell sorting; K. Burling and the MRC MDU Mouse Biochemistry Laboratory (MRC_MC_UU_12012/5) for processing mouse serum samples; and R. El-Khairi for her help with IF images, R. Grandy for his help with providing relevant references, the Cambridge Biorepository for Translational Medicine for the provision of human tissue used in the study; D. Trono (Ecole Polytechnique Federale de Lausanne) for the gift of the plasmids used for the generation of GFP-expressing ECOs and B. McLeod for IT support. The monoclonal antibody TROMA-III, developed by R. Kemler, was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at the University of Iowa.

This work was funded by ERC starting grant Relieve IMDs (281335; L.V., N.R.F.H.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre (L.V., N.R.F.H., S. Sinha., F.S.), the Evelyn Trust (N.H.) and the EU FP7 grant TissuGEN (M.C.D.B.) and was supported in part by the Intramural Research Program of the NIH/NIAID (R.L.G., C.A.R.). F.S. has been supported by an Addenbrooke's Charitable Trust Clinical Research Training Fellowship and a joint MRC–Sparks Clinical Research Training Fellowship. (MR/L016761/1) A.W.J. and A.E.M. acknowledge support from EPSRC (EP/L504920/1) and an Engineering for Clinical Practice Grant from the Department of Engineering, University of Cambridge. J.B. was supported by a BHF Studentship (Grant FS/13/65/30441).

Author information

Author notes

  1. Stephen Sawiak, Edmund M Godfrey and Sara S Upponi: These authors contributed equally to this work.

  2. Kourosh Saeb-Parsy and Ludovic Vallier: These authors jointly directed this work.

Authors and Affiliations

  1. Wellcome Trust–Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK

    Fotios Sampaziotis, Olivia C Tysoe, Miguel Cardoso de Brito, Daniel Ortmann, Loukia Yiangou, Alexander Ross, Johannes Bargehr, Alessandro Bertero, Mariëlle C F Zonneveld, Matthias Pawlowski, Pedro Madrigal, Kirsten E Snijders, Stephanie E Brown, Casey A Rimland, Matthias Zilbauer, Sanjay Sinha & Ludovic Vallier

  2. Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK

    Fotios Sampaziotis, Olivia C Tysoe, Miguel Cardoso de Brito, Daniel Ortmann, Alessandro Bertero, Nikitas Georgakopoulos, Negar Pirmadjid, Stephanie E Brown, Casey A Rimland, Kourosh Saeb-Parsy & Ludovic Vallier

  3. Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Fotios Sampaziotis & William T H Gelson

  4. Department of Engineering, University of Cambridge, Cambridge, UK

    Alexander W Justin & Athina E Markaki

  5. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Stephen Sawiak

  6. Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Edmund M Godfrey & Sara S Upponi

  7. Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Richard L Gieseck III, Casey A Rimland & Thomas A Wynn

  8. Department of Transplantation Medicine, Division of Surgery, Norwegian PSC Research Center, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Natalie Lie Berntsen, Laura Valestrand, Tom H Karlsen & Espen Melum

  9. Department of Pathology, Cambridge Genomic Services, University of Cambridge, Cambridge, UK

    María J Gómez-Vázquez

  10. Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK

    Loukia Yiangou, Johannes Bargehr & Graeme J Alexander

  11. Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK

    Loukia Yiangou, Johannes Bargehr, Matthias Zilbauer & Graeme J Alexander

  12. University Department of Paediatrics, University of Cambridge, Cambridge, UK

    Alexander Ross & Sanjay Sinha

  13. Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Alexander Ross & Kim B Jensen

  14. Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK

    Johannes Bargehr

  15. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

    Marianne T Pedersen

  16. Wellcome Trust Sanger Institute, Hinxton, UK

    Pedro Madrigal & Ludovic Vallier

  17. School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK

    Gregor M Skeldon & Wenmiao Shu

  18. Department of Biomedical Engineering, University of Strathclyde, Glasgow, UK

    Gregor M Skeldon & Wenmiao Shu

  19. Department of Surgery, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, UK

    John Casey

  20. NIHR Cambridge Biomedical Centre (BRC) hIPSCs Core Facility, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK

    Paulina M Materek

  21. University of North Carolina, Chapel Hill, School of Medicine, Chapel Hill, North Carolina, USA

    Casey A Rimland

  22. Medical Genetics Laboratories, Cambridge University Hospitals NHS Trust, Cambridge, UK

    Ingrid Simonic

  23. Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Susan E Davies

  24. Center for Biomolecular Sciences, University of Nottingham, Nottingham, UK

    Nicholas R F Hannan

  25. Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK

    Nicholas R F Hannan

Authors
  1. Fotios Sampaziotis
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  2. Alexander W Justin
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  3. Olivia C Tysoe
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  4. Stephen Sawiak
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  5. Edmund M Godfrey
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  12. Loukia Yiangou
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  13. Alexander Ross
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  38. Thomas A Wynn
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  40. Espen Melum
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  42. Kourosh Saeb-Parsy
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  43. Ludovic Vallier
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Contributions

F.S. conceived and designed the study, performed experiments, acquired, interpreted and analyzed the data, developed and validated the protocols described, generated the figures, and wrote and edited the manuscript. A.W.J. generated the tubular densified collagen scaffolds and conceived and developed the manufacturing technique. O.C.T. contributed to cell culture and performed animal experiments, including kidney capsule injections and provision and dissection of mouse tissue. S. Sawiak performed the magnetic resonance imaging experiments. E.M.G. and S.S.U. reviewed and reported the magnetic resonance images. R.L.G. performed experiments, including animal experiments, IF and tissue histology. M.C.d.B. contributed to cell culture, generated viral particles, performed viral transduction experiments and generated GFP-expressing ECOs. N.L.B. and L. Valestrand performed animal experiments. M.J.G.-V. and P.M. performed bioinformatics analyses. D.O. performed flow cytometry analyses, and L.Y. performed immunoblot analyses. A.R. performed IF and qRT–PCR analyses and provided positive controls for IF and qRT–PCR. A.B. performed flow cytometry analyses and provided bioinformatics support. J.B. contributed to tissue histology and IF experiments. M.C.F.Z. contributed to PGA scaffold preparation and population with cells. M.T.P. generated viral particles, performed viral transduction experiments and generated GFP-expressing ECOs. M.P. generated viral particles. G.M.S. contributed to scaffold generation. P.M.M. and K.E.S. maintained and provided fibroblast controls. N.P. contributed to tissue culture. N.G. and C.A.R. contributed to dissection and provision of primary tissue. I.S. performed karyotyping and comparative genomic hybridization analyses. S.E.D. reviewed and reported the histology images. W.S., J.C., K.B.J., M.Z., S. Sinha, W.T.H.G., G.J.A., S.E.B., T.A.W., T.H.K. and E.M. contributed through critical revision of the manuscript for important intellectual content. N.R.F.H. contributed to the design and concept of the study and provided early study supervision. A.E.M. contributed to the design of the densified collagen scaffold and contributed through critical revision of the manuscript for important intellectual content. K.S.-P. provided primary tissue, performed animal experiments, including biliary reconstruction surgery, contributed to the design and concept of the study, supervised the study, interpreted the data, and wrote and edited the manuscript. L. Vallier designed and conceived the study, supervised the study, interpreted the data, and wrote and edited the manuscript. All of the authors approved the manuscript.

Corresponding author

Correspondence to Ludovic Vallier.

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Competing interests

L. Vallier is a founder and shareholder of DefiniGEN. The remaining authors have nothing to disclose.

Supplementary information

Supplementary Data, Figures and Tables

Supplementary Figures 1–14 and Supplementary Tables 1 and 3–5 (PDF 3856 kb)

Supplementary Table 2

Microarray gene expression data corresponding to the heat map in Figure 1d. (XLSX 817 kb)

41591_2017_BFnm4360_MOESM3_ESM.mp4

Magnetic resonance cholangio-pancreatography (MRCP; sagital plane) of an extrahepatic biliary injury mouse 104 d after biliary reconstruction with an ECO-populated scaffold. (MP4 596 kb)

41591_2017_BFnm4360_MOESM4_ESM.mp4

T1-weighed magnetic resonance imaging (coronal plane) of an extrahepatic biliary injury mouse 104 d after biliary reconstruction with an ECO-populated scaffold. (MP4 2803 kb)

41591_2017_BFnm4360_MOESM5_ESM.mp4

T2-weighed magnetic resonance imaging (coronal plane) of an immunocompromised mouse 1 month after biliary reconstruction with an ECO-populated scaffold. (MP4 1128 kb)

Time-lapse images demonstrating the generation of a fully grown organoid from a single cell. (AVI 109 kb)

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Sampaziotis, F., Justin, A., Tysoe, O. et al. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. Nat Med 23, 954–963 (2017). https://doi.org/10.1038/nm.4360

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