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

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 E Snijders; Stephanie E Brown; Casey A Rimland; Ingrid Simonic; Susan E Davies; Kim B Jensen; Matthias Zilbauer; William T H Gelson; Graeme J Alexander; Sanjay Sinha; Nicholas R F Hannan; Thomas A Wynn; Tom H Karlsen; Espen Melum; Athina E Markaki; Kourosh Saeb-Parsy; Ludovic Vallier

doi:10.1038/nm.4360

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

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 MadrigalNikitas Georgakopoulos, Negar Pirmadjid, Gregor M Skeldon, John Casey, Wenmiao Shu, Paulina M Materek, Kirsten E Snijders, Stephanie E Brown, Casey A Rimland, Ingrid Simonic, Susan E Davies, Kim B Jensen, Matthias Zilbauer, William T H Gelson, Graeme J Alexander, Sanjay Sinha, Nicholas R F Hannan, Thomas A Wynn, Tom H Karlsen, Espen Melum, Athina E Markaki, Kourosh Saeb-Parsy, Ludovic Vallier

96 Citations (Scopus)

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.

Original language	English
Journal	Nature Medicine
Volume	23
Issue number	8
Pages (from-to)	954-963
Number of pages	10
ISSN	1078-8956
DOIs	https://doi.org/10.1038/nm.4360
Publication status	Published - 1 Aug 2017

Keywords

Animals
Bile Ducts, Extrahepatic
Biliary Tract
Cell Transplantation
Cystic Fibrosis Transmembrane Conductance Regulator
Epithelial Cells
Gallbladder
Humans
In Vitro Techniques
Keratin-19
Keratin-7
Mice
Organoids
Regeneration
Secretin
Somatostatin
Tissue Engineering
Tissue Scaffolds
gamma-Glutamyltransferase
Journal Article
Video-Audio Media

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm.4360

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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. F., Pedersen, M. T., Pawlowski, M., Valestrand, L., ... 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

Sampaziotis, F, Justin, AW, Tysoe, OC, Sawiak, S, Godfrey, EM, Upponi, SS, Gieseck, RL, de Brito, MC, Berntsen, NL, Gómez-Vázquez, MJ, Ortmann, D, Yiangou, L, Ross, A, Bargehr, J, Bertero, A, Zonneveld, MCF, Pedersen, MT, Pawlowski, M, Valestrand, L, Madrigal, P, Georgakopoulos, N, Pirmadjid, N, Skeldon, GM, Casey, J, Shu, W, Materek, PM, Snijders, KE, Brown, SE, Rimland, CA, Simonic, I, Davies, SE, Jensen, KB, Zilbauer, M, Gelson, WTH, Alexander, GJ, Sinha, S, Hannan, NRF, Wynn, TA, Karlsen, TH, Melum, E, Markaki, AE, Saeb-Parsy, K & Vallier, L 2017, 'Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids', Nature Medicine, vol. 23, no. 8, pp. 954-963. https://doi.org/10.1038/nm.4360

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title = "Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids",

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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author = "Fotios Sampaziotis and Justin, {Alexander W} and Tysoe, {Olivia C} and Stephen Sawiak and Godfrey, {Edmund M} and Upponi, {Sara S} and Gieseck, {Richard L} and {de Brito}, {Miguel Cardoso} and Berntsen, {Natalie Lie} and G{\'o}mez-V{\'a}zquez, {Mar{\'i}a J} and Daniel Ortmann and Loukia Yiangou and Alexander Ross and Johannes Bargehr and Alessandro Bertero and Zonneveld, {Mari{\"e}lle C F} and Pedersen, {Marianne T} and Matthias Pawlowski and Laura Valestrand and Pedro Madrigal and Nikitas Georgakopoulos and Negar Pirmadjid and Skeldon, {Gregor M} and John Casey and Wenmiao Shu and Materek, {Paulina M} and Snijders, {Kirsten E} and Brown, {Stephanie E} and Rimland, {Casey A} and Ingrid Simonic and Davies, {Susan E} and Jensen, {Kim B} and Matthias Zilbauer and Gelson, {William T H} and Alexander, {Graeme J} and Sanjay Sinha and Hannan, {Nicholas R F} and Wynn, {Thomas A} and Karlsen, {Tom H} and Espen Melum and Markaki, {Athina E} and Kourosh Saeb-Parsy and Ludovic Vallier",

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AU - Sampaziotis, Fotios

AU - Justin, Alexander W

AU - Tysoe, Olivia C

AU - Sawiak, Stephen

AU - Godfrey, Edmund M

AU - Upponi, Sara S

AU - Gieseck, Richard L

AU - de Brito, Miguel Cardoso

AU - Berntsen, Natalie Lie

AU - Gómez-Vázquez, María J

AU - Ortmann, Daniel

AU - Yiangou, Loukia

AU - Ross, Alexander

AU - Bargehr, Johannes

AU - Bertero, Alessandro

AU - Zonneveld, Mariëlle C F

AU - Pedersen, Marianne T

AU - Pawlowski, Matthias

AU - Valestrand, Laura

AU - Madrigal, Pedro

AU - Georgakopoulos, Nikitas

AU - Pirmadjid, Negar

AU - Skeldon, Gregor M

AU - Casey, John

AU - Shu, Wenmiao

AU - Materek, Paulina M

AU - Snijders, Kirsten E

AU - Brown, Stephanie E

AU - Rimland, Casey A

AU - Simonic, Ingrid

AU - Davies, Susan E

AU - Jensen, Kim B

AU - Zilbauer, Matthias

AU - Gelson, William T H

AU - Alexander, Graeme J

AU - Sinha, Sanjay

AU - Hannan, Nicholas R F

AU - Wynn, Thomas A

AU - Karlsen, Tom H

AU - Melum, Espen

AU - Markaki, Athina E

AU - Saeb-Parsy, Kourosh

AU - Vallier, Ludovic

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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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KW - Bile Ducts, Extrahepatic

KW - Biliary Tract

KW - Cell Transplantation

KW - Cystic Fibrosis Transmembrane Conductance Regulator

KW - Epithelial Cells

KW - Gallbladder

KW - Humans

KW - In Vitro Techniques

KW - Keratin-19

KW - Keratin-7

KW - Mice

KW - Organoids

KW - Regeneration

KW - Secretin

KW - Somatostatin

KW - Tissue Engineering

KW - Tissue Scaffolds

KW - gamma-Glutamyltransferase

KW - Journal Article

KW - Video-Audio Media

U2 - 10.1038/nm.4360

DO - 10.1038/nm.4360

M3 - Journal article

C2 - 28671689

SN - 1078-8956

VL - 23

SP - 954

EP - 963

JO - Nature Medicine

JF - Nature Medicine

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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