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 III, 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 & 23 others 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

Research output: Contribution to journalArticle

46 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.
LanguageEnglish
Number of pages14
JournalNature Medicine
Volume23
Issue number8
DOIs
Publication statusPublished - 3 Jul 2017

Fingerprint

Organoids
Biliary Tract
Ducts
Tissue
Common Bile Duct
Forms (concrete)
Scaffolds
Capsules
Biliary Atresia
Repair
Regenerative Medicine
Cholestasis
Bile Ducts
Gallbladder
Kidney Transplantation
Regeneration
Pathologic Constriction
Epithelium
Transplantation
Tissue Donors

Keywords

  • regenerative medicine
  • tissue engineering

Cite this

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). https://doi.org/10.1038/nm.4360
Sampaziotis, Fotios ; Justin, Alexander W ; Tysoe, Olivia C ; Sawiak, Stephen ; Godfrey, Edmund M ; Upponi, Sara S ; Gieseck III, 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 E ; Brown, Stephanie E ; 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. / Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. In: Nature Medicine. 2017 ; Vol. 23, No. 8.
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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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Sampaziotis, F, Justin, AW, Tysoe, OC, Sawiak, S, Godfrey, EM, Upponi, SS, Gieseck III, 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. https://doi.org/10.1038/nm.4360

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 III, 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 E; Brown, Stephanie E; 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.

In: Nature Medicine, Vol. 23, No. 8, 03.07.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids

AU - Sampaziotis, Fotios

AU - Justin, Alexander W

AU - Tysoe, Olivia C

AU - Sawiak, Stephen

AU - Godfrey, Edmund M

AU - Upponi, Sara S

AU - Gieseck III, 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 - 2017/7/3

Y1 - 2017/7/3

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.

KW - regenerative medicine

KW - tissue engineering

U2 - 10.1038/nm.4360

DO - 10.1038/nm.4360

M3 - Article

VL - 23

JO - Nature Medicine

T2 - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 8

ER -