Human branching cholangiocyte organoids recapitulate functional bile duct formation

Floris J M Roos; Gilles S van Tienderen; Haoyu Wu; Ignacio Bordeu; Dina Vinke; Laura Muñoz Albarinos; Kathryn Monfils; Sabrah Niesten; Ron Smits; Jorke Willemse; Oskar Rosmark; Gunilla Westergren-Thorsson; Daniel J Kunz; Maurice de Wit; Pim J French; Ludovic Vallier; Jan N M IJzermans; Richard Bartfai; Hendrik Marks; Ben D Simons; Martin E van Royen; Monique M A Verstegen; Luc J W van der Laan

doi:10.1016/j.stem.2022.04.011

Human branching cholangiocyte organoids recapitulate functional bile duct formation

Cell Stem Cell. 2022 May 5;29(5):776-794.e13. doi: 10.1016/j.stem.2022.04.011.

Authors

Floris J M Roos¹, Gilles S van Tienderen², Haoyu Wu³, Ignacio Bordeu⁴, Dina Vinke², Laura Muñoz Albarinos², Kathryn Monfils², Sabrah Niesten², Ron Smits⁵, Jorke Willemse², Oskar Rosmark⁶, Gunilla Westergren-Thorsson⁶, Daniel J Kunz⁷, Maurice de Wit⁸, Pim J French⁹, Ludovic Vallier¹⁰, Jan N M IJzermans², Richard Bartfai³, Hendrik Marks³, Ben D Simons⁴, Martin E van Royen⁸, Monique M A Verstegen², Luc J W van der Laan¹¹

Affiliations

¹ Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
² Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands.
³ Radboud University, Department of Molecular Biology, Nijmegen, the Netherlands.
⁴ Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK.
⁵ Erasmus MC, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands.
⁶ Lung Biology, Department Experimental Medical Science, Lund University, Lund, Sweden.
⁷ Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, University of Cambridge, Cambridge, UK.
⁸ Erasmus MC, University Medical Center Rotterdam, Department of Pathology, Rotterdam, the Netherlands.
⁹ Erasmus MC, University Medical Center Rotterdam, Cancer Treatment Screening Facility, Department of Neurology, Rotterdam, the Netherlands.
¹⁰ Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
¹¹ Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands. Electronic address: l.vanderlaan@erasmusmc.nl.

PMID: 35523140
DOI: 10.1016/j.stem.2022.04.011

Abstract

Human cholangiocyte organoids show great promise for regenerative therapies and in vitro modeling of bile duct development and diseases. However, the cystic organoids lack the branching morphology of intrahepatic bile ducts (IHBDs). Here, we report establishing human branching cholangiocyte organoid (BRCO) cultures. BRCOs self-organize into complex tubular structures resembling the IHBD architecture. Single-cell transcriptomics and functional analysis showed high similarity to primary cholangiocytes, and importantly, the branching growth mimics aspects of tubular development and is dependent on JAG1/NOTCH2 signaling. When applied to cholangiocarcinoma tumor organoids, the morphology changes to an in vitro morphology like primary tumors. Moreover, these branching cholangiocarcinoma organoids (BRCCAOs) better match the transcriptomic profile of primary tumors and showed increased chemoresistance to gemcitabine and cisplatin. In conclusion, BRCOs recapitulate a complex process of branching morphogenesis in vitro. This provides an improved model to study tubular formation, bile duct functionality, and associated biliary diseases.

Keywords: branching morphogenesis; cholangiocarcinoma; cholangiocyte organoids; cholangiocytes; disease modeling; embryonic bile duct development; intrahepatic bile duct.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Ducts
Cholangiocarcinoma*
Epithelial Cells
Humans
Organoids*
Transcriptome

Abstract

Publication types

MeSH terms

Grants and funding