Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease
Open accessAbstract
The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.
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Berkers and colleagues used forskolin to induce organoid swelling due to chloride and fluid flux into the lumen.
“Berkers and colleagues used forskolin, a CFTR activator, to induce organoid swelling due to chloride and fluid flux into the lumen191.”
From Organoids (2022) · cites this paper as [191]
The Methods section (“Forskolin-induced swelling assay”) says that this paper’s authors added forskolin to activate CFTR and that anion secretion drove fluid into the organoid lumen, increasing its volume. The Results section reports swelling in both organoid types. The cited paper is by Verstegen and colleagues, however, and our copy does not establish that Berkers and colleagues performed this experiment. (LLM, conf=0.88)
Experimental — accuracy not yet measuredReduced swelling of patient-derived rectal organoids correlated with clinical response parameters and could mimic individualized clinical responses to specific therapeutic regimens.
“They demonstrated how reduced swelling of patient-derived rectal organoids correlated with clinical response parameters of patients and could mimic individualized clinical responses to specific therapeutic regimens191.”
From Organoids (2022) · cites this paper as [191]
The Methods section describes a swelling assay for bile-duct organoids, and the Results section reports CFTR dysfunction in organoids derived from a patient’s extrahepatic bile duct (pages unavailable). Our copy does not report rectal organoids, a correlation between swelling and clinical response parameters, or tests of individualized responses to therapeutic regimens; searches for those terms found no such passage. (LLM, conf=0.78)
Experimental — accuracy not yet measuredHeterogeneity in treatment responses is being exploited for the treatment of cystic fibrosis patients, with a large ongoing European multicentre clinical trial led by the HIT-Cystic Fibrosis consortium to identify potential responders.
“This heterogeneity in treatment responses is now being exploited for the treatment of cystic fibrosis patients191, with a large ongoing European multicentre clinical trial study, led by the HIT-Cystic Fibrosis consortium, to identify potential responders214.”
From Organoids (2022) · cites this paper as [191]
The Results section (‘Modelling cystic fibrosis biliary disease in ECO’; page unavailable) describes organoids from one cystic fibrosis patient and suggests future personalized drug testing. Searches for HIT-Cystic Fibrosis and a European multicentre clinical trial found no passage in our copy establishing that such a trial is ongoing or identifying responders. (LLM, conf=0.74)
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References 42 · Cited by 86
- Authors
- Verstegen, M. M. A., Roos, F. J. M., Burka, K., Gehart, H., Jager, M., de Wolf, M., Bijvelds, M. J. C., de Jonge, H. R., Ardisasmita, A. I., van Huizen, N. A., Roest, H. P., de Jonge, J., Koch, M., Pampaloni, F., Fuchs, S. A., Schene, I. F., Luider, T. M., van der Doef, H. P. J., Bodewes, F. A. J. A., de Kleine, R. H. J., Spee, B., Kremers, G.-J., Clevers, H., IJzermans, J. N. M., Cuppen, E., & van der Laan, L. J. W.
- Affiliations
- Erasmus MC (NL)
- Royal Netherlands Academy of Arts and Sciences (NL)
- University Medical Center Utrecht (NL)
- Goethe University Frankfurt (DE)
- University Medical Center Groningen (NL)
- Utrecht University (NL)
- Corresponding author
- Verstegen, Monique M. A.
- ORCID
- Venue
- Scientific Reports
- Published
- 2020-12-14
- Volume
- 10
- Issue
- 1
- Pages
- 21900-21900
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7736890
- OpenAlex
- W3112935818
- Cited by
- 86
- References
- 42
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 23 · 2023: 15 · 2022: 15 · 2021: 12
- FWCI
- 9.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- Maag Lever Darm Stichting (MLDS-Diagnostiek D16-26)
- Topics
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- cholangiocyte organoids, extrahepatic bile ducts, intrahepatic bile ducts, cystic fibrosis, CFTR, Wnt signaling, organoid differentiation, chloride channels, common bile duct, disease modeling
- MeSH terms
- Adolescent, Bile Duct Diseases, Bile Ducts, Intrahepatic, Cell Differentiation, Cystic Fibrosis, Humans, Male, Organoids
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