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Cited by 13Drug-Induced Hepatotoxicity and ProtectionDrug Transport and Resistance MechanismsLiver physiology and pathology

Cholangiocyte organoids to study drug-induced injury

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Wang, Zhenguo, Xing, Chen, van der Laan, Luc J. W., Verstegen, Monique M. A., Spee, Bart, Masereeuw, Rosalinde·2024·Stem Cell Research & Therapy
DOI 10.1186/s13287-024-03692-6PMC PMC10935784

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Abstract

Background: Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. Methods: Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. Results: CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 ( TJP1 ), E-cadherin 1 ( CDH1 ) and lysyl oxidase homolog 2 ( LOXL2 ). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. Conclusion: These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.

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  • A physiologically valid renal I/R model has not yet been fully established.

    “a physiologically valid renal I/R model has not yet been fully established”

    From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Wang et al., 2024

    The Introduction and Conclusion discuss models of drug-induced bile duct injury, not renal ischemia–reperfusion (I/R). Searches for a physiologically valid renal I/R model and for kidney ischemia–reperfusion found no passage addressing whether such a model has been established. No page numbers are available in our copy. (LLM, conf=0.78)

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  • It is difficult to strictly control the changes in the oxygen environment associated with ischemia and reperfusion.

    “it is difficult to strictly control the changes in the oxygen environment associated with ischemia and reperfusion”

    From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Wang et al., 2024

    The Results section on chlorpromazine-induced oxidative stress reports reactive oxygen species in drug-treated organoids, not changes in oxygen during ischemia and reperfusion. Searches for ischemia–reperfusion and hypoxia–reoxygenation found no passage in our copy addressing whether those oxygen changes are difficult to control. (LLM, conf=0.74)

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Cited by

Sorted by citations

Authors
Wang, Z., Xing, C., van der Laan, L. J. W., Verstegen, M. M. A., Spee, B., & Masereeuw, R.
Affiliations
  • Utrecht University (NL)
  • Erasmus MC (NL)
Corresponding author
Masereeuw, Rosalinde
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2024-03-13
Volume
15
Issue
1
Pages
78-78
ISSN
1757-6512 (ISSN-L)
DOI
10.1186/s13287-024-03692-6
PMC
PMC10935784
OpenAlex
W4392756012
Cited by
13
References
2
Citations by year
2026: 4 · 2025: 6 · 2024: 3
FWCI
4.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • China Sponsorship Council (201808620130)
  • Health~Holland (LSHM20045-SGF)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Project OCENW.XS21.2.003)
  • Medical Delta (Regenerative Medicine 4D program)
  • Erasmus Universitair Medisch Centrum Rotterdam (Convergence Health Technology Flagship)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
cholangiocyte organoids, chlorpromazine, bile duct injury, tight junction proteins, E-cadherin, lysyl oxidase, bile acid transporters, bile acid accumulation, oxidative stress, TNF-α, hepatotoxicity, cholestasis
MeSH terms
Adenosine Triphosphate, Bile Acids and Salts, Bile Ducts, Organoids, Cadherins

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