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Human branching cholangiocyte organoids recapitulate functional bile duct formation

Roos, Floris J.M. ; van Tienderen, Gilles S. ; Wu, Haoyu ; Bordeu, Ignacio ; Vinke, Dina ; Albarinos, Laura Muñoz ; Monfils, Kathryn ; Niesten, Sabrah ; Smits, Ron and Willemse, Jorke , et al. (2022) In Cell Stem Cell 29(5). p.13-794
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.... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
branching morphogenesis, cholangiocarcinoma, cholangiocyte organoids, cholangiocytes, disease modeling, embryonic bile duct development, intrahepatic bile duct
in
Cell Stem Cell
volume
29
issue
5
pages
13 - 794
publisher
Cell Press
external identifiers
  • pmid:35523140
  • scopus:85129623622
ISSN
1934-5909
DOI
10.1016/j.stem.2022.04.011
language
English
LU publication?
yes
id
b61d9290-4889-4c3a-ba63-cad22f6e4e81
date added to LUP
2022-07-06 14:56:30
date last changed
2024-11-16 03:11:40
@article{b61d9290-4889-4c3a-ba63-cad22f6e4e81,
  abstract     = {{<p>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.</p>}},
  author       = {{Roos, Floris J.M. and van Tienderen, Gilles S. and Wu, Haoyu and Bordeu, Ignacio and Vinke, Dina and Albarinos, Laura Muñoz and Monfils, Kathryn and Niesten, Sabrah and Smits, Ron and Willemse, Jorke and Rosmark, Oskar and Westergren-Thorsson, Gunilla and Kunz, Daniel J. and de Wit, Maurice and French, Pim J. and Vallier, Ludovic and IJzermans, Jan N.M. and Bartfai, Richard and Marks, Hendrik and Simons, Ben D. and van Royen, Martin E. and Verstegen, Monique M.A. and van der Laan, Luc J.W.}},
  issn         = {{1934-5909}},
  keywords     = {{branching morphogenesis; cholangiocarcinoma; cholangiocyte organoids; cholangiocytes; disease modeling; embryonic bile duct development; intrahepatic bile duct}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{13--794}},
  publisher    = {{Cell Press}},
  series       = {{Cell Stem Cell}},
  title        = {{Human branching cholangiocyte organoids recapitulate functional bile duct formation}},
  url          = {{http://dx.doi.org/10.1016/j.stem.2022.04.011}},
  doi          = {{10.1016/j.stem.2022.04.011}},
  volume       = {{29}},
  year         = {{2022}},
}