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ResearchIn-Press PreviewHepatology Open Access | 10.1172/jci.insight.181857

WNT signaling contributes to the extrahepatic bile duct proliferative response to obstruction in mice

Ashley N. Calder,1 Mirabelle Q. Peter,1 John W. Tobias,2 Nureen H. Mohamad Zaki,1 Theresa M. Keeley,3 Timothy L. Frankel,4 Linda C. Samuelson,1 and Nataliya Razumilava1

1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

2Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America

4Department of Surgery, University of Michigan, Ann Arbor, United States of America

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1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

2Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America

4Department of Surgery, University of Michigan, Ann Arbor, United States of America

Find articles by Peter, M. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

2Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America

4Department of Surgery, University of Michigan, Ann Arbor, United States of America

Find articles by Tobias, J. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

2Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America

4Department of Surgery, University of Michigan, Ann Arbor, United States of America

Find articles by Mohamad Zaki, N. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

2Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America

4Department of Surgery, University of Michigan, Ann Arbor, United States of America

Find articles by Keeley, T. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

2Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America

4Department of Surgery, University of Michigan, Ann Arbor, United States of America

Find articles by Frankel, T. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

2Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America

4Department of Surgery, University of Michigan, Ann Arbor, United States of America

Find articles by Samuelson, L. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

2Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States of America

4Department of Surgery, University of Michigan, Ann Arbor, United States of America

Find articles by Razumilava, N. in: JCI | PubMed | Google Scholar

Published December 5, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.181857.
Copyright © 2024, Calder et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 5, 2024 - Version history
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Abstract

Biliary obstruction and cholangiocyte hyperproliferation are important features of cholangiopathies affecting the large extrahepatic bile duct (EHBD). The mechanisms underlying obstruction-induced cholangiocyte proliferation in the EHBD remain poorly understood. Developmental pathways, including WNT signaling, are implicated in regulating injury responses in many tissues, including the liver. To investigate the contribution of WNT signaling to obstruction-induced cholangiocyte proliferation in the EHBD, we used complementary in vivo and in vitro models with pharmacologic interventions and transcriptomic analyses. To model obstruction, we used bile duct ligation (BDL) in mice. Human and mouse biliary organoids and mouse biliary explants were used to investigate the effects of WNT activation and inhibition in vitro. We observed an upregulation of WNT ligand expression associated with increased biliary proliferation following obstruction. Cholangiocytes were identified as both WNT ligand-expressing and WNT responsive cells. Inhibition of WNT signaling decreased cholangiocyte proliferation in vivo and in vitro, while activation increased proliferation. WNT effects on cholangiocyte proliferation were β-catenin-dependent, and we showed a direct effect of WNT7B on cholangiocyte growth. Our studies suggested that cholangiocyte-derived WNT ligands can activate WNT signaling to induce proliferation after obstructive injury. These findings implicated the WNT pathway in injury-induced cholangiocyte proliferation within the EHBD.

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