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ResearchIn-Press PreviewHepatologyStem cells Open Access | 10.1172/JCI164997

Metalloprotease inhibitors regulate biliary progenitor cells through sDLK1 in organoid models of liver injury

Virginie Defamie,1 Kazeera Aliar,1 Soumili Sarkar,1 Foram Vyas,1 Ronak Shetty,1 Swami Reddy Narala,1 Hui Fang,1 Sanjay Saw,1 Pirashaanthy Tharmapalan,1 Otto Sanchez,2 Jennifer J. Knox,3 Paul D. Waterhouse,1 and Rama Khokha1

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

Find articles by Defamie, V. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

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1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

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1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

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1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

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1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

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1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

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1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

Find articles by Saw, S. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

Find articles by Tharmapalan, P. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

Find articles by Sanchez, O. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

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

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

Find articles by Waterhouse, P. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Ontario Tech University, Oshawa, Canada

3Department of Medical Oncology and Hematology, Princess Margaret Cancer Cen, University of Toronto, Toronto, Canada

Find articles by Khokha, R. in: JCI | PubMed | Google Scholar

Published December 19, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI164997.
Copyright © 2024, Defamie 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 19, 2024 - Version history
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Abstract

Understanding cell fate regulation in the liver is necessary to advance cell therapies for hepatic disease. Liver progenitor cells (LPC) contribute to tissue regeneration after severe hepatic injury yet signals instructing progenitor cell dynamics and fate are largely unknown. The Tissue Inhibitor of Metalloproteinases, TIMP1 and TIMP3 control the sheddases ADAM10 and ADAM17, key for NOTCH activation. Here we uncover the role of the TIMP/ADAM/NOTCH/DLK1 axis in LPC maintenance and cholangiocyte specification. Combined TIMP1/TIMP3 loss in vivo caused abnormal portal triad stoichiometry accompanied by collagen deposits, dysregulated Notch signalling and increased soluble DLK1. The MIC1-1C3+CD133+CD26– biliary progenitor population was reduced following acute CCl4 or chronic DDC liver injury and in aged TIMP deficient livers. ScRNA-seq data interrogation and RNAscope identified portal mesenchymal cells co-expressing ADAM17/DLK1 as enzymatically equipped to process DLK1 and direct LPC differentiation. Specifically, TIMP deficient biliary fragment-derived organoids displayed increased propensity for cholangiocyte differentiation. ADAM17 inhibition reduced Sox9-mediated cholangiocyte differentiation, prolonging organoid growth and survival, whereas soluble DLK1-treated WT organoids triggered Sox9 expression and cholangiocyte specification in mouse and patient-derived liver organoids. Thus, metalloprotease inhibitors regulate instructive signals for biliary cell differentiation and LPC preservation within the portal niche, providing a new basis for cell therapy strategies.

Graphical Abstract
graphical abstract
Supplemental material

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View Cell population signatures used for scRNA-seq analyses.

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Version history
  • Version 1 (December 19, 2024): In-Press Preview
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