Oncotarget

Research Papers: Pathology:

A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis

Miryam Müller, Sebastian Wetzel, Julia Köhn-Gaone, Karel Chalupsky, Renate Lüllmann-Rauch, Roja Barikbin, Juri Bergmann, Birte Wöhner, Olga Zbodakova, Ivo Leuschner, Gregor Martin, Gisa Tiegs, Stefan Rose-John, Radislav Sedlacek, Janina E.E. Tirnitz-Parker, Paul Saftig and Dirk Schmidt-Arras _

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Oncotarget. 2016; 7:17431-17441. https://doi.org/10.18632/oncotarget.7836

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Abstract

Miryam Müller1,*, Sebastian Wetzel1,*, Julia Köhn-Gaone2, Karel Chalupsky3, Renate Lüllmann-Rauch4, Roja Barikbin5, Juri Bergmann1,6, Birte Wöhner1, Olga Zbodakova3, Ivo Leuschner7, Gregor Martin3,9, Gisa Tiegs5, Stefan Rose-John1, Radislav Sedlacek3, Janina E.E. Tirnitz-Parker2,8, Paul Saftig1 and Dirk Schmidt-Arras1

1 Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany

2 School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, Australia

3 Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic

4 Institute of Anatomy, Christian-Albrechts-University, Kiel, Germany

5 Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6 Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

7 Institute of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

8 School of Medicine and Pharmacology, University of Western Australia, Fremantle, Australia

9 Laboratory of Integrative Biology, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic

* These authors contributed equally to this work

Correspondence to:

Dirk Schmidt-Arras, email:

Keywords: ADAM10, liver progenitor cell, c-Met, Notch, hepatocyte differentiation, Pathology Section

Received: February 01, 2016 Accepted: February 17, 2016 Published: March 01, 2016

Abstract

A Disintegrin And Metalloprotease (ADAM) 10 exerts essential roles during organ development and tissue integrity in different organs, mainly through activation of the Notch pathway. However, only little is known about its implication in liver tissue physiology.

Here we show that in contrast to its role in other tissues, ADAM10 is dispensable for the Notch2-dependent biliary tree formation. However, we demonstrate that expression of bile acid transporters is dependent on ADAM10. Consequently, mice deficient for Adam10 in hepatocytes, cholangiocytes and liver progenitor cells develop spontaneous hepatocyte necrosis and concomitant liver fibrosis.

We furthermore observed a strongly augmented ductular reaction in 15-week old ADAM10Δhep/Δch mice and demonstrate that c-Met dependent liver progenitor cell activation is enhanced. Additionally, liver progenitor cells are primed to hepatocyte differentiation in the absence of ADAM10.

These findings show that ADAM10 is a novel central node controlling liver tissue homeostasis.

Highlights:

Loss of ADAM10 in murine liver results in hepatocyte necrosis and concomitant liver fibrosis.

ADAM10 directly regulates expression of bile acid transporters but is dispensable for Notch2-dependent formation of the biliary system.

Activation of liver progenitor cells is enhanced through increased c-Met signalling, in the absence of ADAM10.

Differentiation of liver progenitor cells to hepatocytes is augmented in the absence of ADAM10.


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