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

TY - JOUR

T1 - A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis

AU - Müller, Miryam

AU - Wetzel, Sebastian

AU - Köhn-Gaone, Julia

AU - Chalupsky, Karel

AU - Lüllmann-Rauch, Renate

AU - Barikbin, Roja

AU - Bergmann, Juri

AU - Wöhner, Birte

AU - Zbodakova, Olga

AU - Leuschner, Ivo

AU - Martin, Gregor

AU - Tiegs, Gisa

AU - Rose-John, Stefan

AU - Sedlacek, Radislav

AU - Tirnitz-Parker, Janina E E

AU - Saftig, Paul

AU - Schmidt-Arras, Dirk

PY - 2016/4/5

Y1 - 2016/4/5

N2 - UNLABELLED: 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 ADAM10(Δhep/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.

AB - UNLABELLED: 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 ADAM10(Δhep/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.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.18632/oncotarget.7836

DO - 10.18632/oncotarget.7836

M3 - SCORING: Journal article

C2 - 26942887

VL - 7

SP - 17431

EP - 17441

JO - ONCOTARGET

JF - ONCOTARGET

SN - 1949-2553

IS - 14

ER -