A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis
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A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis. / Müller, Miryam; Wetzel, Sebastian; Köhn-Gaone, Julia; Chalupsky, Karel; Lüllmann-Rauch, Renate; Barikbin, Roja; Bergmann, Juri; Wöhner, Birte; Zbodakova, Olga; Leuschner, Ivo; Martin, Gregor; Tiegs, Gisa; Rose-John, Stefan; Sedlacek, Radislav; Tirnitz-Parker, Janina E E; Saftig, Paul; Schmidt-Arras, Dirk.
in: ONCOTARGET, Jahrgang 7, Nr. 14, 05.04.2016, S. 17431-41.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -