A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis
MetadataShow full item record
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.
This open access article is distributed under the Creative Commons license http://creativecommons.org/licenses/by/3.0/
Showing items related by title, author, creator and subject.
The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injuryGrzelak, C.; Martelotto, L.; Sigglekow, N.; Patkunanathan, B.; Ajami, K.; Calabro, S.; Dwyer, Benjamin; Tirnitz-Parker, Janina; Watkins, D.; Warner, F.; Shackel, N.; McCaughan, G. (2014)Background & Aims: In vertebrates, canonical Hedgehog (Hh) pathway activation requires Smoothened (SMO) translocation to the primary cilium (Pc), followed by a GLI-mediated transcriptional response. In addition, a similar ...
Expansion and Hepatocytic Differentiation of Liver Progenitor Cells In Vivo Using a Vascularized Tissue Engineering Chamber in MiceForster, N.; Palmer, J.; Yeoh, G.; Ong, W.; Mitchell, G.; Slavin, J.; Tirnitz-Parker, Janina; Morrison, W. (2011)Current cell-based treatment alternatives to organ transplantation for liver failure remain unsatisfactory. Hepatocytes have a strong tendency to dedifferentiate and apoptose when isolated and maintained in culture. In ...
Tirnitz-Parker, Nina; Olynyk, John; Ramm, G. (2014)Failure of fibrotic liver to regenerate after resection limits therapeutic options and increases demand for liver transplantation, representing a significant clinical problem. The mechanism underlying regenerative failure ...