Z Gastroenterol 2014; 52 - P_1_17
DOI: 10.1055/s-0033-1360861

Expression pattern of the stem/progenitor cell marker Neighbor of Punc E 11 in different mouse models of liver regeneration

V Hoffmann 1, A Bowe 1, S Schievenbusch 2, HM Curth 3, T Goeser 1, D Nierhoff 1
  • 1University Hospital of Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
  • 2Ludwig-Maximilians University Munich, Department of Internal Medicine IV, Division of Clinical Pharmacology and Center of Integrated Protein Science, Munich, Germany
  • 3University of Cologne, Institute for Genetics, Centre for Molecular Medicine, Cologne, Germany

Background: Regeneration after acute liver injury naturally arises from the compartment of parenchymal liver cells. If proliferation capacity of hepatocytes is inadequate, liver progenitor cells – with expected origin from the stem cell niche in the canals of Hering – are activated and can give rise to mature hepatocytes and cholangiocytes. In this project we have focused on the expression pattern of the oncofetal marker Neighbor of Punc E 11 (Nope) in liver regeneration after acute and chronic liver injury.

Methods: 10-week old C57Bl6 mice, Mdr2-/- mice and mice on a DDC (3,5-diethoxycarbonyl-1,4-dihydro-collidin) diet were subjected to a partial hepatectomy (PH) for acute liver injury. In subgroups of each injury model, retrorsine was injected twice intraperitoneally 2 weeks apart before partial hepatectomy to block hepatocyte proliferation. After defined time periods between 24 hours and 6 months, mice were sacrificed and quantitative RT-PCR and immunohistochemical stainings of the liver tissue for Nope, CK19, A6, EpCAM and HNF4α were performed.

Results: Partial hepatectomy in C57Bl6 mice with or without retrorsine did not induce any Nope expression. In the Mdr2-/- mice however, we were able to detect clearly confined Nope positive hepatocytic cell clusters mainly in proximity to Nope positive ductular structures. In the DDC model, we were also able to detect Nope positive ductular proliferations and Nope positive periductular small hepatocytic cells. The oval cell markers CK19, A6 and EpCAM showed co-expression with Nope in proliferating ductular cells, but only A6 also stained positive in a minor cell fraction within periductular Nope positive hepatocytic cell populations. Clearly distinguishable from these Nope expressing cell populations, expression of Nope was infrequently induced in HNF4α positive parenchymal hepatocytes of several mice.

Discussion: The oncofetal marker Nope is expressed in CK19, A6 and EpCAM positive ductular cells as well as in CK19 negative periductular small hepatocytic cells presumably representing early hepatocytes. These Nope positive early hepatocytes can form confined regenerative clusters with a minor fraction staining positive for A6.

In conclusion, Nope is a marker for progenitor cells and periductular early hepatocytes in different mouse models of liver regeneration.