Different mouse models of oval cell induction can lead to reactivation of the oncofetal marker Neighbor of Punc E 11

Background:

The oncofetal marker Neighbor of Punc E 11 (Nope) is physiologically expressed on hepatoblasts in the murine fetal liver, but its expression decreases rapidly until postnatal week 3 and remains undetectable in hepatocytes of the adult liver. The aim of our study was to analyzse whether expression of Nope can be reactivated in different mouse models of oval cell induction.

Methods:

We investigated C57Bl6 mice on a 3,5-diethoxycarbonyl-1,4-dihydro-collidin (DDC) diet as well as mice on a choline-deficient, ethionine-supplemented (CDE) diet in comparison with mice on normal chow. DDC and CDE diet were optionally followed by a regenerative period on normal chow. For an alternative acute liver injury, normal mice were subjected to a partial hepatectomy (PH). After defined time periods between 3 to 6 weeks, mice were sacrificed and quantitative RT-PCR and immunohistochemical costainings of the liver for Nope with CK19, A6, EpCAM (oval cell markers), E-cadherin or HNF4α (hepatocyte markers) were performed.

Results:

Partial hepatectomy did not induce any expression of Nope above background level in the adult liver. After DDC diet, the expression level of Nope was increased as measured by RT-PCR. In the CDE model, the expression level of Nope even reached a high level as in the fetal liver.

Immunohistochemically, we were able to detect ductular proliferations in both injury models with coexpression of CK19, A6, EpCAM and Nope. In the DDC model followed by normal chow, the Nope expression level decreased rapidly, but small hepatocytic cells in proximity to ductular structures stained positive for Nope. Only A6 also stained positive in a minor cell fraction within periductular Nope positive hepatocytic cells. In the CDE model, we were able to detect clearly confined Nope positive hepatocytic cell clusters mainly in proximity to Nope positive ductular structures.

Clearly distinguishable from these Nope expressing cell populations, expression of Nope was infrequently induced in E-cadherin and HNF4α positive parenchymal hepatocytes.

Discussion:

Reinduction of the oncofetal marker Nope in the adult liver can be effected in the DDC and in the CDE model. 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 after liver injury. In conclusion, Nope is a marker for adult progenitor cells and periductular early hepatocytes in different mouse models of liver regeneration.

Corresponding author: Hoffmann, Vera

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