Human Hepatic Progenitor Cells in Hepatic Fibrosis of Elderly Cadavers: Lobular Distribution of Cytokeratin 7 and 19 Expressing Hepatic Progenitor Cells

Human hepatic progenitor cells (HPCs) are small oval‐shaped cells with an ovoid nucleus and scant cytoplasm. Cytokeratin (CK) 7 and CK19 are strongly expressed by HPCs and have been widely used as phenotypic markers for HPCs. In normal liver, HPCs reside in a quiescent state in the canals of Hering that are located in the periportal parenchyma. When the liver is damaged, as in alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, and chronic cholestasis, the HPCs become activated. Since elderly cadavers with diverse causes of death demonstrated progressive stages of liver fibrosis (Mak et al., 2012, Anat Rec 295:40–50), we aimed to evaluate whether the cadaveric livers served as a model for fibrosis‐associated HPC activation in the aged liver. To that effect, consecutive paraffin liver sections from embalmed cadavers were immunoperoxidase stained using monoclonal CK7 and CK19 antibodies, in conjunction with EDTA‐based antigen unmasking. Sections were post‐stained with Sirius red stain for assessment of fibrosis. Positive CK7 and CK19 staining of intraportal bile ducts and ductules validated the specificity of the immunoreaction. HPCs were identified by the CK7 or CK19 immunostaining of the cytoplasm. In livers with minimal fibrotic changes, CK7 and CK19 positive HPCs were generally distributed in proximity to the portal tracts, as well as in the lobular parenchyma at variable distance from the portal tracts. These CK7 or CK19 immunoreactive cells appeared either as individual cells, small clusters of cells or strings of cuboidal cells. In septal fibrosis, CK7 positive HPCs, along with occasional CK19 stained HPCs, could be seen in proximity to the developing septa, bridging septa and parenchymal fibrotic foci. In cirrhosis, the matrix of fibrotic bands often revealed CK7 positive HPCs, while the parenchyma of the nodules contained variable numbers of CK7 stained HPCs. Strikingly, CK19 immunoreactive HPCs were either rare or undetectable in cirrhotic livers. Conclusions The deep intralobular distribution of HPCs likely resulted from their migration from the periportal area into the lobular parenchyma, possibly relating to hepatic regeneration consequent to liver damage caused by fibrosis. CK7 expressing HPCs were found in all stages of fibrosis, while CK19 HPCs were absent from cirrhosis, suggesting that CK7 serves as a more sensitive phenotypic marker for HPCs than CK19. Hence, embalmed livers from elderly cadavers provide a potentially useful model for assessing HPC activation in association with liver fibrosis progression in the aged liver.