Background/aims/methods: Since in rat experiments, activation of progenitor cells is seen in conditions associated with hepatocyte injury or inhibited replication, we compared the activation and fate of human putative progenitor cells in regenerating liver versus chronic cholestatic disease, using immunohistochemistry, rat oval cell marker OV6 and a panel of bile ductular cell markers. We compared the results with different rat models: the choline-deficient acetylaminofluorene (CDAAF)- and alpha-naphthylisothiocyanate (ANIT)-model, using immunohistochemistry and electron microscopy.
Results: In very early stages of human liver regeneration, putative progenitor cells in the vicinity of portal tracts were immunoreactive for OV6, CK7, CK19 and chrom-A. In later stages of regeneration and in chronic cholestasis, reactive bile ductules (immunoreactive for OV6, CK7, CK19, chrom-A, NCAM) and intermediate hepatocyte-like cells (immunoreactive for OV6, CK7, chrom-A), became apparent, suggesting bidirectional differentiation of the putative progenitor cells. In regenerating human liver, intermediate hepatocyte-like cells became more numerous with time and extended far into the lobule. In advanced cholestasis, intermediate hepatocyte-like cells were less numerous and formed periportal rosettes and small clusters. In the CDAAF rat model (associated with inhibited hepatocyte replication), but not in the ANIT model, gradual differentiation of oval cells into hepatocytes was seen after stopping the diet.
Conclusions: Our results in human liver suggest that reactive ductules and intermediate hepatocyte-like cells originate at least partly from activation and differentiation of "progenitor cells". In regeneration after submassive necrosis, in analogy with what is seen in rat models, differentiation towards hepatocytes is more pronounced than in chronic cholestasis.