MODULATION OF KERATIN-14 AND ALPHA-FETOPROTEIN EXPRESSION DURING HEPATIC OVAL CELL-PROLIFERATION AND LIVER-REGENERATION

Keratin 14 (K14) expression has recently been demonstrated in cell lin es of nonparenchymal hepatic origin (Bisgaard et al., 1993, Mel. Carci nog., 7:60-66; Bisgaard et al., 1991, J. Cell. Physiol., 747:333-343). These cell lines are thought to represent a progeny of a dormant stem cell compartment present in the adult rat liver, which may participat e in the restoration of the liver mass after experimental liver injury . Utilizing a combination of 2-acetylaminofluorene (2-AAF) administrat ion and partial hepatectomy to activate liver regeneration by prolifer ation of oval cells, we examined the modulation of K14 as well as alph a-fetoprotein (AFP) expression in proliferating oval cells and lineage s hypothesized to be derived here from. We showed by Northern blot and in situ hybridization analyses that K14 and AFP transcripts were init ially accumulating in epithelial cells located in subsets of ductal st ructures in the portal areas. As oval cells infiltrated the liver pare nchyma, K14 transcripts were detected in oval cells, in foci of small basophilic hepatocytes, and in structures resembling glandular intesti nal-type epithelium. AFP was expressed in oval cells, and at low but d etectable levels in foci of basophilic hepatocytes, but not in glandul ar intestinal-type epithelium. Neither K14 nor AFP transcripts were de tected in bile ducts or mature hepatocytes at any time during oval cel l proliferation and reconstitution of the liver mass. To further study the modulation of K14 and AFP expression we utilized an in vitro mode l in which spontaneous transformation of rat liver epithelial (RLE) ce lls appeared to mimic the process of early differentiation along the h epatic lineage in vivo. We demonstrated that undifferentiated RLE cell s at a late passage expressed K14 and vimentin, whereas transformation and differentiation to hepatoblast-like progeny resulted in an abroga tion of K14 and vimentin expression and an induction of K18 and AFP. W e propose that K14 and AFP are sequentially modulated in subpopulation s of oval cells involved in the ongoing reconstitution of the liver ma ss. (C) 1994 Wiley-Liss, Inc.