Oval cell differentiation into hepatocytes in the acetylaminofluorene-treated regenerating rat liver

Abstract

When hepatocyte regeneration after a two-thirds partial hepatectomy (PH) in rats is blocked by oral gavage of acetylaminofluorene, a proliferation of ductular cells ensues that results in a profusion of neoductules radiating from each portal tract. To examine the possibility that this population of newly emerging cells harbors cells capable of differentiating into hepatocytes, we have looked in these cells for expression of functional markers of hepatocyte commitment at both the RNA and protein levels. Expression of albumin and a-fetoprotein (a-FPI messenger RNA (mRNA) transcripts were sought in situ using antisense riboprobes, and the expression of a number of cytochrome P450 enzymes was examined immunohistochemically. Before any signs of differentiation the ductular cells strongly expressed cytokeratins 7, 8, 18, and 19 in the same manner as authentic bile ducts, but unlike the latter also expressed vimentin. In situ hybridization studies showed that small bile ducts close to the limiting plate, as well as the newly formed ducts, expressed albumin and a-fetoprotein messenger RNAs, and immunocytochemistry showed that the distribution of the respective proteins was similar. Beginning at 1 week after partial hepatectomy, areas of differentiation could be found in the new ducts, with cells resembling either columnar intestinal-type epithelia or hepatocytes. Intestinal-like cells expressed neither albumin, a-FP, nor cytochrome P450 enzymes, whereas ductular cells appearing like hepatocytes with the typical membranous distribution of cytokeratin 8 strongly expressed a variety of cytochrome P450 enzymes normally associated with functional hepatocytes. These observations further support the belief that reactive ductules, sprouted from small ducts, can represent an adaptive response of the liver to replenish lost hepatocytes, al-

Immuno-histochemical detection of human telomerase reverse transcriptase in human liver tissues

“…It was reported that proliferating hepatocytes were found mainly in periportal areas in chronic active hepatitis (Seki et al, 1990;Kawakita et al, 1992). In experimental animals such as rats, oval cells arose in the periportal area of the liver after treatment with hepatocarcinogens or hepatotoxins, and these cells had the ability to proliferate and di erentiated into both mature hepatocytes and biliary epithelial cells (Dunsford et al, 1985, Evarts et al, 1989;Elmore et al, 1991;Noviko et al, 1996;Golding et al, 1995). The presence of oval cells in human liver has been reported, these cells proliferated in the periportal region and were suggested to be derived from a stem cell compartment (De Vos and Desmet, 1992;Haque et al, 1996;Demetris et al, 1996;Roskams et al, 1996;Ruck et al, 1996).…”

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

“…These cells are small in size (approximately 10 μm), with a large nuclear-to-cytoplasm ratio and with an ovalshaped nucleus (hence their name) [2]. Although oval cells are thought to emanate from the periportal area [4][5][6][7][8], their lineage remains controversial. Immunofluorescence studies revealed that oval cells express cytokeratin 19 (CK19), a marker specific for the biliary tree that includes bile ducts as well as the canal of Hering [8,9].…”

Immunohistochemical demonstration of ?-naphthoflavone-inducible cytochrome P450 1A1/1A2 in rat intrahepatic biliary epithelial cells

“…16,[19][20][21][22][23][24]28,29 The results of the present study demonstrate that CYP1A1/1A2 is present and can be induced within these cells in rat liver by a polycyclic aromatic hydrocarbon such as BNF. Thus, these findings provide an explanation for why intrahepatic biliary epithelial cells are susceptible to damage following their in vivo exposure to 2-acetylaminofluorene and other promutagens and procarcinogens.…”

“…[22][23][24] It has also been demonstrated that the reactive metabolite of 2-acetylaminofluorene, Nhydroxy-2-acetylaminofluorene, forms a DNA adduct, Ndeoxyguanosine (8-yl)aminofluorene, that accumulates within intrahepatic biliary epithelial cells as well as hepatocytes after rats are fed 2-acetylaminofluorene. 30 Because this electrophilically reactive metabolite is highly unstable, it is reasonable to assume from our findings that N-hydroxy-2-acetylaminofluorene might be generated, at least in part, by the CYP1A1/1A2-catalyzed N-hydroxylation of 2-acetylaminofluorene within intrahepatic biliary epithelial cells, rather than being formed solely in hepatocytes and then transported to intrahepatic biliary epithelial cells.…”

“…[15][16][17] Intrahepatic biliary epithelial cells have recently received considerable attention because of their ability to proliferate under certain pathophysiological conditions and because of the possibility that they might serve as the progenitor cell in the liver. [18][19][20][21][22][23][24] Although these cells have been shown to be capable of conjugating various xenobiotics and/or their metabolites with reduced glutathione and uridine 5Ј-phosphate (UDP)-glucuronic acid, they appear to be unable to catalyze cytochrome P450 (CYP)-dependent monooxygenase activities, at least in vitro. [15][16][17][25][26][27] Nonetheless, intrahepatic biliary epithelial cells are the targets for certain procarcinogens.…”