We have analyzed the histological changes in rat liver after 2-acetylaminofluorene (AAF) administration. The data demonstrate that AAF-induced oval cells were preferentially generated by proliferation of the terminal biliary ductules that we suggest constitute the primary hepatic stem cell niche. The oval cells formed ductular structures, representing an extension of the canals of Hering. This histological organization provides continuous bile drainage of the hepatocytes and uninterrupted blood flow in the sinusoids. The oval cell ductules are surrounded by a continuous basement membrane that is intermittently disrupted by processes of stellate cells that form direct cell-cell contact with the oval cells. Although both AAF treatment and bile duct ligation results in proliferation of biliary epithelial cells, the mechanism(s) responsible for the proliferation of the biliary epithelium seems to differ in the two models. In contrast to the biliary proliferation stimulated by bile ligation, AAF-induced oval cell proliferation as well as the capacity of these cells to differentiate into hepatocytes, bile epithelial cells and possibly other cell lineages can be blocked by administration of dexamethasone.

Recent advances have implicated the importance of tumor necrosis factor (TNF) and interleukin 6 (IL-6) in the regulation of liver growth. Therefore, we studied how dexamethasone, a well-known inhibitor of these cytokines, influences the proliferation of different hepatic cell populations. As we expected, dexamethasone pretreatment suppressed the expression of both TNF and IL-6 after partial hepatectomy and significantly reduced the proliferative response of the hepatocytes. Furthermore, the proliferative response of hepatocytes could be rescued by IL-6 administration. Dexamethasone also severely diminished the induction and expansion of oval cells induced by the 2-acetylaminofluorene/partial hepatectomy (AAF/PH) protocol but did not have any effect on the proliferation of the bile duct cells stimulated by bile duct ligation. The differential inhibition of these two morphologically very similar cell types may be used to characterize divergent regulatory mechanisms responsible for the proliferative response of oval cells and adult bile epithelial cells. (HEPATOLOGY 1998;28:423-429.)Although the adult liver is mitotically silent, the proliferation of different hepatic cell populations can be triggered by appropriate stimulation. An increasing number of compounds have been described recently that are able to induce liver hyperplasia without preceding necrosis or cell loss. [1][2][3] Hepatocyte proliferation is traditionally studied by surgical partial hepatectomy (PH). 4 Similar mitotic activity is seen in these experimental models, but biologically they are not equal. For example, although compensatory hyperplasia promotes tumorigenesis in the liver, direct mitogens do not exert any promoting effect. 5 Regulation of the two proliferative processes also is not identical. Transforming growth factor (TGF) ␣ and hepatocyte growth factor (HGF) are thought to be the major mitogenic growth factors driving proliferation after PH, but these cytokines are not upregulated during chemically induced primary hyperplasia of the liver. 6 When PH is performed and the hepatocytic response is inhibited, the liver regenerates via the proliferation and differentiation of facultative stem cells traditionally referred to as oval cells. 7 Ligation of the common bile duct and consequent bile congestion is an established model for induction of the proliferation of bile duct cells. 8 Although the different proliferative models must be regulated differently, there may be common regulatory mechanisms. In fact, dexamethasone has been shown to abrogate the proliferative response of primary mitogens effectively by inhibiting tumor necrosis factor (TNF) production. 9,10 TNF is also required for compensatory liver growth after PH. 11 However, little is known about the effect of dexamethasone on the proliferation of different cell types in other models of hepatic proliferation. Therefore, we compared the effects of dexamethasone on the proliferative capacity of hepatocytes, bile duct cells, and oval cells in vivo.The results show that dexamethasone ...

The liver has an extremely effective regenerative capacity. When 70% of a rat liver is removed by surgery, the liver mass regrows in 7 to 10 days by the compensatory hyperplasia of the remnant part. In case of damage to the surviving hepatocytes, the facultative stem-cell compartment is activated and the liver regenerates by means of oval-cell proliferation/differentiation. In the present study, we demonstrate that when both hepatocyte proliferation and stem-cell activation were prevented by dexamethasone (Dex) administration, the liver mass was restored in the absence of DNA synthesis. The restoration of the liver was accomplished by the preferential enlargement/hypertrophy of the periportal hepatocytes. A similar response was observed when cell proliferation was arrested by 5-fluorouracil (FU) following partial hepatectomy. Therefore, the hepatocytic hypertrophy appears to provide an alternative mechanism of livermass restoration. This hypertrophic condition of the liver is not stable, because following the withdrawal of Dex, the enlarged hepatocytes entered in the cell cycle and the normal liver structure and DNA content was re-established. The liver/body weight ratio is strictly regulated in animals and humans. As observed in both clinical and experimental situations, transplanted livers that are of small size for the recipient grow, while large ones decrease in size. [1][2][3] The most extensively studied model of this accommodation is the partial hepatectomy (PH). When a portion of the liver is removed by surgery or destroyed by toxic injury, the remnant piece reacts with immediate regeneration. The differentiated hepatocytes enter the cell cycle and in 7 to 10 days replace the 70% loss of the liver mass via compensatory hyperplasia. 4 Studies during the last decade revealed that a second backup mechanism for liver regeneration exists. The normally dormant stem-cell compartment of the liver is activated if the hepatocytes are compromised and cannot respond to the proliferative stimulus. 5 The progeny of the stem cells, the so-called oval cells, invade the liver lobule from the periportal space and replace the lost parenchyma by proliferation and differentiation. 6 We have described recently 7 that a single administration of dexamethasone (Dex) is able to reversibly reduce the proliferative response of the hepatocytes following PH. Furthermore, repeated administration of Dex almost completely blocked the oval-cell proliferation/differentiation induced by the 2-acetylaminofluorene/PH reaction. Therefore, Dex is able to inhibit both the hepatocytic-and stem-cell-driven mechanisms of liver regeneration. Based on these observations, we decided to study the effect on the liver when we performed PH and blocked the hepatocyte replication, as well as stem-cell activation, by prolonged Dex administration. Surprisingly, we found that the liver mass was restored in spite of the severe inhibition of DNA synthesis. The reconstitution of the liver occurred by the preferential enlargementhypertrophy-of the periportal hepa...

These phenotypic similarities confirm that the atypical ductules in the human liver may be equivalent of oval cells in the rat liver, which are regarded as the progeny of stem cells. That is, the atypical ductular proliferation may correspond to a stem cell-fed regenerative process.

Since the increased TGF-beta 1 production in the liver slowed down the regression of the liver fibrosis, the behaviour of these transgenic mice is more similar to the human situation, where cirrhosis is irreversible. We propose that this transgenic model is more suitable for investigating fibrotic liver diseases than the experiments done previously on wild-type rodents.

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