Structural analysis of oval-cell–mediated liver regeneration in rats

Abstract

We have analyzed the architectural aspects of progenitor-cell-driven regenerative growth in rat liver by applying the 2-acetaminofluorene/partial hepatectomy experimental model. The regeneration is initiated by the proliferation of so-called oval cells. The oval cells at the proximal tips of the ductules have a more differentiated phenotype and higher proliferative rate. This preferential growth results in the formation of a seemingly random collection of small hepatocytes, called foci. These foci have no clonal origin, but possess a highly organized structure, which shows similarities to normal hepatic parenchyma. Therefore, they can easily remodel into the lobular structure. Eventually, the regenerated liver is constructed by enlarged hepatic lobules; no new lobules are formed during this process. The foci of the Solt-Farber experimental hepatocarcinogenesis model have identical morphological features; accordingly, they also represent only regenerative, not neoplastic, growth. Conclusion: Progenitor-cell-driven liver regeneration is a well-designed, highly organized tissue reaction, and better comprehension of the architectural events may help us to recognize this process and understand its role in physiological and pathological reactions. (HEPATOLOGY 2012;56:1457-1467 T here are several alternative mechanisms of liver regeneration. 1 Hepatocytes can enter the cell cycle or enlarge, and the consequent compensatory hyperplasia or hypertrophy replaces the lost liver mass. We have demonstrated that new hepatic lobules are not formed during this type of regeneration, but the remaining lobes grow exclusively by the enlargement of preexistent hepatic lobules. 2 If the hepatocytes are compromised, the progenitor cell compartment is activated and the liver regenerates by means of the socalled oval cells in the rat. 3 Oval cells invade the liver parenchyma from the periportal region. They form ductules, which are the extensions of the canals of Hering. 4 The distribution of the differentiating cells can be different, depending on the species and etiology. In human liver, singular intermediate hepatobiliary cells can often be observed in proliferating ductules after extensive necrosis, 5 but small groups of differentiating cells are also described in chronic hepatitis and cirrhosis. 6,7 The 2-acetaminofluorene/partial hepatectomy (AAF-PH) model 8 is one of the most widely applied experiments to study oval cell proliferation and differentiation in rats. We characterized the differentiating progenitor cells in this experimental model. Two alternative patterns of differentiation were observed previously depending on the applied dose of AAF. 9 In the case of a low dose (2.5 mg/kg/day of AAF), differentiation occurred earlier and practically all the oval cells transformed into small, newly formed hepatocytes. If the dose of AAF was higher (5 mg/kg/ day of AAF), differentiation occurred later and involved only a small portion of oval cells. Sharply

Alterations in hepatic lobar function in regenerating rat liver

“…In a separate study, the size of liver lobules was determined before (n ¼ 4) and 7 d after portal vein ligation (n ¼ 4) as previously described [17,18]. Briefly, hepatic veins and sinusoids were filled up through the inferior vena cava by a fluorescent dye containing polystyrene resin.…”

Expression of Tight Junction Components in Hepatocyte-Like Cells Differentiated from Human Embryonic Stem Cells

“…Thus, we aimed to characterize the expression pattern of TJ components, mainly claudins, in endodermlike and hepatocyte-like cells differentiated from HUES cell lines. The differentiated cells were characterized by morphological analysis [46], functional assays, and expression profiles of cytokeratins and ABC transporters characteristic of liver cells.…”

Lineage tracing reveals conversion of liver sinusoidal endothelial cells into hepatocytes

“…Two-thirds PH may be particularly relevant to clinical scenarios in which the quantity of liver tissue is a limiting factor, such as small-for-size syndrome following liver transplantation and necrosis, inflammation, fibrosis accompanying regeneration in acute viral hepatitis, and other liver diseases (Rutherford & Chung 2008;Curado & Stainier 2010). Following two-thirds PH, cells other than hepatocytes also contribute to the liver regeneration (Dezso et al 2012). Our results showed that biliary epithelial cells (Fig.…”

“…Following two‐thirds PH, cells other than hepatocytes also contribute to the liver regeneration (Dezso et al . ). Our results showed that biliary epithelial cells (Fig.…”