Precursor-product relationship between oval cells and hepatocytes: comparison between tritiated thymidine and bromodeoxyuridine as tracers

Evarts, Ritva P.; Hu, Zongyi; Omori, Nobuhiko; Omori, Masako; Marsden, Elizabeth R.; Thorgeirsson, Snorri S.

doi:10.1093/carcin/17.10.2143

Cited by 71 publications

(58 citation statements)

References 20 publications

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“…14 For example, a high dose of AAF caused a delay in the differentiation of oval cells into hepatocytes. 15 Similar results also were obtained by Alison et al 16,17 We revisited the issue of AAF dose dependency on oval cell differentiation. In particular, we asked how the dose of AAF modifies oval cell differentiation.…”

supporting

confidence: 79%

2-acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: Confocal and electron microscopic studies

et al. 2004

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The 2-acetylaminofluorene (AAF)/partial hepatectomy (PH) model is one of the most extensively studied experimental systems for oval cell proliferation and differentiation. We have previously described the oval cells as forming ductular structures surrounded by basement membrane, representing extensions of the canals of Hering. Herein we analyze the differentiation of oval cells into hepatocytes after varying degrees of liver damage induced by AAF. At a low dose of AAF, most oval cells synchronously differentiate into small hepatocytes by 6 days after the PH, resulting in complete restoration of the liver structure in 10 days. Higher doses of AAF delay the differentiation process and the new hepatocytes form foci, in contrast to what is observed at the low dose. Qualitatively, the differentiation process seems to be identical at the cellular level under both conditions. The transition from the expanding oval cell population into hepatocytes was correlated with the upregulation of hepatocyte nuclear factor 4 and the disappearance of the basement membrane. Also, the differentiation of oval cells into hepatocytes coincided with the loss of alpha-fetoprotein and OV-6 staining, and the replacement of the biliary cell-specific ␣6 integrin and connexin 43 with the hepatocyte-specific ␣1 integrin and connexin 32. In addition, bile canaliculi form between the new hepatocytes. In conclusion, these results indicate the rate of oval cell differentiation into hepatocytes is context dependent and suggest that, under favorable conditions, oval cells can complete this process much faster than previously appreciated.

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confidence: 79%

2-acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: Confocal and electron microscopic studies

et al. 2004

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“…42 The subsequent partial hepatectomy provides the necessary growth stimulus for transient amplification of oval cells before they differentiate within the hepatic lineage to hepatocytes or bile duct cells. 3,42 Additionally, in the AAF/PHx protocol of liver regeneration oval cells may differentiate along the intestinal cell lineage giving rise to intestinal-like structures within the hepatic parenchyma. The phenotype of oval cells resembles that of bipotential hepatoblasts in the distinct expression of AFP, which on differentiation into mature hepatocytes or bile duct cells is turned off.…”

Section: Cellular Localization Of Dlk Protein In Regenerating Livermentioning

confidence: 99%

“…The transit-amplifying ductular (oval) cells share some phenotypic characteristics with the bipotential fetal hepatoblasts and may, if needed, differentiate to hepatocytes or bile duct cells and reconstitute the architecture and function of the damaged liver tissue. [1][2][3][4] Although the origin of oval cells has not been conclusively established, evidence points to endogenous stem cells located at the junctions between bile duct cells and hepatocytes in the terminal bile ductules (the canal of Hering) as a potential source. 4 -6 It is also well established that reconstruction of liver mass lost to surgical resection is accomplished by proliferation of residual, normally quiescent hepatocytes and bile duct cells responding rapidly and giving rise to a large number of progeny while maintaining their differentiated phenotype.…”

mentioning

confidence: 99%

Transit-Amplifying Ductular (Oval) Cells and Their Hepatocytic Progeny Are Characterized by a Novel and Distinctive Expression of Delta-Like Protein/Preadipocyte Factor 1/Fetal Antigen 1

Jensen

Jauho

Santoni-Rugiu

et al. 2004

The American Journal of Pathology

131

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Hepatic regeneration from toxic or surgical injury to the adult mammalian liver, endorses different cellular responses within the hepatic lineage. The molecular mechanisms determining commitment of a cell population at a specific lineage level to participate in liver repair as well as the fate of its progeny in the hostile environment created by the injury are not well defined. Based on the role of the Notch/Delta/Jagged system in cell fate specification and recent reports linking Notch signaling with normal bile duct formation in mouse and human liver, we examined the expression of Notch1, Notch2, Notch3, Delta1, Delta3, Jagged1, and Jagged2, and delta-like protein/ preadipocyte factor 1/fetal antigen 1 (dlk) in four well-defined experimental rat models of liver injury and regeneration. Although Delta3 and Jagged2 were undetectable by reverse transcriptase-polymerase chain reaction and Northern blot, we observed the most significant up-regulation of all other transcripts in the 2-acetylaminofluorene-70% hepatectomy (AAF/ PHx) model, in which liver mass is restored by proliferation and differentiation of transit-amplifying ductular (oval) cells. The most profound change was observed for dlk. Accordingly, immunohistochemical analyses in the AAF/PHx model showed a specific expression of dlk in atypical ductular structures composed of oval cells. Delta-like protein was not observed in proliferating hepatocytes or bile duct cells after partial hepatectomy or ligation of the common bile duct whereas clusters of dlk immunoreactive oval cells were found in both the retrorsine and the AAF/ PHx models. Finally, we used dlk to isolate ␣-fetoprotein-positive cells from fetal and adult regenerating rat liver by a novel antibody panning technique.

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“…Oval cells are facultative stem cells in the adult liver but are activated only if hepatocyte proliferation is inhibited [1][2][3] . These cells can differentiate into hepatocytes and bile duct cells and can thus restore the architecture and function of the damaged liver tissue [4][5][6][7] . Oval cells are usually present in normal fetal livers but have been implicated in hepatic carcinogenesis in a variety of hepatic pathologies [8,9] .…”

Section: Introductionmentioning

confidence: 99%

GSK-3β suppresses the proliferation of rat hepatic oval cells through modulating Wnt/β-catenin signaling pathway

Xie

Zhong

et al. 2015

Acta Pharmacol Sin

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Aim: Glycogen synthase kinase 3β (GSK-3β) plays a crucial role in hepatic biology, including liver development, regeneration, proliferation and carcinogenesis. In this study we investigated the role of GSK-3β in regulation of growth of hepatic oval cells in vitro and in liver regeneration in partially hepatectomized rats. Methods: WB-F344 cells, the rat hepatic stem-like epithelial cells, were used as representative of oval cells. Cell viability was examined using a WST-8 assay. The cells were transfected with a recombinant lentivirus expressing siRNA against GSK-3β (GSK3βRNAiLV) or a lentivirus that overexpressed GSK-3β (GC-GSK-3βLV). Adult rats underwent partial (70%) hepatectomy, and liver weight and femur length were measured at d 7 after the surgery. The expression of GSK-3β, phospho-Ser 9 -GSK-3β, β-catenin and cyclin D1 was examined with immunoblotting assays or immunohistochemistry. Results: Treatment of WB-F344 cells with the GSK-3β inhibitor SB216763 (5 and 10 µmol/L) dose-dependently increased the levels of phospho-Ser 9 -GSK-3β, but not the levels of total GSK-3β, and promoted the cell proliferation. Knockout of GSK-3β with GSK-3βRNAiLV increased the cell proliferation, whereas overexpression of GSK-3β with GC-GSK-3βLV decreased the proliferation. Both SB216763 and GSK-3βRNAiLV significantly increased the levels of β-catenin and cyclin D1 in the cells, whereas GSK-3β overexpression decreased their levels. In rats with a partial hepatectomy, administration of SB216763 (2 mg/kg, ip) significantly increased the number of oval cells, the levels of phospho-Ser 9 -GSK-3β, β-catenin and cyclin D1 in liver, as well as the ratio of liver weight to femur length at d 7 after the surgery. Conclusion: GSK-3β suppresses the proliferation of hepatic oval cells by modulating the Wnt/β-catenin signaling pathway.

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Precursor-product relationship between oval cells and hepatocytes: comparison between tritiated thymidine and bromodeoxyuridine as tracers

Cited by 71 publications

References 20 publications

2-acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: Confocal and electron microscopic studies

2-acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: Confocal and electron microscopic studies

Transit-Amplifying Ductular (Oval) Cells and Their Hepatocytic Progeny Are Characterized by a Novel and Distinctive Expression of Delta-Like Protein/Preadipocyte Factor 1/Fetal Antigen 1

GSK-3β suppresses the proliferation of rat hepatic oval cells through modulating Wnt/β-catenin signaling pathway

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