Wnt/β-Catenin Signaling in Murine Hepatic Transit Amplifying Progenitor Cells

Hu, Min; Kurobe, Masashi; Jeong, Young Beom; Fuerer, Christophe; Ghole, Saif A.; Nusse, Roel; Sylvester, Karl G.

doi:10.1053/j.gastro.2007.08.036

Cited by 149 publications

(145 citation statements)

References 49 publications

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“…Wnt/ β-catenin signaling is induced in the livers of mice exposed to DDC, and oval cells isolated from DDC-exposed livers display nuclear localization of β-catenin in response to Wnt3a stimulation [32] . In rats, Wnt/β-catenin signaling is also activated by 2AAF/PH [33] . Moreover, the activation of β-catenin signaling in response to Wnt ligands was recently observed in WB-F344 cells, resulting in their proliferation [34] .…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Hatch et al [95] have highlighted the significance of the up-regulation of the chemokine SDF-1 by hepatocytes in the CCl 4 -damaged liver for the activation of CXCR4-expressing oval cells; importantly, SDF-1 was only up-regulated in the face of such damage when hepatocyte DNA synthesis was concurrently blocked by 2-AAF. Autocrine and paracrine Wnt signalling is also clearly involved in the oval cell response in mice [96], rats [97] and humans [98], and is likely responsible for the expression of EpCAM [99]. Hedgehog (Hh) signalling acting through the receptor Patched (PTC) on oval cells/HPCs is required for their survival [76].…”

Section: The Facultative Stem Cell Response: Oval/hepatic Progenitor mentioning

confidence: 99%

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

199

149

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The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.

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“…10 In the liver, expression of canonical wnt ligands is increased in proliferating cholangiocytes and ductular progenitor cells and these cells proliferate in response to wnt ligands. [15][16][17] We Foxl1 and cholangiocyte proliferation SD Sackett et al determine whether reduced wnt expression in the Foxl1 À/À livers resulted in impaired b-catenin signaling in cholangiocytes, we investigated whether the expression of the wnt target gene Cyclin D1 was reduced in Foxl1 À/À cholangiocytes. Cyclin D1 expression was significantly decreased in Foxl1 À/À cholangiocytes 5 days after BDL corresponding to the time at which Wnt3a and Wnt7b expression was reduced.…”

Section: Resultsmentioning

confidence: 99%

Foxl1 promotes liver repair following cholestatic injury in mice

Sackett

Gao

Shin

et al. 2009

Laboratory Investigation

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Cholangiocyte proliferation is one of the hallmarks of the response to cholestatic injury. We previously reported that the winged helix transcription factor Foxl1 is dramatically induced in cholangiocytes following bile duct ligation. In this study, we investigated the function of Foxl1 in the bile duct ligation model of cholestatic liver injury in Foxl1 À/À and control mice. We found that Foxl1 À/À livers exhibit an increase in parenchymal necrosis, significantly impaired cholangiocyte and hepatocyte proliferation, and failure to expand bile ductular mass. Wnt3a and Wnt7b expression was decreased in the livers of Foxl1 À/À mice along with reduced expression of the b-catenin target gene Cyclin D1 in Foxl1 À/À cholangiocytes. These results show that Foxl1 promotes liver repair after bile-duct-ligation-induced liver injury through activation of the canonical wnt/b-catenin pathway.

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Wnt/β-Catenin Signaling in Murine Hepatic Transit Amplifying Progenitor Cells

Cited by 149 publications

References 49 publications

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

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

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Foxl1 promotes liver repair following cholestatic injury in mice

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