Genomic expression analysis implicates Wnt signaling pathway and extracellular matrix alterations in hepatic specification and differentiation of murine hepatic stem cells

Plescia, Christopher; Rogler, Charles E.; Rogler, Leslie E.

doi:10.1046/j.1432-0436.2001.680413.x

Cited by 40 publications

(34 citation statements)

References 42 publications

(41 reference statements)

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“…Gene expression of Wnt-4 and AFP was highest at day 3 and decreased by day 7, in contrast to WT-1 which was unchanged at day 3 and highest at day 7. These findings are consistent with the transient activation of these transcription factors (WT-1 and Wnt-4) known to occur in liver re-modeling and differentiation [16,26,27] . HNF-6, a marker strongly associated with hepatocyte proliferation [28] , was unchanged, as also noted in a previous study of non-hepatocyte mediated (but progenitor cell mediated) liver regeneration [16] .…”

Section: Discussionsupporting

confidence: 88%

“…1 Wnt-4: Wingless-type mouse mammary tumor virus integration site family, member 4 [21,26,27] ; WT-1: Wilm's tumor suppressor gene [16,22] ; Nanog: One of the gene markers of pluripotency [24] ; AFP: α-fetoprotein [15,23] ; Oct-4: Octomer-4 [25] ; HNF-6: Hepatic nuclear factor-6 [16,28] ; 2 Accessed from http://www.ncbi.nlm.nih.gov; 3 Numbers in parentheses after forward (F) and reverse primers (R) denote the nucleotide number in the cDNA sequence. Figure 2 Liver mass (as a ratio of body weight) at different times after injury and fusing of the activated omentum to the wound.…”

Section: Fusion Of the Omentum To The Wounded Liver Resulted In New Lmentioning

confidence: 99%

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Omentum facilitates liver regeneration

Singh¹,

Pancholi²,

Patel³

et al. 2009

WJG

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AIM:To investigate the mechanism of liver regeneration induced by fusing the omentum to a small traumatic injury created in the liver. We studied three groups of rats. In one group the rats were omentectomized; in another group the omentum was left in situ and was not activated, and in the third group the omentum was activated by polydextran particles. METHODS:We pre-activated the omentum by injecting polydextran particles and then made a small wedge wound in the rat liver to allow the omentum to fuse to the wound. We monitored the regeneration of the liver by determining the ratio of liver weight/body weight, by histological evaluation (including immune staining for cytokeratin-19, an oval cell marker), and by testing for developmental gene activation using reverse transcription polymerase chain reaction (RT-PCR). RESULTS:There was no liver regeneration in the omentectomized rats, nor was there significant regeneration when the omentum was not activated, even though in this instance the omentum had fused with the liver. In contrast, the liver in the rats with the activated omentum expanded to a size 50% greater than the original, and there was histologically an interlying tissue between the wounded liver and the activated omentum in which bile ducts, containing cytokeratin-19 positive oval cells, extended from the wound edge. In this interlying tissue, oval cells were abundant and appeared to proliferate to form new liver tissue. In rats pre-treated with drugs that inhibited hepatocyte growth, liver proliferation was ongoing, indicating that regeneration of the liver was the result of oval cell expansion. CONCLUSION:Activated omentum facilitates liver regeneration following injury by a mechanism that depends largely on oval cell proliferation.

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Section: Discussionsupporting

confidence: 88%

Section: Fusion Of the Omentum To The Wounded Liver Resulted In New Lmentioning

confidence: 99%

Omentum facilitates liver regeneration

Singh¹,

Pancholi²,

Patel³

et al. 2009

WJG

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“…29,30 The downregulation of the laminin receptor was described in differentiating HBC-3 hepatic stem cells in culture. 31 The disappearance of the ␣6 integrin from differentiating oval cells is in good agreement with the disintegration of the basement membrane. In the normal liver, ␣6 and ␣1 integrins are expressed on biliary cells and hepatocytes, respectively.…”

Section: Discussionmentioning

confidence: 58%

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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“…7 These findings are consistent with our data suggesting that Wnt signaling blocks hepatoblast/hepatocyte fate, as suggested by previous in vitro studies. 33 Based on the apparent discrepancies between zebrafish and xenopus, murine models in which ␤-catenin signaling is activated or inactivated in the ventral foregut endoderm before liver bud induction are now needed to have a full view of the importance of the Wnt pathway in liver development.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of β-catenin affects mouse embryonic liver growth and hepatoblast fate

et al. 2007

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During hepatogenesis, after the liver has budded out of the endoderm, the hepatoblasts quickly expand and differentiate into either hepatocytes or biliary cells, the latter of which arise only within the ductal plate surrounding the portal vein. Because the Wnt/␤-catenin pathway is involved in liver homeostasis and regeneration and in liver carcinogenesis, we investigated here a role for Wnt/␤-catenin signaling in the embryonic liver. A cyclization recombination (Cre)/locus of X-over P1 (loxP) strategy was chosen to perform adenomatous polyposis coli (Apc) invalidation in order to activate ectopic ␤-catenin signaling in hepatoblasts; an appropriate transgenic model expressing the Cre recombinase was used. Phenotypic and immunolocalization studies, together with messenger RNA analyses, by microarray and real-time quantitative polymerase chain reaction approaches were performed on this model during normal hepatogenesis. The loss of Apc allowed ␤-catenin activation in the hepatoblasts after the formation of the liver bud and led to embryonic lethality. In this model, the liver became hypoplastic, and hepatocyte differentiation failed, whereas ␤-catenin-activated ducts developed and gave rise to fully differentiated bile ducts when transplanted into adult recipient livers. Microarray analyses suggested that ␤-catenin plays a role in repressing the hepatocyte genetic program and remodeling the ductal plate. According to these data, in normal embryonic livers, ␤-catenin was transiently activated in the nascent bile ducts. Conclusion: We demonstrated a key role for the Wnt/␤-catenin pathway in liver embryonic growth and in controlling the fate of hepatoblasts, preventing them from differentiating toward the hepatocyte lineage, and guiding them to biliary ductal morphogenesis. (HEPATOLOGY 2008;47:247-258.)

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Genomic expression analysis implicates Wnt signaling pathway and extracellular matrix alterations in hepatic specification and differentiation of murine hepatic stem cells

Cited by 40 publications

References 42 publications

Omentum facilitates liver regeneration

Omentum facilitates liver regeneration

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

Stabilization of β-catenin affects mouse embryonic liver growth and hepatoblast fate

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