Activation of NF-κB and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration

Sánchez, Aránzazu; Factor, Valentina M.; Schroeder, Insa S.; Nagy, Péter; Thorgeirsson, Snorri S.

doi:10.1002/hep.20040

Cited by 48 publications

(27 citation statements)

References 41 publications

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“…As previously reported, progenitor cells expressed both A6 and CD34 markers (25). Some progenitor cells expressed CD34 but not A6, which suggests that they represent a less mature population (26,41). Thus, it is likely that the observed oval cells represent various maturation stages, up to definitive BECs.…”

Section: Figuresupporting

confidence: 71%

TWEAK induces liver progenitor cell proliferation

Jakubowski

Ambrose²,

Parr³

et al. 2005

J. Clin. Invest.

372

357

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Progenitor ("oval") cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors.

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Section: Figuresupporting

confidence: 71%

TWEAK induces liver progenitor cell proliferation

Jakubowski

Ambrose²,

Parr³

et al. 2005

J. Clin. Invest.

372

357

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“…The thyroid hormone has been recently described to increase the NF-B and STAT3 activity in the liver (Fernández et al 2007). These transcriptional factors play role in the growth regulation of the oval cells (Sánchez et al 2004), therefore, alterations of these nuclear factors also might participate in the rapid diVerentiation.…”

Section: Figmentioning

confidence: 99%

Triiodothyronine accelerates differentiation of rat liver progenitor cells into hepatocytes

László

Dezső

Baghy

et al. 2008

Histochem Cell Biol

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The 2-acetaminofluorene/partial hepatectomy (AAF/Phx) model is widely used to induce oval/progenitor cell proliferation in the rat liver. We have used this model to study the impact of a primary hepatocyte mitogen, triiodothyronine (T3) on the liver regenerating by the recruitment of oval/progenitor cells. Administration of T3 transiently accelerates the proliferation of the oval cells, which is followed by rapid differentiation into small hepatocytes. The oval cell origin of the small hepatocytes has been proven by tracing retrovirally transduced and BrdU marked oval cells. The differentiating oval cells become positive for hepatocyte nuclear factor-4 and start to express hepatocyte specific connexin 32, alpha1 integrin, Prox1, cytochrom P450s, and form CD 26 positive bile canaliculi. At the same time oval cell specific OV-6 and alpha-fetoprotein expression is lost. The upregulation of hepatocyte specific mRNAs: albumin, tyrosine aminotransferase and tryptophan 2,3-dioxygenase detected by real-time PCR also proves hepatocytic maturation. The hepatocytic conversion of oval cells occurs on the seventh day after the Phx in this model while the first small hepatocytes appear 5 days later without T3 treatment. The administration of the primary hepatocyte mitogen T3 accelerates the differentiation of hepatic progenitor cells into hepatocytes in vivo, and that may have therapeutic potential.

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“…Alternatively, when periportal hepatocytes are damaged or their division is inhibited, a small pool of hepatic progenitor cells (HPCs), also known as oval cells, expands and differentiates into mature hepatocytes and biliary epithelial cells in an attempt to restore functional tissue mass. [4][5][6][7][8][9] These regenerative processes are often complicated by the coexistence of other liver pathologies such as hepatitis C virus infection or recipient-mediated autoimmune reactions to the donor tissue. 10 Moreover, ischemia and reperfusion injury occurring during the storage and transplantation procedures also complicates the regenerative response.…”

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confidence: 99%