Progenitor cell involvement in cirrhotic human liver diseases: from controversy to consensus

Roskams, Tania

doi:10.1016/s0168-8278(03)00333-7

Cited by 87 publications

(63 citation statements)

References 45 publications

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“…4,5 These proliferating ductules are postulated to arise from hepatic progenitor cells (HPC), [6][7][8] small periportal cells that are bipotential and capable of proliferation and differentiation into both hepatocytes and bile ductular epithelium. They are synonymous with oval cells in the rodent.…”

Section: Abbreviations: Hcv Chronic Hepatitis C; Bmi Body Mass Indementioning

confidence: 99%

Fibrosis correlates with a ductular reaction in hepatitis C

et al. 2005

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The mechanisms for progressive fibrosis and exacerbation by steatosis in patients with chronic hepatitis C (HCV) are still unknown. We hypothesized that proliferative blockade in HCVinfected and steatotic hepatocytes results in the default activation of hepatic progenitor cells (HPC), capable of differentiating into both biliary and hepatocyte lineages, and that the resultant ductular reaction promotes portal fibrosis. To study this concept, 115 liver biopsy specimens from subjects with HCV were scored for steatosis, inflammation, and fibrosis. Biliary epithelium and HPC were decorated by cytokeratin 7 immunoperoxidase, and the replicative state of hepatocytes was assessed by p21 and Ki-67 immunohistochemistry. A ductular reaction at the portal interface was common. There was a highly significant correlation between the area of ductular reaction and fibrosis stage (r ‫؍‬ 0.453, P < .0001), which remained independently associated after multivariate analysis. HPC numbers also correlated with fibrosis (r ‫؍‬ 0.544, P < .0001) and the ductular area (r ‫؍‬ 0.624, P < .0001). Moreover, steatosis correlated with greater HPC proliferation (r ‫؍‬ 0.372, P ‫؍‬ .0004) and ductular reaction (r ‫؍‬ 0.374, P < .0001) but was not an obligate feature. Impaired hepatocyte replication by p21 expression was independently associated with HPC expansion (P ‫؍‬ .002) and increased with the body mass index (P < .001) and lobular inflammation (P ‫؍‬ .005). In conclusion, the strong correlation between portal fibrosis and a periportal ductular reaction with HPC expansion, the exacerbation by steatosis, and the associations with impaired hepatocyte replication suggest that an altered regeneration pathway drives the ductular reaction. We believe this triggers fibrosis at the portal tract interface. This may be a stereotyped response of importance in other chronic liver diseases. (HEPATOLOGY 2005;41: 809-818.)

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Section: Abbreviations: Hcv Chronic Hepatitis C; Bmi Body Mass Indementioning

confidence: 99%

Fibrosis correlates with a ductular reaction in hepatitis C

et al. 2005

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“…These cells are viewed as a progenitor cell type because of their known ability to differentiate into either hepatocytes or biliary epithelial cells (BECs) (1). With the development of improved techniques for detecting oval cells in liver sections, it has become apparent that the oval cell compartment participates in a range of injuries to human liver (2) and may be critical to the survival of patients with acute liver failure (3,4). There are many rodent models for oval cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

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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“…HPCs are small periportal cells capable of proliferation and differentiation into both hepatocytes and bile ductular epithelium (Clouston et al, 2005;Roskams, 2003). They express stem cell, hepatocyte and bile duct cell markers, including CD133, Nanog, α-Fetoprotein (AFP), CK19, Lin29 and c-Myc (Clouston et al, 2005;Oliva et al, 2010).…”

Section: Cancer Stem Cells 121 Potential Cancer Stem Cellsmentioning

confidence: 99%

Epigenetic Mechanisms in Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Potential New Link Between Stem Cells, Virology and Cancer

Feng¹

2013

American Medical Journal

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Recent studies suggest that epigenetic mechanisms are not only essential for the dynamic transcriptional regulation in embryonic and somatic stem cells, but are also actively involved in tumorigenesis: genes important for pluripotency are epigenetically regulated and aberrant epigenetic changes have been detected in virtually all human malignancies studied, including Hepatocellular Carcinoma (HCC). Infection with Hepatitis C Virus (HCV) is a major risk factor for the development of HCC. Despite the fact that HCV is a RNA virus without a DNA intermediate, recent studies demonstrate that HCV viral proteins may actively participate in epigenetic regulation of hepatic cancer stem cell phenotypes and induce HCC-specific epigenetic changes. Identification of host epigenetic alterations induced by HCV infection and epigenetic differences between hepatic cancer stem cells and the bulk non-tumorigenic cancer cells, may yield potential biomarkers for early detection, as well as therapeutic targets for HCV associated HCC.

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Progenitor cell involvement in cirrhotic human liver diseases: from controversy to consensus

Cited by 87 publications

References 45 publications

Fibrosis correlates with a ductular reaction in hepatitis C

Fibrosis correlates with a ductular reaction in hepatitis C

TWEAK induces liver progenitor cell proliferation

Epigenetic Mechanisms in Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Potential New Link Between Stem Cells, Virology and Cancer

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