The histogenesis of regenerative nodules in human liver cirrhosis

Lin, Wey‐Ran; Lim, Siew‐Na; McDonald, Stuart; Graham, Trevor A.; Wright, Victoria L.; Peplow, Claire L.; Humphries, Adam; Kocher, Hemant M.; Wright, Nicholas A.; Dhillon, Amar P.; Alison, Malcolm R.

doi:10.1002/hep.23483

Cited by 89 publications

(72 citation statements)

References 24 publications

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“…It raises a possibility that human HCC may originate from enriched progenitor cells in the liver under conditions in which the proliferation of hepatocytes is inhibited. By tracing the mitochondrial DNA mutations, Lin et al recently showed that some monoclonal human cirrhotic regenerative nodules could be derived from hepatic progenitor cells (25). However, the details still need to be studied by using appropriate animal models.…”

Section: Discussionmentioning

confidence: 99%

Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development

Wang¹,

Yeh

Tsai³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Depletion of β-catenin impairs regeneration of the rapid turn-over gut epithelial cells, but appears dispensable for that of the slow turn-over mature hepatocytes in mice until 1 y of age. As the life span of mature murine hepatocytes is about 400 d, we studied conditional β-catenin knockout mice (Alb-Cre;Ctnnb1 flx/flx ) until 20 mo of age to determine the function of β-catenin in the postnatal liver. β-catenin was absent from the hepatocytes of β-catenin knockout mice 4 wk after delivery. From 9 mo of age, hepatocytes were gradually replaced by newly formed β-catenin-positive hepatocytes, which constituted about 90% of hepatocytes at 18-20 mo of age. This process was accompanied by active proliferation of bile duct/ductule cells. β-catenin-positive hepatocytes exhibited elevated proliferation activity and expression of progenitor cell markers, but lower albumin and Cre. This might explain their intact β-catenin protein, and suggest their origins from hepatic progenitor cells. Liver tumors arose spontaneously from β-catenin-positive cells, and tumorigenesis was accelerated by hepatitis B X protein.These results indicate β-catenin critical for the regeneration of mature hepatocytes. Failure to regenerate mature hepatocytes results in proliferation of hepatic progenitor cells that are able to maintain liver function but are predisposed to form liver tumors.HBx protein | liver cancer | postnatal liver regeneration T he Wnt/β-catenin pathway has long been considered involved in embryonic liver development and hepatocarcinogenesis (1, 2). However, its role in the regeneration of mature hepatocytes has remained inconclusive.In normal mature hepatocytes, the activity of this pathway is tightly controlled. Most cytosolic β-catenin is phosphorylated by glycogen synthase kinase 3β at specific serine/threonine residues, resulting in its degradation. Somatic Wnt-activation mutations of β-catenin and Axin-1 genes were identified in 20% to 30% of hepatocellular carcinoma (HCC) cases (2-4). In addition, downregulation of two negative regulators of this pathway, APC and Ecadherin (2, 5), and overexpression of the Fzd type 7 receptor were frequently observed in HCC (6), all of which result in accumulation of β-catenin. Therefore, β-catenin accumulation in the cytoplasm and nucleus is present in 50% to 70% of HCCs (7). Mutations of β-catenin also occur in the majority of childhood hepatoblastomas (8) and in a subgroup of adult hepatic adenomas predisposing to HCC (9). Activation of the Wnt/β-catenin pathway is thus considered a key event in hepatocarcinogenesis.Several transgenic (Tg) mouse models were established to investigate the role of an activated Wnt/β-catenin pathway in hepatocarcinogenesis. Tg mice expressing a Wnt-activating mutant of β-catenin in mature hepatocytes developed hepatomegaly with elevated proliferation activity but low compensatory apoptosis, but which was insufficient to cause HCC (10, 11). Additional events, such as H-ras activation or diethylnitrosamine treatment, are required for HCC formation (11, 12...

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Section: Discussionmentioning

confidence: 99%

Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development

Wang¹,

Yeh

Tsai³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Histopathology: Biliary fibrosis is the subtype of hepatic fibrosis which is frequently associated with ductular reactions (hyperplasia/proliferation which form pseudo-bile ducts) and structural alteration [24,40]. The biliary fibrotic lesions of the present cattle were characterized by pseudolobule formation, proliferation/hyperplasia of bile ducts and fibrotic bridges.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Characterization of Macrophages and Myofibroblasts in Fibrotic Liver Lesions Due to <i>Fasciola</i> Infection in Cattle

Golbar

Izawa

Juniantito

et al. 2013

The Journal of Veterinary Medical Science

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ABSTRACT. Histopathologically, fibrosis in Fasciola-infected cattle livers was characterized by inflammatory cell infiltration, such as eosinophils and macrophages, pseudo-lobule, pseudo-bile ducts and fibrotic bridges separating pseudo-lobules; the fibrotic lesions were developed in the Glisson's sheath. Pseudo-bile ducts consisting of epithelial cells reacted clearly to cytokeratin (CK) 19, indicating cholangiocyte origin. Immunophenotypes of macrophages and myofibroblasts were investigated in the fibrotic livers. Macrophages positive for CD68 (reflecting phagocytosis) and CD163 (representing proinflammatory cytokine production) were increased, and those for CD204 (implying lipid metabolism) and Iba-1 (a calcium-binding protein playing role in chemotaxis) decreased in fibrotic livers compared to control livers. Spindle-shaped myofibroblasts positive for vimentin, desmin and α-smooth muscle actin (α-SMA) increased in the peribiliary connective tissues, although the desmin-positive cells were fewer. In addition to the usefulness of these antibodies for macrophage detection in cattle livers, this study shows that macrophages with different immunophenotypes participate in Fasciola-infected cattle livers, in relation to development of myofibroblasts expressing mainly vimentin and α-SMA.

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“…The regenerating nodules can be either polyclonal or monoclonal in origin [48]. The monoclonal origin of RN cells was reported by Lin et al [49], who stated that the cells of origin are more likely to be a facultative stem cell from the biliary tree.…”

Section: Inflammatory Bed Inflammasomes and Regenerating Nodules Durmentioning

confidence: 99%

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Ramakrishna¹,

Rastogi²,

Trehanpati³

et al. 2013

Liver Cancer

174

121

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Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-κB, STAT3 and JNK as possible missing links. In addition, the “inflammasome” (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver.

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The histogenesis of regenerative nodules in human liver cirrhosis

Cited by 89 publications

References 24 publications

Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development

Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development

Immunohistochemical Characterization of Macrophages and Myofibroblasts in Fibrotic Liver Lesions Due to <i>Fasciola</i> Infection in Cattle

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

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