Detection of proliferating liver cells in various diseases by a monoclonal antibody against DNA polymerase-α: With special reference to the relationship between hepatocytes and sinusoidal cells

Seki, Shuichi; Sakaguchi, Hiroki; Kawakita, Nobuyoshi; Yanai, Akira; Kuroki, Tetsuo; Mizoguchi, Yasuhiro; Kobayashi, Kenzo; Monna, Takeyuki

doi:10.1002/hep.1840140507

Cited by 14 publications

(2 citation statements)

References 37 publications

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“…Hepatocytes, the target of infection, are generally long lived with a lifetime thought to exceed 6 months and a liver turnover rate possibly in excess of a year (2)(3)(4)(5)(6). Histologic evidence reveals an increase in hepatocyte destruction during chronic infections (7) with a shortening of hepatocyte lifetime.…”

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Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection

Mason

Jilbert²,

Summers³

2005

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

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Chronic hepadnavirus infections cause liver damage with ongoing death and regeneration of hepatocytes. In the present study we set out to quantify the extent of liver turnover by measuring the clonal proliferation of hepatocytes by using integrated viral DNA as a genetic marker for individual hepatocyte lineages. Liver tissue from woodchucks with chronic woodchuck hepatitis virus (WHV) infection was assayed for randomly integrated viral DNA by using inverse PCR. Serial endpoint dilution of viral-cell junction fragments into 96-well plates, followed by nested PCR and DNA sequencing, was used to determine the copy number of specific viral cell junctions as a measure of the clonal distribution of infected cell subpopulations. The results indicated that the livers contained a minimum of 100,000 clones of >1,000 cells containing integrated DNA, representing at least 0.2% of the hepatocyte population of the liver. Because cells with integrated WHV DNA comprised only 1-2% of total liver cells, it is likely that the total number of clones far exceeds this estimate, with as much as one-half of the liver derived from high copy clones of >1,000 cells. It may be inferred that these clones have a strong selective growth or survival advantage. The results provide evidence for a large amount of hepatocyte proliferation and selection having occurred during the period of chronic WHV infection (Ϸ1.5 years) in these animals.endpoint dilution ͉ inverse PCR ͉ hepatocyte clones

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confidence: 99%

Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection

Mason

Jilbert²,

Summers³

2005

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

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“…The method was as reported elsewhere. 14,25,26 In brief, fresh liver specimens were fixed in a mixture of periodate, lysine, and 2% paraformaldehyde (PLP), embedded in OCT compound, and frozen in liquid nitrogen. Frozen sections 6 pm thick were covered with a solution of mouse monoclonal antibody against DNA-PA or else normal mouse serum without the antibody (control).…”

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confidence: 99%

Detection of the preneoplastic lesions of small hepatocellular carcinoma in cirrhotic livers

Seki

Sakaguchi

Kawakita

et al. 1993

J of Gastro and Hepatol

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To identify the preneoplastic lesions of hepatocellular carcinoma and the fine structure of preneoplastic hepatocytes, we studied proliferative conditions in cirrhosis of the liver. In all, 46 foci of cellular alteration (FCA), three regions of adenomatous hyperplasia (ADH), and 21 small hepatocellular carcinomas (sHCC) were studied by published criteria for sHCC and by the proliferative activity of the lesions as examined with monoclonal antibodies against DNA polymerase alpha and proliferating cell nuclear antigen. The four patients with FCA composed of basophilic hepatocytes were classified by the criteria as having sHCC; cells had features similar to those of sHCC. Two of these four patients with FCA were found to have HCC several years later. The number of hepatocytes stained for proliferating cell nuclear antigen was 72 and 81 per 1000 hepatocyte nuclei in the two patients who developed HCC. In one of the three patients with ADH, a sHCC was found 1 year later, and dysplastic hepatocytes from the region of ADH in this patient had features similar to those of HCC cells by light and electron microscopy. In this patient, the number of hepatocytes stained for DNA polymerase alpha was 452 per 1000 nuclei. Therefore, FCA and ADH might be preneoplastic lesions of sHCC in cirrhosis of the liver. Preneoplastic hepatocytes seem to be small cells with basophilic cytoplasm, with a large nucleus to cytoplasm ratio, finely indented nuclei with a smaller amount of condensed chromatin than normal, and poorly to moderately developed organelles.

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Expression of antigens related to apoptosis and cell proliferation in chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis

Kuroki

Seki

Kawakita

et al. 1996

Vichows Archiv A Pathol Anat

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The initial injury in primary biliary cirrhosis (PBC) is the destruction of portal bile ducts. Little information is available on apoptosis and cell proliferation in such bile ducts, so we used immunohistochemical techniques to locate molecules related to apoptosis [Fas antigen, Lewis Y antigen (BM1/JIMRO), and bcl-2 protein] and to cell proliferation (proliferating cell nuclear antigen, PCNA) in 21 patients with PBC. In addition, nick-end labelling was done to locate DNA fragmentation. The expression of these molecules in chronic nonsuppurative destructive cholangitis (CNSDC) was examined. Cell death and PCNA expression were both found in portal bile ducts affected by CNSDC in 7 of the 13 CNSDC patients examined. Fas antigen was found on the plasma membrane and rough endoplasmic reticulum of bile-duct cells with CNSDC in the frozen sections of all 6 patients with CNSDC out of the 9 patients inspected, and this antigen was found also in bile-duct cells without CNSDC in 2 of these 9 patients. It was not found in anatomically normal liver (from 2 patients with Gilbert's disease). The Lewis Y antigen was found in bile ducts with CNSDC and in proliferated ductules in all 16 patients examined. No bcl-2 protein was found in any bile-duct or ductule cells, but it was found in the cytoplasm of lymphocytes surrounding or invading CNSDC. DNA fragmentation was found in the nuclei of bile-duct cells with CNSDC by nick-end labelling. Our study indicated that Fas-mediated apoptosis might be involved in CNSDC, but that bcl-2 protein seems to participate less than Fas. Although the Lewis Y antigen was found in many bile ducts, the relationship between the antigen and apoptosis remains unknown because there was no evidence that this antigen mediates apoptosis.

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Detection of proliferating liver cells in various diseases by a monoclonal antibody against DNA polymerase-α: With special reference to the relationship between hepatocytes and sinusoidal cells

Cited by 14 publications

References 37 publications

Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection

Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection

Detection of the preneoplastic lesions of small hepatocellular carcinoma in cirrhotic livers

Expression of antigens related to apoptosis and cell proliferation in chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis

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