The Kinetics of Cellular Proliferation in Regenerating Liver

Fabrikant, Jacob I.

doi:10.1083/jcb.36.3.551

Cited by 276 publications

(118 citation statements)

References 18 publications

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“…This could suggest that the remaining periportal parenchymal cells would be the preferential candidates for liver regeneration (Fabrikant, 1968;Grisham, 1962). Since these periportal cells are mostly diploid (Sulkin, 1943) it could be expected that emerging cycling cells would have this ploidy level.…”

Section: Resultsmentioning

confidence: 99%

Cell population kinetics and ploidy rate of early focal lesions during hepatocarcinogenesis in the rat

Castelain

Deleener²,

Kirsch‐Volders³

et al. 1989

Br J Cancer

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Summary We have studied the changes in cell population kinetics and DNA-content of cycling parenchymal cells during the very early steps of rat hepatocarcinogenesis in Faber's protocol. Adult rats were initiated by a single dose of diethylnitrosamine (DENA, 200 mg kg-1), followed 2 weeks later by a 2-week diet of 0.03% 2-acetylaminofluorene (2-AAF) as selection phase. In the middle of selection time, a single necrogenic dose of carbon tetrachloride (CCL4, 2 ml kg-) was administered by gavage. Twenty four hours thereafter, radiolabelled thymidine (3H-TdR, 1.5 ftCi g' ) was given by repeated injections during 24 h. An emergence of small, pyroninophilic ('tigroid') foci was observed at the second, fifth and eighth days after the proliferative stimulus. The focal putative precancerous cells presented a significant higher labelling index (LI) than the non-affected parenchymal cells for all exposure times. However, the labelling intensity decreased from the second to the eighth day after CC14, suggesting a dilution of the radiolabelled DNA by repeated divisions within the foci. The nuclei of the same foci were analysed for DNA-content by feulgen microdensitometry on neighbouring sections. A gradual reduction of nuclear DNA-content was observed in 66% of the foci at the fifth day and in 100% of foci at the eight day, as compared to surrounding tissue and untreated animals, where labelling and DNA-content remain in the same ratio.

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Section: Resultsmentioning

confidence: 99%

Cell population kinetics and ploidy rate of early focal lesions during hepatocarcinogenesis in the rat

Castelain

Deleener²,

Kirsch‐Volders³

et al. 1989

Br J Cancer

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“…Age has a bearing on the response, as only in young rats (2-3 months old) do all hepatocytes enter the cell cycle at least once after a two-thirds PH, but in aged rats (>2 years old) a significant number of hepatocytes do not respond and so appear to have become reproductively senescent [8]. After a two-thirds PH there is a lag period of about 15 h before the first periportal hepatocytes enter DNA synthesis, and at the peak of the response at 24 h the hepatocyte DNA labelling index reaches 40% [9]. After 4 days this hyperplastic response is effectively curtailed and further increases in liver mass are achieved through hepatocyte hypertrophy.…”

Section: Hepatocytesmentioning

confidence: 99%

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

201

149

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The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.

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“…After PH or chemical injury (CCl4, galactosamine) the liver deficit is replaced by proliferating hepatocytes that are derived from adult hepatocytes (82)(83)(84)(85)(86). For example, after two-third PH of the rat, each hepatocyte in the remaining lobes divides once or twice within a 48-hr period, without involvement of a stem cell (83,84,86,87). In fact, AFP can be identified in large, dividing hepatocytes after PH in the rat (88) and adjacent to zones of liver injury after CCl4 injury in the mouse (59).…”

Section: Liver Stem Cell and Restitutive Proliferationmentioning

confidence: 99%

Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?

Sell

1993

Environ Health Perspect

191

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Given the fundamental principle that cancer must arise from a cell that has the potential to divide, two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises a) from stem cells due to maturation arrest or b) from dedifferentiation of mature cells that retain the ability to proliferate. The role of stem cells in carcinogenesis is clearly demonstrated in teratocarcinomas. The malignant stem cells of teratocarcinomas are derived from normal multipotent stem cells and have the potential to differentiate into normal benign mature tissue. A widely studied model supporting dedifferentiation has been the putative origin of hepatocarcinomas from "premalignant" foci and nodules induced in the rat liver by chemicals. However, the dedifferentiation concept for hepatocarcinogenesis is challenged by more recent interpretations indicating that hepatocellular carcinoma arises from maturation arrest caused by abherrant differentiation of determined stem cells. Either hypothesis is supported by the cellular changes that occur in the rodent liver after different hepatocarcinogenic regimens. The formation of foci and nodules from altered hepatocytes supports dedifferentiation; the proliferation of small oval cells with the potential to differentiate into either biliary ducts or hepatocytes supports arrested maturation of determined stem cells. It is now postulated that foci and nodular change reflect adaptive changes to the toxic effects of carcinogens and not "preneoplastic" stages to cancer. The stem cell model predicts that genotoxic chemicals induce mutations in the determined stem cell which may be expressed in its progeny. Proliferation of initiated cells is induced by promoting events which also allow additional mutations to occur.

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The Kinetics of Cellular Proliferation in Regenerating Liver

Cited by 276 publications

References 18 publications

Cell population kinetics and ploidy rate of early focal lesions during hepatocarcinogenesis in the rat

Cell population kinetics and ploidy rate of early focal lesions during hepatocarcinogenesis in the rat

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?

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