Mature hepatocytes are the source of small hepatocyte-like progenitor cells in the retrorsine model of liver injury

Avril, Audrey; Pichard, Virginie; Bralet, Marie‐Pierre; Ferry, Nicolas

doi:10.1016/j.jhep.2004.07.029

Cited by 59 publications

(55 citation statements)

References 29 publications

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“…These cell clusters lack CYP enzymes that are usually readily induced by retrorsine, and this probably accounts for their resistance to the anti-proliferative effects of retrorsine. Ferry and colleagues [108] have provided persuasive evidence that these SHPCs are clonally-derived, seemingly at random from amongst all hepatocytes, but we have no further clues as to the identity of these seemingly relatively undifferentiated hepatocytes.…”

Section: Digestive Tractmentioning

confidence: 75%

Attributes of adult stem cells

Alison

Islam

2008

The Journal of Pathology

153

115

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While cultured embryonic stem (ES) cells can be harvested in abundance and appear to be the most versatile of cells for regenerative medicine, adult stem cells also hold promise, but the identity and subsequent isolation of these comparatively rare cells remains problematic in most tissues, perhaps with the notable exception of the bone marrow. The ability to continuously self-renew and produce the differentiated progeny of the tissue of their location are their defining properties. Identifying surface molecules (markers) that would aid in stem cell isolation is a major goal. Considerable overlap exists between different putative organspecific stem cells in their repertoire of gene expression, often related to self-renewal, cell survival and cell adhesion. More robust tests of 'stemness' are now being employed, using lineage-specific genetic marking and tracking to show production of long-lived clones and multipotentiality in vivo. Moreover, the characterization of normal stem cells in specific tissues may provide a dividend for the treatment of cancer. The successful treatment of neoplastic disease may well require the specific targeting of neoplastic stem cells, cells that may well have many of the characteristics of their normal counterparts.

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Section: Digestive Tractmentioning

confidence: 75%

Attributes of adult stem cells

Alison

Islam

2008

The Journal of Pathology

153

115

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“…Cell foci resembling SHPCs have also been observed in retrorsine-treated mice with chronic liver injury [24]. From retroviral lineage tracing studies in rats, the origin of these cells is thought to be hepatocytes [25] but their location is unclear, seeming to be located at random in the parenchyma rather than confined to a particular niche.…”

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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“…Data from recent studies provide contradictory results suggesting that either oval cells or mature hepatocytes are the origin of the SHPCs (15,16). We have investigated the possibility that SHPCs are the progeny of oval cells by combining the retrorsine/PH (RP) model of liver injury with 2-AAF treatment.…”

Section: Introductionmentioning

confidence: 99%

Treatment with 2-AAF blocks the small hepatocyte-like progenitor cell response in retrorsine-exposed rats

Best

Coleman

2007

Journal of Hepatology

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Background/Aims-Liver regeneration after partial hepatectomy (PH) in retrorsine-exposed rats is accomplished through proliferation and differentiation of small hepatocyte-like progenitor cells (SHPCs). The cells of origin of SHPCs are not known. We investigated the possibility that SHPCs are directly derived from oval cells, a known liver progenitor cell, by combining the retrorsine/PH (RP) model with 2-acetamidofluorene (2-AAF), an anti-mitotic agent that elicits an oval cell reaction in response to liver deficit. Methods-MaleFischer 344 rats were treated with retrorsine (30 mg/kg ip) at 6 and 8 weeks of age, with PH 5 weeks after the final treatment. Seven days prior to PH, a 21 day 2-AAF (50 mg) time-release pellet was inserted subcutaneously. Livers were harvested at 3, 7, 10, 14, and 21-days post-PH.Results-Liver sections from animals treated with 2-AAF/retrorsine/PH (2-AAF/RP) contain significant numbers of proliferating oval cells, but no SHPCs at 7-days post-PH, while RP animals exhibit significant numbers of SHPCs and minimal oval cell reaction. Between 10 and 14-days post-PH, new hepatocyte clusters appear in 2-AAF/RP treated rats. Labeling of proliferating oval cells with BrdU at 6-days post-PH demonstrated that these new hepatocytes represent the progeny of differentiating oval cells.Conclusions-The observed differences in progenitor cell responses between 2-AAF/RP and RP animals strongly suggest that SHPCs are not the progeny of oval cell precursors, but represent an independent liver progenitor cell population.

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Mature hepatocytes are the source of small hepatocyte-like progenitor cells in the retrorsine model of liver injury

Cited by 59 publications

References 29 publications

Attributes of adult stem cells

Attributes of adult stem cells

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

Treatment with 2-AAF blocks the small hepatocyte-like progenitor cell response in retrorsine-exposed rats

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