Massive Liver Replacement by Transplanted Hepatocytes in the Absence of Exogenous Growth Stimuli in Rats Treated with Retrorsine

Laconi, Sergio; Pillai, Sara; Porcu, Pietro Paolo; Shafritz, David A.; Pani, P.; Laconi, Ezio

doi:10.1016/s0002-9440(10)64019-9

Cited by 96 publications

(112 citation statements)

References 26 publications

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“…This report suggests the presence of progenitor cells in a cell suspension obtained via a widely used technique for the isolation of hepatocytes. This observation is important because certain qualities attributed to mature hepatocytes, such as the capacity to trans-differentiate into biliary cells 26,27 and the extensive potential to repopulate damaged liver, 28,29 might be related to the presence of these progenitor cells. Data obtained in previous studies using so-called hepatocyte suspensions should at least be critically reviewed.…”

Section: Discussionmentioning

confidence: 99%

Morphological and biochemical characterization of a human liver in a uPA‐SCID mouse chimera†‡

et al. 2005

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D espite decades of research, the processes that govern liver development and regeneration are only partially understood. A good understanding of the mechanisms that play a role in these processes is important because it may lead to new treatments of human liver diseases. Several in vivo experimental conditions have been used to study liver regeneration and repair and the interaction of different cell types in these processes. These include partial hepatectomy, administration of toxic compounds, or a combination of both, and transgenic expression of certain proteins. 1,2 In contrast to in vitro experiments, these approaches raise fewer questions concerning the influence of artificial matrices on the function and behavior of hepatocytes and other liver cell types.Although these procedures have generated useful information on rodent liver regeneration, stem cell activation, and other processes, extrapolating these findings to the Abbreviations: uPA, urokinase plasminogen activator; HBV, hepatitis B virus; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; PAS, periodic-acid-Schiff. From the

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Section: Discussionmentioning

confidence: 99%

Morphological and biochemical characterization of a human liver in a uPA‐SCID mouse chimera†‡

et al. 2005

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“…Important from a human standpoint, such cells can be cryopreserved for up to 20 months with no loss of repopulating activity [50]. Many studies have also examined the transplantation potential of adult hepatocytes in the DPPIV − mutant rat, combining retrorsine treatment with a mitogenic stimulus, such as partial hepatectomy or triidothyronine (T3), leading to the rapid replacement of DPPIV − cells by DPPIV + donor cells [51,52]; even in the absence of a mitogenic stimulus, near-total replacement by donor cells occurs within 12 months [53].…”

Section: Mr Alison Et Almentioning

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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“…Other DNAbinding agents such as diethylnitrosamine cannot maintain the proliferation of transplanted hepatocytes, indicating the peculiarity of alkaloid [22] . Laconi et al found that in the absence of exogenous growth stimuli, such as partial hepatectomy, retrorsine treatment may give rise to results similar to those of a combination of retrorsine treatment and partial hepatectomy, suggesting that besides maintenance of selective growth vigor of transplanted hepatocytes, there may be another mechanism of retrorsine action [26] .…”

Section: Discussionmentioning

confidence: 99%

Proliferation of L02 human hepatocytes in tolerized genetically immunocompetent rats

Lin

Mao²,

Wang³

et al. 2008

WJG

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AIM:To investigate whether human hepatocytes could proliferate after transplantation to normal immunocompetent rats treated with 2-acetaminofluorene or Retrorsine and partial hepatectomy. METHODS:L02 hepatocyte-tolerant Sprague-Dawley rats were injected with Retrorsine, 2-acetaminofluorene or normal saline. L02 hepatocytes were then transplanted via the spleen. Human albumin and its mRNA, specific proliferating cell nuclear antigen (PCNA), L02 hepatocyte dynamic distribution, number density and area density of PCNA-positive cells in the liver were determined. RESULTS:All the examined indicators were not significantly different between the rats treated with 2-acetaminofluorene and normal saline, which was not the case with rats treated with Retrorsine. A dynamic distribution of L02 hepatocytes in the rat liver was detected from wk 1 to mo 6 after transplantation in the Retrorsine group and from wk 1 to 10 in the 2-acetaminofluorene group. Human albumin and its mRNA were detected from wk 2 to mo 6 in the Retrorsine group and from wk 1 to 8 in the 2-acetaminofluorene group. Specific human PCNA was detected in the rat liver from wk 2 to mo 6 in the Retrorsine group and from wk 2 to 6 in the 2-acetaminofluorene group. Human albumin and its mRNA contents as well as the number of PCNA positive cells reached a peak at wk 4. CONCLUSION:L02 human hepatocytes could not proliferate significiantly after transplantation to the normal, immunocompetent rats treated with 2-acetaminofluorene.L02 human hepatocytes can survive for 10 wk after transplantation and express human albumin for 8 wk. L02 human hepatocytes can proliferate and express human albumin for 6 mo after transplantation to the rats treated with Retrorsine. The chimeric L02 human hepatocytes, which then underwent transplantation into tolerant rats, were normal in morphogenesis, biochemistry and function.

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Massive Liver Replacement by Transplanted Hepatocytes in the Absence of Exogenous Growth Stimuli in Rats Treated with Retrorsine

Cited by 96 publications

References 26 publications

Morphological and biochemical characterization of a human liver in a uPA‐SCID mouse chimera†‡

Morphological and biochemical characterization of a human liver in a uPA‐SCID mouse chimera†‡

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

Proliferation of L02 human hepatocytes in tolerized genetically immunocompetent rats

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