Liver Repopulation by Transplanted Hepatocytes and Risk of Hepatocellular Carcinoma

Laconi, Sergio; Montisci, Stefania; Doratiotto, Silvia; Greco, Marianna; Pasciu, Daniela; Pillai, Sara; Pani, P.; Laconi, Ezio

doi:10.1097/01.tp.0000228239.78290.13

Cited by 11 publications

(11 citation statements)

References 70 publications

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“…To test this possibility, the origin of such a putative common precursor cell compartment was analyzed in the repopulated liver. We first confirmed and extended our earlier observation concerning the stability of the donor hepatocyte phenotype in the RS-exposed and repopulated liver (Laconi et al 2006). As shown in Fig.…”

Section: Resultssupporting

confidence: 89%

“…In rats exposed to retrorsine (RS) and then injected with normal syngeneic hepatocytes, near-total replacement of the resident parenchyma by donor-derived cells is observed (Laconi et al 2001). Notably, liver repopulation in this system is stable, persisting for at least 2 years after cell transplantation (Laconi et al 2006). The latter observation is important, because it implies that any rate of hepatocyte turnover in these animals must be sustained by cells of donor origin, irrespective of their specific phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Cell turnover in the repopulated rat liver: distinct lineages for hepatocytes and the biliary epithelium

et al. 2014

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The dynamics of cell renewal in the normal adult liver remains an unresolved issue. We investigate the possible contribution of a common biliary precursor cell pool to hepatocyte turnover in the chimeric long-term repopulated rat liver. The retrorsine (RS)-based model of massive liver repopulation was used. Animals not expressing the CD26 marker (CD26-) were injected with RS, followed by transplantation of 2 million syngeneic hepatocytes isolated from a normal CD26-expressing donor. Extensive (80-90 %) replacement of resident parenchymal cells was observed at 1 year post-transplantation and persisted at 2 years, as expected. A panel of specific markers, including cytokeratin 7, OV6, EpCAM, claudin 7 and α-fetoprotein, was employed to locate the in situ putative progenitor and/or biliary epithelial cells in the stably repopulated liver. No overlap was observed between any of these markers and the CD26 tag identifying transplanted cells. Exposure to RS was not inhibitory to the putative progenitor and/or biliary epithelial cells, nor did we observe any evidence of cell fusion between these cells and the transplanted cell population. Given the long-term (>2 years) stability of the donor cell phenotype in this model of liver repopulation, the present findings suggest that hepatocyte turnover in the repopulated liver is fuelled by a cell lineage distinct from that of the biliary epithelium and relies largely on the differentiated parenchymal cell population. These results support the solid biological foundation of liver repopulation strategies based on the transplantation of isolated hepatocytes.

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Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Cell turnover in the repopulated rat liver: distinct lineages for hepatocytes and the biliary epithelium

et al. 2014

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“…While any direct involvement of the immune system was not investigated in our present study, our findings appear difficult to reconcile with the above proposition. In fact, there is no evidence that RS-induced senescent hepatocytes display any direct pre-neoplastic potential [41]; on the other hand, they are able to support the growth of transplanted nodular hepatocytes and their progression to HCC [8]. Thus, it appears that, under the conditions described in our studies, the role of cell senescence is to promote the growth of carcinogen-induced altered cells, possibly through the effect(s) of SASP/SMS components, including IL-6 [42].…”

Section: Discussionmentioning

confidence: 99%

Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma

Marongiu

Serra

Sini

et al. 2014

Aging

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Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease. Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease.

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“…80 As a corollary to these findings, it is important to note that experimental liver repopulation per se does not result in any increased risk of donor cell-derived neoplastic disease. 22,81 In summary, the analysis of available models for liver repopulation provides compelling evidence to indicate that any cytotoxic microenvironment (the same coin) sustaining the selective growth of normal transplanted hepatocytes (side one) can also select for the emergence of rare resistant cells with an altered phenotype (the other side of the coin). This establishes a close mechanistic link between liver repopulation on one hand and early phases of cancer development on the other.…”

Section: Significance and Future Perspectivesmentioning

confidence: 99%

Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin?

Marongiu

Doratiotto

Montisci

et al. 2008

The American Journal of Pathology

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Liver repopulation by transplanted normal hepatocytes has been described in a number of experimental settings. Extensive repopulation can also occur from the selective proliferation of endogenous normal hepatocytes, both in experimental animals and in the human liver. This review highlights the intriguing association between clinical and experimental conditions related to liver repopulation and an increased risk for development of hepatocellular carcinoma. It is suggested that any microenvironment that is able to sustain the clonal growth of normal transplanted (or endogenous) hepatocytes is also geared to select for the emergence of rare resistant cells with an altered phenotype. Whereas the first pathway leads to liver repopulation with normal histology, the latter results in the growth of focal proliferative lesions and carries an increased risk of neoplastic disease. The implications of this association are discussed, both in terms of pathogenetic significance and possible therapeutic exploitation.

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Liver Repopulation by Transplanted Hepatocytes and Risk of Hepatocellular Carcinoma

Cited by 11 publications

References 70 publications

Cell turnover in the repopulated rat liver: distinct lineages for hepatocytes and the biliary epithelium

Cell turnover in the repopulated rat liver: distinct lineages for hepatocytes and the biliary epithelium

Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma

Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin?

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