Relative importance and specificity of factors influencing liver regeneration in the rat : studies in a model of portal vein branches ligation
(2000)
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- Authors
- Supervisors
- Horsmans, Yves
- Abstract
- The liver is unique in its almost infinite capacity to regenerate. It possesses the capacity to restore a loss of up to 75% of its tissues mass within 7 to 10 days. The mechanisms governing this extraordinary regeneration phenomenon remain poorly defined. Nevertheless, studied conducted after realization of a partial hepatectomy comprising 70% of the liver parenchyma (PH) have led several authors to propose the following sequence of events: PF TNF NHkB Interleukin-6 STAT3 proto-oncogenes cyclins regeneration. <BR> A 70% ¨F rapidly induces the expression of TNF activating a cascade of events which terminates with the induction of cyclins and cell cycle traverse. This overview of the regeneration process is, however, not applicable to all models of liver regeneration. Other models of hepatocyte proliferation (CC14, primary mitogens) differ from the PH model by a late and prolonged activation, by a partial or even by an absent response of cytokines, transcription factors and proto-oncogenes. These data suggest that certain events observed after PH, which are indicated in the scheme above, are not always present and might not event be required for liver regeneration. Thus, they might simply constitute intermediate steps in the regenerative process implying that the key event still remains to be determined. <BR> In an attempts to do so, we used the model of portal vein branch ligation (PBL). In this model, the branch of the portal vein feeding the anterior and lateral liver lobes is ligated. The lobes deprived of portal blood will undergo a progressive atrophy whereas a compensatory hypertrophy will be induced in the lobes still receiving portal blood. The time course of this PBL-induced regeneration is very similar to that described in the PH model. The study of the early response (first hours) after PBL and after sham surgery (laparotomy without ligation) demonstrated a similar activation of NFkB, interleukin (IL)-6, STAT3, c-myc, c-jun, and c-fos in the ligated and non-ligated lobes as well as an induction of IL-6 and STAT3 in sham-operated animals. This suggests that these phenomenons do not allow predicting the future evolution of the lobes towards atrophy or hypertrophy. They rather seem to constitute a non-specific response most likely related to the surgical stress. <BR> In its progression through the cell cycle, the hepatocyte should undergo, at a given time point, modifications which transform the process into a specific, irreversible one. Our studies in this direction allowed us to define a delayed response, essentially linked to cellular proliferation, which seems to start around the 8th hour after PBL. This process of cellular proliferation is characterized by the selective induction of the proto-oncogenes p53, and c-HA-ras, of cyclin E as well as the cyclin-dependent kinase Cdk2 in the non-ligated lobes. <BR> Prolonged activation of IL-β in the lobes heading towards atrophy suggests that this molecule might be a regulatory and/or inhibitory factor of cellular proliferation. In contrast, TGF-β, considered as an inhibitor of hepatocyte proliferation, does not seem to influence the proliferation-atrophy balance between the 8th and 12th hour, given the absence of modifications of its mRNA and protein levels during this time period. The presence of 2 peaks of the p21 protein, an early one in both lobes and a late one in the lobes undergoing atrophy, indicates a dual role for this inhibitor of cylcin-Cdk complexes : 1. Restrain a premature activation of cyclin-Cdks, 2. Maintain cell cycle suppression in the lobes heading towards atrophy.<BR> In conclusion, the regeneration process is characterized by an initial, non-specific response which is most likely related to the surgical stress. The cellular response starts to diverge between the 8th and 12th hour after PBL and is characterized by modifications which are specifically related to cellular proliferation or evolution towards cellular atrophy. The final fate of each cell is probably determined by a subtle balance of factor stimulating and inhibiting proliferation of hepatocytes and not by a sole key factor
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Citations
Starkel, P. (2000). Relative importance and specificity of factors influencing liver regeneration in the rat : studies in a model of portal vein branches ligation. https://hdl.handle.net/2078.5/111062