Abstract
BackgroundAfter partial hepatectomy (PHx), the liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5% has been re-established. To investigate the genetic regulation of the terminating phase of liver regeneration, we performed a 60% PHx in a porcine model. Liver biopsies were taken at the time of resection, after three weeks and upon termination the sixth week. Gene expression profiles were obtained using porcine oligonucleotide microarrays. Our study reveals the interactions between genes regulating the cell cycle, apoptosis and angiogenesis, and the role of Transforming Growth Factor-β (TGF-β) signalling towards the end of liver regeneration.ResultsMicroarray analysis revealed a dominance of genes regulating apoptosis towards the end of regeneration. Caspase Recruitment Domain-Containing Protein 11 (CARD11) was up-regulated six weeks after PHx, suggesting the involvement of the caspase system at this time. Zinc Finger Protein (ZNF490) gene, with a potential negative effect on cell cycle progression, was only up-regulated at three and six weeks after PHx indicating a central role at this time. TGF-β regulation was not found to be significantly affected in the terminating phase of liver regeneration. Vasohibin 2 (VASH2) was down-regulated towards the end of regeneration, and may indicate a role in preventing a continued vascularization process.ConclusionsCARD11, ZNF490 and VASH2 are differentially expressed in the termination phase of liver regeneration. The lack of TGF-β up-regulation suggests that signalling by TGF-β is not required for termination of liver regeneration.
Highlights
After partial hepatectomy (PHx), the liver regeneration process terminates when the normal livermass/body-weight ratio of 2.5% has been re-established
Microarray analysis General trends By analysing contrasts between resection, sham and control groups using a false discovery rate (FDR) = 0.20, we found a total of 609 genes differentially expressed (362 genes by comparing control and sham, 215 genes by comparing control and resection, and 32 by comparing sham and resection pigs)
Cell cycle and cell proliferation within the control group For time contrast 3–0 weeks, we found one downregulated gene
Summary
After partial hepatectomy (PHx), the liver regeneration process terminates when the normal livermass/body-weight ratio of 2.5% has been re-established. To investigate the genetic regulation of the terminating phase of liver regeneration, we performed a 60% PHx in a porcine model. Our study reveals the interactions between genes regulating the cell cycle, apoptosis and angiogenesis, and the role of Transforming Growth Factor-β (TGF-β) signalling towards the end of liver regeneration. Reestablishment of liver volume after resection is probably regulated by the functional needs of the organism, as the liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5% has been restored. Two distinct pathways are activated during liver regeneration, the growth factor and cytokine regulated and SNON (ski-related novel gene N) are up-regulated during regeneration. Previous studies have shown that intact TGF-β signalling is not required to stop hepatocyte proliferation once the deficit in liver mass has been replaced [13]
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