The number of the genes in a functional category matters during rat liver regeneration after partial hepatectomy

J of Cellular Biochemistry

et al. 2011

Self Cite

Liver regeneration after partial hepatectomy is a process with various types of cells involved. The role of Kupffer cells (KCs) in liver regeneration is still controversial. In this study we isolated KCs from regenerating liver and conducted cell-specific microarray analysis. The results demonstrated that the controversial role of KCs in liver regeneration could be explained with the expression patterns of TGF-α, IL-6, TNF, and possibly IL-18 during liver regeneration. IL-18 may play an important role in negative regulation of liver regeneration. The functional profiles of gene expression in KCs also indicated that KC signaling might play a negative role in cell proliferation: signaling genes were down regulated before cell division. Immune response genes in KCs were also down regulated during liver regeneration, demonstrating similar expression profiles to that of hepatocytes. The expression patterns of key genes in these functional categories were consistent with the temporal functional profiles.

Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

The role of kupffer cells in rat liver regeneration revealed by cell‐specific microarray analysis

Jiang

J of Cellular Biochemistry

et al. 2011

Self Cite

“…2). The RT-PCR results for the other genes were previously published [24,31,[35][36][37][38][39][40][41]. The expression profiles of genes related to the EPO-mediated signaling pathway According to the data from NCBI, RGD, etc.…”

Section: Confirmation Of the Rat Genome 230 20 Microarray Resultsmentioning

confidence: 99%

“…Most recently, a growing body of evidence suggests that the beneficial effect of EPO treatment on liver resection and living donor liver transplantation in rats [14,[17][18]. Moreover, microarray analysis is a powerful approach for monitoring molecular events during liver regeneration after PH, which has been demonstrated in previous studies [24,25,[33][34][35][36][37][38][39][45][46][47][48].…”

Section: Discussionmentioning

confidence: 99%

Expression profiles uncover the relationship between erythropoietin and cell proliferation in rat hepatocytes after a partial hepatectomy

Cellular and Molecular Biology Letters

Yang

et al. 2014

Erythropoietin (EPO) has a beneficial effect on hepatic cell proliferation during liver regeneration. However, the underlying mechanism has not yet been elucidated. To uncover the proliferation response of EPO in rat liver regeneration after partial hepatectomy (PH) at the cellular level, hepatocytes (HCs) were isolated using Percoll density gradient centrifugation. The genes of the EPO-mediated signaling pathway and the target genes of the transcription factor (TF) in the pathway were identified in a pathway and TF database search. Their expression profiles were then detected using Rat Genome 230 2.0 Microarray. The results indicated that the EPO-mediated signaling pathway is involved in 19 paths and that 124 genes participate, of which 32 showed significant changes and could be identified as liver regeneration-related genes. In addition, 443 targets regulated by the TFs of the pathway and 60 genes associated with cell proliferation were contained in the array. Subsequently, the synergetic effect of these genes in liver regeneration was analyzed using the E(t) mathematical model based on their expression profiles. The results demonstrated that the E(t) values of paths 3, 8, 12 and 14–17 were significantly strengthened in the progressing phase of liver regeneration through the RAS/MEK/ERK or PI3K/AκT pathways. The synergetic effect of the target genes, in parallel with target-related cell proliferation, was also enhanced 12–72 h after PH, suggesting a potential positive effect of EPO on HC proliferation during rat liver regeneration. These data imply that the EPO receptor may allow EPO to promote HC proliferation through paths 3, 8, 12 and 14–17, mediating the RAS/MEK/ERK and PI3K/AκT pathways in rat liver regeneration after PH.

“…A better understanding of how the liver regenerates in its attempts to recover from injuries, such as from exposure to drugs or alcohol or from infection by hepatitis viruses, could lead to new treatments with immense impact on the natural history of liver diseases. Previous efforts have relied on the easily accessible partial hepatectomy model in rodents (Fausto and Mead 1989;Fausto 1990Fausto , 2000Fausto , 2004Fausto et al 1995;Michalopoulos 2010), and many candidate genes were identified by expression profiling after partial hepatectomy (Kelley-Loughnane et al 2002;Su et al 2002;Fukuhara et al 2003;White et al 2005;Guo and Xu 2008;Cao et al 2009;Li et al 2009;Jiang et al 2011;Schug et al 2013). These results have implicated numerous pathways as being involved in regeneration, including growth factor pathways, kinases, transcription factors, and nuclear receptors, but did not inform us on the relative impact of the various genes on liver repopulation following toxic injury.…”

mentioning

confidence: 99%

A genetic screen reveals Foxa3 and TNFR1 as key regulators of liver repopulation

Wangensteen¹,

Greenbaum

et al. 2015

Genes Dev.

The fundamental question of which genes are most important in controlling liver regeneration remains unanswered. We employed a parallel screen to test the impact of 43 selected genes on liver repopulation in the Fah −/− mouse model of hereditary tyrosinemia. We discovered that the transcription factor Foxa3 was a strong promoter of liver regeneration, while tumor necrosis factor receptor 1 (TNFR1) was the most significant suppressor of repopulation among all of the genes tested. Our approach enabled the identification of these factors as important regulators of liver repopulation and potential drug targets for the promotion of liver repopulation.Supplemental material is available for this article.Received January 19, 2015; revised version accepted April 7, 2015. A better understanding of how the liver regenerates in its attempts to recover from injuries, such as from exposure to drugs or alcohol or from infection by hepatitis viruses, could lead to new treatments with immense impact on the natural history of liver diseases. Previous efforts have relied on the easily accessible partial hepatectomy model in rodents (Fausto and Mead 1989;Fausto 1990Fausto , 2000Fausto , 2004Fausto et al. 1995;Michalopoulos 2010), and many candidate genes were identified by expression profiling after partial hepatectomy (Kelley-Loughnane et al. 2002;Su et al. 2002;Fukuhara et al. 2003;White et al. 2005;Guo and Xu 2008;Cao et al. 2009;Li et al. 2009;Jiang et al. 2011;Schug et al. 2013). These results have implicated numerous pathways as being involved in regeneration, including growth factor pathways, kinases, transcription factors, and nuclear receptors, but did not inform us on the relative impact of the various genes on liver repopulation following toxic injury. Sequencing of multiple hepatocellular carcinomas (HCCs) identified a number of regulators of proliferation as well (Nishida and Kudo 2013;Tornesello et al. 2013). Despite an abundant number of genes that have been identified, no single gene, when mutated in animal models, seems to be absolutely required for the recovery of liver mass following partial hepatectomy, suggesting that genetic redundancy may be an adaptation for such an important and conserved biological process as liver regeneration (Vogel 2006).Genetic screens could be used to sort out the pathways that are key to the genetic control of liver regeneration. Recently, a shRNA screen of genes mutated in HCC was employed in a repopulation model to suggest the map kinase MKK4 as a regulator of liver repopulation (Wuestefeld et al. 2013). The experimental paradigm used was the Fah −/− mouse model of liver repopulation, which has a defect in the last step of tyrosine catabolism, resulting in accumulation of the toxic metabolite fumarylacetoacetate (FAA) and injury to hepatocytes (Grompe 2001). Fah −/− mice can be kept alive by treatment with 2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione (NTBC), a drug that inhibits an upstream enzyme in the tyrosine catabolic cascade to prevent formation of FAA. This...