Reversal of post-hepatectomy liver failure using a bioartifical liver supporting system implanted with clinical-grade human induced hepatocytes
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ABSTRACT:
ORGANISM(S): Sus scrofa
PROVIDER: GSE200124 | GEO | 2023/04/05
REPOSITORIES: GEO
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Project description:In the partial liver resection and regeneration model, the early regeneration of the liver has strict gene regulation, and the regulation of liver genes is different in different resection proportions, which is a strictly controlled genetic procedure. Different genes are activated in liver resection of different proportions.For example, genes such as apoptotic autophagy inflammation were significantly expressed in 85% of liver resection cases. We used microarrays to describe in detail the global program of gene expression in regenerative livers and identify different classes of up-regulated or down-regulated genes in the process.
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Project description:The liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5 % has been re-established. We aimed to generate and analyse global expression profiles to study the genetic interactions in relation to liver regeneration, to illuminate the genetic interactions between genes regulating the cell cycle and apoptosis, and to clarify the role of TGF-M-CM-^_ signalling in the terminating phase of liver regeneration. Twelve pigs were randomised to either 60% liver resection (n=4), sham operation (n=4) or control animals (n=4). Liver biopsies were taken at time of resection, after three weeks and upon termination the sixth week. Global gene expression profiles in the biopsies were obtained using porcine oligonucleotide microarrays, representing approximately 20000 porcine genes. Microarray analysis revealed a clear dominance of genes regulating apoptosis towards the end of regeneration, compared to the sham and control groups. Caspase Recruitment Domain-Containing Protein 11 (CARD11) was upregulated six weeks after liver resection, suggesting the involvement of the caspase system at this time. Zinc Finger Protein (ZNF490) gene, with a potential negative effect on cell cycle progression and promotion of apoptosis, was only up regulated at three and six weeks after liver resection indicating a central role at this time. TGF-M-CM-^_ was not found to be significantly affected. CARD11 and ZNF490 appear to play a central role in the termination of liver regeneration in the present study. The lack of TGF-M-CM-^_ could indicate that signaling by TGF-M-CM-^_ is not required for termination of liver regeneration. time course, treatment comparison
2013-01-01 | E-GEOD-14396 | biostudies-arrayexpress
Project description:The liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5 % has been re-established. We aimed to generate and analyse global expression profiles to study the genetic interactions in relation to liver regeneration, to illuminate the genetic interactions between genes regulating the cell cycle and apoptosis, and to clarify the role of TGF-ß signalling in the terminating phase of liver regeneration. Twelve pigs were randomised to either 60% liver resection (n=4), sham operation (n=4) or control animals (n=4). Liver biopsies were taken at time of resection, after three weeks and upon termination the sixth week. Global gene expression profiles in the biopsies were obtained using porcine oligonucleotide microarrays, representing approximately 20000 porcine genes. Microarray analysis revealed a clear dominance of genes regulating apoptosis towards the end of regeneration, compared to the sham and control groups. Caspase Recruitment Domain-Containing Protein 11 (CARD11) was upregulated six weeks after liver resection, suggesting the involvement of the caspase system at this time. Zinc Finger Protein (ZNF490) gene, with a potential negative effect on cell cycle progression and promotion of apoptosis, was only up regulated at three and six weeks after liver resection indicating a central role at this time. TGF-ß was not found to be significantly affected. CARD11 and ZNF490 appear to play a central role in the termination of liver regeneration in the present study. The lack of TGF-ß could indicate that signaling by TGF-ß is not required for termination of liver regeneration.
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Project description:Hepatocellular carcinoma (HCC) and cholangiocarcinoma (ICC) are two main forms liver cancers with poor prognosis. Models for studying HCC and ICC development using human liver cells are urgently needed. Organoids serve as in vitro models for cancer studies as it recapitulates in vivo structures and microenvironment of solid tumors. Herein, we established liver cancer organoid models by introducing specific mutations into human induced hepatocyte (hiHep)-derived organoids. c-MYC and hRASG12V overexpression in hiHep organoids with repressed p53 activation by large T led to distinct HCC and ICC signatures. With these oncogenic mutations, the neoplastic hiHep organoids formed cancerous structures and possessed cancer-specific hallmarks. Comprehensive transcriptional analysis of liver cancer organoids revealed genes and pathways with disease-stage-specific alterations. Notably, with RAS mutations, hiHep organoids acquired biliary trans-differentiation, and showed a process of conversion from hepatocytes to ICC. To sum up, we have established a useful and convenient in vitro human organoid systems modeling liver cancer development.
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Project description:The liver has the unique capacity to regenerate after surgical resection. However, the regulation of liver regeneration is not completely understood. We performed miRNA microarray analyses of liver tissue from Wistar rats at different time points after 70% partial hepatectomy (0, 2, 6, 12, 24, 48 hours, and 5 days) and after sham laparotomy (12, 24, and 48 hours). We demonstrate that miRNA expression patterns changed during liver regeneration and that these changes were most evident during the peak of DNA replication at 24 hours after resection. Expression of 13 miRNAs, including five members of the let-7 family, was significantly reduced 12-48 hours after resection, whereas 3 miRNAs were significantly upregulated (> 25% change). We provide a temporal miRNA expression dataset of the regenerating rat liver, which indicates a primary function for miRNA during the peak of DNA replication. These data will assist further functional studies on the role of miRNAs during liver regeneration. This project analyzed the miRNA expression in 30 different sample types of the organism rattus norvegicus. The miRNA expression was compared at 7 different growth time points after liver resection (0, 2, 6, 12, 24, 48 hours, 5 days) and at 3 different time points after sham laparotomy (12, 24, and 48 hours). Three biological replicates were used per time point.
2011-03-28 | E-GEOD-23696 | biostudies-arrayexpress
Project description:The liver has the unique capacity to regenerate after surgical resection. However, the regulation of liver regeneration is not completely understood. We performed miRNA microarray analyses of liver tissue from Wistar rats at different time points after 70% partial hepatectomy (0, 2, 6, 12, 24, 48 hours, and 5 days) and after sham laparotomy (12, 24, and 48 hours). We demonstrate that miRNA expression patterns changed during liver regeneration and that these changes were most evident during the peak of DNA replication at 24 hours after resection. Expression of 13 miRNAs, including five members of the let-7 family, was significantly reduced 12-48 hours after resection, whereas 3 miRNAs were significantly upregulated (> 25% change). We provide a temporal miRNA expression dataset of the regenerating rat liver, which indicates a primary function for miRNA during the peak of DNA replication. These data will assist further functional studies on the role of miRNAs during liver regeneration.
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Project description:Disrupted hepatocyte regeneration following surgical resection remains a clinical problem with few therapeutic options. The current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration may provide an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration in both normal and diseased murine preclinical models. mCLC846 demonstrated on target inhibition of MST1 and reduced EGFR inhibition which resulted in Yes-associated protein (YAP) activation. Oral delivery of mCLC846 perioperatively resulted in accelerated liver regeneration and improved survival in diet induced NASH models. Transcriptional analysis suggested that mCLC846 enhanced the normal regenerative pathways induced following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided survival benefit in models of diet induced non-alcoholic steatohepatitis.
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Project description:Surgical resection is the preferred treatment for Hepatocellular carcinoma; however, it induces tumor recurrence. Our objective was to understand the molecular mechanisms linking liver regeneration under chronic-inflammation to tumorigenesis. Mdr2-knockout mice, a model of inflammation-associated cancer, underwent partial-hepatectomy which led to enhanced hepatocarcinogenesis. Yet, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage response machinery and altered genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis and cell-cycle arrest, and suggest their involvement in tumor recurrence subsequent to partial hepatectomy. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic-inflammation, escape apoptosis and reenter the cell-cycle, triggering the enhanced tumorigenesis At present, there is a great organ shortage worldwide, thus the main treatment for Hepatocellular carcinoma (HCC) is liver resection. However, liver resection induces recurrence and mortality. In our study, we decipher, for the first time, the contribution of the DNA damage response in HCC development and recurrence, the immediate and long term effect. This is an important finding regarding the association between carcinogenesis and DNA damage response. Additionally, we demonstrate yet another link between inflammation, inducing DNA damage and genome instability, and carcinogenesis that has not been explored in the past. These results may assist in developing treatments that will reduce tumor recurrence and additionally, new prophylactic therapies during early inflammatory stages. Keywords: time course, regeneration
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