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Transcriptomic signatures of p16-high (p16h) hepatocytes in CCl4-treated liver

ABSTRACT: The mechanisms by which aging promotes fibrotic processes remain to be elucidated. The preceding observation indicating a robust correlation between the severity of fibrosis in human cirrhotic patients and the population of hepatocytes expressing elevated levels of p16Ink4a (p16h), propose that p16h hepatocytes might serve as initiators of fibrogenic processes in response to liver injury. In this study, we employed a CCl4-induced hepatitis model to promote a fibrogenic process and observed the accumulation of p16h hepatocytes in zone 3.

ORGANISM(S): Mus musculus

PROVIDER: GSE312919 | GEO | 2026/04/08

REPOSITORIES: GEO

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Project description:Hepatocellular carcinoma (HCC) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC, we used a human disease-relevant mouse model of fibrosis-associated hepatocarcinogenesis. In this model, marked liver tumor response caused by a pro-mutagenic chemical N-nitrosodiethylamine in presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations (CNAs), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis-associated hepatocarcinogenesis. We evaluated DNA CNAs and changes in gene expression in the mouse liver (normal, tumor and non-tumor cirrhotic tissues). In addition, we compared our findings to those in human HCC (tumor and non-tumor cirrhotic/fibrotic tissues). We observed that while fibrotic liver tissue is largely devoid of DNA CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. When compared to CNAs in human HCC, we found that 33% of genes in these segments are similarly affected in the mouse tumors. Our results suggest that CNAs most commonly arise in neoplastic tissue rather than in fibrotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC. Genomic DNA was extracted from frozen liver samples from vehicle-control and DEN+CCl4-treated mice using a DNEasy kit (Qiagen, Valencia, CA). Eighteen mouse tumor samples were included in the study, as well as 18 matched non-tumor samples taken from fibrotic, non-tumorous, surrounding liver tissue from the same mice. Liver DNA from 6 vehicle control-mice was pooled and used as the reference genome in the aCGH experiments. Copy number alterations were identified using the normalized data.

Project description:Background: HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. Treatment with HGF has been shown to accelerate resolution of fibrotic liver lesions in experimental animal models. To formally address the importance of c-Met signaling in hepatocytes in the context of chronic liver injury, we have used hepatocyte-specific Metfl/fl;Alb-Cre+/- conditional knockout mice (KO) and a model of liver fibrosis. Methods: CCl4 was administrated biweekly over a period of 4 weeks (injury phase), and the animals were followed over the next 4 weeks (healing phase). Macroscopic and microscopic changes during the injury and healing phases were monitored by IHC. Deposition of ECM was assessed by Sirius red staining and hydroxiproline content. Activation of hepatic stellate cells (HSC) was estimated by a-SMA using WB and IHC. Expression levels of the selected key fibrotic molecules were evaluated by RT-qPCR and WB. Time-dependent global transcriptomic changes from whole livers and isolated hepatocytes were examined using gene expression microarrays. Results: Loss of HGF/c-Met signaling in hepatocytes altered the hepatic microenvironment and dramatically aggravated hepatic fibrogenesis. Increased liver damage was associated with decreased hepatocyte proliferation, progressive accumulation of HSCs, and delayed fibrinolysis causing increased collagen deposit. Dystrophic calcification of necrotic areas impaired phagocytosis, resulting in sustained inflammatory and fibrogenic signaling further augmenting severity of fibrogenesis. Global gene-expression analysis demonstrated upregulation of key fibrogenic molecules, such as Tgf-Ã¢ and Pdgf-Ã¢, paralleled by a decreased expression of genes important for cell cycle, stress response and regeneration, which could be attributed to the c-Met deficiency in hepatocytes. Additionally, key chemotactic and inflammatory cytokines, including Ccl2, SDF1/Cxcr4 and Spp1, were upregulated in Metfl/fl;Alb-Cre+/- hepatocytes. However, the major pro-fibrotic signaling originated from the non-parenchymal cell compartments, as revealed by cell type-specific gene expression signatures. Conclusion: These results indicate that lack of c-Met signaling in hepatocytes disrupts the balance between extracellular matrix production and degradation and establish a protective role for c-Met against adverse microenvironment leading to the development of fibrotic liver disease.

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Transcriptomic signatures of p16-high (p16h) hepatocytes in CCl4-treated liver

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