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Polyploid hepatocytes are protected from cancer but maintain regenerative capacity in chronic liver disease

ABSTRACT: BACKGROUND & AIMS: Thirty to ninety percent of hepatocytes contain whole genome duplications, making it imperative to understand the fates and functions of these polyploid cells and how they affect development of liver disease. An important question is how polyploid cells respond to chronic proliferative demands, which are characteristic of liver diseases, but a challenging situation for cells with multiple genomes. METHODS: To interrogate liver polyploidy, we employed a mouse with reversible ANLN ( Anillin actin binding protein) knockdown that drives hepatocyte polyploidization in a doxycycline inducible fashion. Diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) were used to induce chronic liver damage and hepatocellular carcinoma (HCC). We performed partial hepatectomies to test regeneration and RNA-seq to assess gene expression changes. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. In vivo imaging of mitotic hepatocytes estimated the frequency of aneuploidy during regeneration, and exome sequencing of 54 human cirrhotic nodules was used to quantify aneuploidy. RESULTS: Hepatocytes from mice given chronic CCl4 alone showed significant increases in ploidy. Super-polyploid mice with 97% polyploid hepatocytes, due to induced knockdown of Anln , were almost completely protected from tumorigenesis induced by DEN and chronic CCl4 . The protection was not associated with differences in regenerative capacity, tissue fitness, gene regulation, or mitotic errors. Regenerative contributions from a non-hepatocyte population were ruled out using lineage tracing, confirming that polyploids can replenish tissues during chronic damage. No lagging chromosomes or micronuclei were found in mitotic polyploid cells and there was no evidence of chromosomal copy number variations in 54 nodules, suggesting that aneuploidy is not a common outcome of polyploid cell divisions. CONCLUSION: During chronic injury, polyploid hepatocytes readily divide and regenerate while being buffered from tumor suppressor loss and tumorigenesis. Therapeutic strategies to increase numbers of polypoid hepatocytes could prevent cancer while preserving regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE145084 | GEO | 2020/02/12

REPOSITORIES: GEO

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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. In the present study, we reported a detailed and comprehensive dynamic characterization of the cellular and molecular alterations involved in fibrosis in the liver of c-Met transgenic mice. Liver samples from female animals were collected at various time-points after fibrosis induction using CCL4 ranging from 0 weeks to 3 weeks. Tissue samples were divided into two parts; one was fixed in 10% formalin for histological evaluation and the other was used for RNA analysis.

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Polyploid hepatocytes are protected from cancer but maintain regenerative capacity in chronic liver disease

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