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Spatiotemporal characterization of the cellular and molecular contributors to liver fibrosis in a murine hepatotoxic-injury model

ABSTRACT: The interplay between the inflammatory infiltrate and tissue resident cell populations (e.g. epithelial cells, fibroblasts and macrophages) invokes fibrogenesis. However, the temporal and mechanistic contributions of these cell populations to fibrosis remain poorly defined. To address this issue, liver inflammation, ductular reaction (DR) and fibrosis were induced in C57BL/6 mice by thioacetamide (TAA) administration for up to 12 weeks. TAA treatment induced two phases of liver fibrosis. A rapid peri-central inflammatory infiltrate enriched in F4/80+ monocytes co-localized with SMA+ myofibroblasts resulted in early collagen deposition, marking the start of an initial fibrotic phase (1-6 weeks). An expansion of bone marrow derived macrophages proceeded a second phase, characterized by accelerated progression of fibrosis (> 6 weeks) followed the migration of the DR from the portal tracts to the centrilobular site of injury, in association an increase in DR/macrophage interactions. Although CCL2 mRNA was rapidly induced in response to TAA, CCL2 deficiency only partially abrogated fibrosis. In contrast, CSF-1R blockade diminished CCR2neg (Ly6Clo) monocytes, attenuated the DR and significantly reduced fibrosis, illustrating the critical role of CSF-1 dependent monocyte/macrophage differentiation and linking the two phases of injury. We demonstrate that in response to liver injury, CSF-1 drives early monocyte mediated myofibroblast activation and collagen deposition, subsequent macrophage differentiation and their association with the advancing DR, the formation of fibrotic septa and the progression of liver fibrosis to cirrhosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE74605 | GEO | 2015/12/01

SECONDARY ACCESSION(S): PRJNA300950

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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Spatiotemporal characterization of the cellular and molecular contributors to liver fibrosis in a murine hepatotoxic-injury model

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