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A cyclic peptide-grafted Fc with hepatocyte growth factor functionality ameliorates hepatic fibrosis in a non-alcoholic steatohepatitis mouse model.

ABSTRACT: Although growth factors have significant therapeutic potential because of their regenerative functions, their poor pharmacokinetics and low stability hinder their therapeutic application. Nonalcoholic steatohepatitis (NASH) is characterized by lipid accumulation, inflammation, and fibrosis in the liver, which can progress to life-threatening conditions such as cirrhosis and liver cancer. The hepatocyte growth factor (HGF)-Met receptor pathway has been proposed as a potential therapy for liver diseases including NASH due to its effects on liver regeneration, but the short half-life of recombinant HGF limits its clinical use. Here, we designed a Met agonist with a long half-life by grafting two Met-binding macrocyclic peptides into loops of the crystallizable region (Fc) of immunoglobulin. This surrogate Met agonist ameliorated liver fibrosis and inflammation in a mouse model of NASH, indicating its potential therapeutic use. This study provides a foundation to develop growth factor and cytokine mimetics and to expand their therapeutic applications.

ORGANISM(S): Mus musculus

PROVIDER: GSE233051 | GEO | 2024/07/04

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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A cyclic peptide-grafted Fc with hepatocyte growth factor functionality ameliorates hepatic fibrosis in a non-alcoholic steatohepatitis mouse model.

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