Chronic liver injury is present in diseases such as chronic hepatitis or liver cancer and ends up causing liver tissue fibrosis, which is followed by an inflammatory process. Although the main executors of this activation were already known, the mechanisms that led to the inflammatory process and the production of profibrotic factors were, to date, not well characterized.

Now, a study led by Dr. Isabel Fabregat, head of the TGF-beta and cancer group at the Bellvitge Biomedical Research Institute (IDIBELL) and researcher at the Network Biomedical Research Center (CIBER) in the area of Liver and Digestive Diseases (CIBEREHD), has managed to demonstrate the essential role of molecular signaling through the epidermal growth factor receptor (EGFR) in the liver tissue fibrotic process regulation. As shown in the scientific paper, published in the prestigious Journal of Pathology, the absence of EGFR activity in genetically modified mice’s hepatocytes induces changes in the immune cells pattern in the liver, with a notable increase of the macrophage population related to the fibrosis resolution, as well as in the population of lymphocytes that are related to damage eradication. Researchers Aránzazu Sánchez and Blanca Herrera, from the Complutense University of Madrid, have actively participated in this work, which, in turn, has received funding from the Ramon Areces Foundation and reflects an intra-CIBER collaboration with the participation of the CIBERDEM group led by Ángela M Valverde.

In essence, Fabregat’s group generated a mouse model that expresses a truncated and inactive form of EGFR specifically in hepatocytes. Using this model, and experimentally inducing a pro-inflammatory and fibrotic process in the liver, it was observed that mice without EGFR activity attenuated the liver fibrosis development, which led to a faster resolution of the fibrotic process and an improvement of the damage. The subsequent in vivo and in vitro analysis of the hepatocytes’ gene expression profile (or transcriptome) and the study of the molecules released into the medium (or secretome) allowed scientists to elucidate the specific EGFR-regulated molecular mechanisms that mediate the profibrotic and proinflammatory factors production in hepatocytes.

According to Dr. Fabregat, “the findings obtained in the mouse model could be transferred to human patients suffering from a fibrotic process.” Indeed, transcriptomic data analysis of liver biopsies from patients with fat deposition-associated liver disease and untreated hepatocellular carcinoma demonstrated that the EGFR signaling pathway is increased in advanced fibrosis stages and it correlates with the expression of fibrotic and inflammatory genes previously identified in in vivo and in vitro experiments. Ester Gonzalez-Sanchez and Javier Vaquero, first authors of the article, conclude that “these results indicate that genes playing essential functions during liver fibrosis and inflammation may be under the control of the EGFR pathway.”

[In the photograph, from left to right, Blanca Herrera, Ester Gonzalez-Sanchez, Javier Vaquero, Aránzazu Sánchez and Isabel Fabregat]

The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).