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Home Research In vitro toxicology Connexin-based cellular signaling in liver disease

Over the years, the In Vitro Toxicology team has built a considerable expertise in the area of connexin- and pannexin-based signalling in the liver, specifically with respect to its role in liver functioning and cell death in primary hepatocyte cultures. In essence, we found that intercellular communication mediated by gap junctions is indispensable for the maintenance of the differentiated phenotype in an in vitro setting.

In a follow-up project, we scrutinize the role of gap junctions and connexin- and pannexin-based hemichannels in cell death and inflammation in disease. Focus is hereby put on both acute and chronic liver pathologies, i.e. acetaminophen-induced acute liver failure, liver steatosis and liver fibrosis, respectively. A first cornerstone of this research relates to the study of the expression and activity of connexin- and pannexin-based hemichannels in animal models of both pathologies as well as in liver tissue of human patients. New technologies are hereby developed to probe channel activity in vivo. A second pillar includes the generation and characterization of novel peptide inhibitors, in casu of connexin- and pannexin-based hemichannels. These new tools are tested in vitro and in vivo, namely in primary hepatocytes cultures and hepatic stellate cells lincs, and diseased animal models, respectively. Main focus lies in examining their selectivity in targeting selected connexin- or pannexin-based channels, as well as their efficacy in reducing cell death, inflammation and the clinical manifestation of acetaminophen-induced acute liver failure, liver steatosis and liver fibrosis. The overall translational goal thus is to establish novel diagnostic biomarkers and therapeutic drug targets of liver disease.

In this research context, a VUB-UGent Alliance Research Group, called 'Connexin Signalling Research Group' has been established with the team of Prof. Luc Leybaert (Dept. of Basic Medical Sciences-Physiology Group, UGent). In addition, a FWO research network was raised entitled 'Connexin and pannexin channels: regulation, function and applications'. We also established an international alliance research group and joint PhD programme with the group of Prof. Bruno Cogliati (University of Sao Paulo, Brazil). For more information about this alliances and research, please visit http://www.vub.ac.be/en/research/project/connect-team.

This connexin and pannexin research is supported by a Starting Grant from the European Research Council on the Belgian side, and by a Sao Paulo Excellence Chair Grant from the Sao Paulo Research Foundation on the Brazilian side.

 

Researchers

Prof. Mathieu Vinken
PhD student Michael Maes
PhD student Joost Willebrords
PhD student Sara Crespo-Yanguas

 

Relevant Publications

  • Vinken M., Henkens T., Vanhaecke T., Papeleu P., Geerts A., Van Rossen E., Chipman J.K., Meda P., Rogiers V. (2006) Trichostatin A enhances gap junctional intercellular communication in primary cultures of adult rat hepatocytes. Toxicological Sciences 91: 484-492.
  • Vinken M., Henkens T., De Rop E., Fraczek J., Vanhaecke T., Rogiers V. (2008) Biology and pathobiology of gap junctional channels in hepatocytes. Hepatology 43: 1077-1088.
  • Vinken M., Doktorova T., Decrock E., Leybaert L., Vanhaecke T., Rogiers V. (2009) Gap junctional intercellular communication as a target for liver toxicity and carcinogenicity. Critical Reviews in Biochemistry and Molecular Biology 44: 201-222.
  • Vinken M., Decrock E., De Vuyst E., De Bock M., Vandenbroucke R.E., De Geest B.G., Demeester J., Sanders N.N., Vanhaecke T., Leybaert L., Rogiers V. (2010) Connexin32 hemichannels contribute to the apoptotic-to-necrotic transition during Fas-mediated hepatocyte cell death. Cellular and Molecular Life Sciences 67: 907-918.
  • Vinken M., Decrock E., Bultynck G., Vanhaecke T., Leybaert L., Rogiers V. (2012) Connexin43 signalling contributes to spontaneous apoptosis in cultures of primary hepatocytes. Toxicological Sciences 125: 175-186.
  • Vinken M. (2012) Gap junctions and non-neoplastic liver disease. Journal of Hepatology 57: 655-662.
  • Maes M., Crespo Yanguas S., Willebrords J., Cogliati B., Vinken M. (2015) Connexin and pannexin signaling in gastrointestinal and liver disease. Translational Research 166: 332-343.
  • Maes M., Crespo Yanguas S., Willebrords J., Vinken M. (2015) Models and methods for in vitro testing of hepatic gap junctional communication. Toxicology In Vitro 30: 569-577.
  • Willebrords J., Veloso Alves Pereira I., Maes M., Crespo Yanguas S., Colle I., Van Den Bossche B., da Silva T.C., Oliveira C.P., Andraus W., Alves V.A., Cogliati B., Vinken M. (2015) Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research. Progress in Lipid Research 59: 106-125.
  • Maes M., Vinken M., Jaeschke H. (2016) Experimental models of hepatotoxicity related to acute liver failure. Toxicology and Applied Pharmacology 290: 86-97.

 

Collaboration opportunities

We are continuously seeking for research partners that could complement our connexin- and pannexin-related studies with relevant expertise. Since connexins, pannexins and their channels represent generic drug targets and biomarkers, these features can be extrapolated to other diseases, whether or not in liver. Such pathology-specific knowledge could be embedded in joint projects together with our experience in the area of connexin and pannexin research. At the same time, we also could benefit from technical input, in particular with respect to the assays and inhibitors to study the different connexin- and pannexin-based channel types. To substantiate the translational value of our work, we would strive to expand testing on liver tissue originating from human clinical patients suffering from liver disease by addressing tissue biobanks. Furthermore, we are looking for industrial partners to elaborate the valorisation potential of connexin- and pannexin-based channels as disease biomarkers of drug targets.

Our fields of research

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