Cellular interplay in the fibrotic liver: Adhesion molecules JAM-B and JAM-C as mediators of sinusoid/pericyte interaction.

• Applicant: Privatdozentin Dr. Edith Hintermann
• Subject Area: Gastroenterology ; Immunology ; Cell Biology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261286070

Repeated injury of the liver induces chronic wound healing, which leads to pathological scar tissue formation. Such fibrotic tissue is generated due to increased production of collagen-rich extracellular matrix, which is mainly secreted by hepatic stellate cells (HSCs). In the chronically damaged tissue, HSCs transdifferentiate into an activated, myofibroblastic phenotype and upregulate not only matrix production but also proliferation, migration and contractility. Since HSCs act as pericytes (PCs), adhering to and embracing liver sinusoidal endothelial cells (LSECs), an increase in their contractility leads to sinusoid constriction. In parallel, LSECs get defenestrated, transforming sinusoids into tightly sealed capillaries with a strongly reduced transvascular exchange between blood and surrounding tissue. Overall, these processes lead to a rise in sinusoidal resistance in the fibrotic liver. In addition, the growth of blood vessels is induced due to a reduced supply of fibrotic tissue with nutrients and oxygen. These findings demonstrate a close relationship between angiogenesis and fibrosis. If untreated, fibrosis progresses to cirrhosis, which is characterized by strong morphological changes combined with portal hypertension and reduced liver function, eventually leading to liver failure. During fibrogenesis sinusoidal stability raises as the increasing number of HSCs attach to the vessel walls. When mural HSCs upregulate contractility the sinusoid diameter decreases. This poses the question as to how HSCs can attach to LSECs and trigger contractile forces. Our preliminary data in mouse models have shown that capillarized LSECs amplify JAM-B expression, whereas myofibroblastic HSCs induce JAM-C production. JAM-B and JAM-C are junctional adhesion molecules which mediate the interaction between different cell types like endothelial cells and leukocytes. Therefore, it is the aim of this work to study the role of JAM-B and JAM-C during the interaction between activated HSCs and capillarized LSECs in the fibrotic liver. To this end, we will analyze two different fibrosis models: Adenovirus-induced autoimmune hepatitis and chronic liver damage by the toxin carbon tetrachloride. Our initial studies demonstrate that HSCs can bind soluble JAM-B in a JAM-C-dependent manner. Furthermore, HSC contractility can be inhibited by blocking homophilic but not heterophilic JAM-C interaction. Therefore, it is possible that JAM-B/JAM-C binding is important for HSC adhesion to LSECs, whereas JAM-C/JAM-C binding plays a role in HSC contractility. Specific blockade of JAM-B and/or JAM-C controlled processes could reduce fibrosis-associated vascular remodelling e.g. sinusoid constriction or increased angiogenesis, and could therefore act as an anti-fibrotic therapy.

• DFG Programme: Research Grants