B2: Hepatic angiodiversity: Vascular control of liver function and disease
Philipp-Sebastian Koch / Sergij Goerdt
Microvascular endothelial cells (EC) act as organ-specific gatekeepers of their microenvironment to control organ function in health and disease. Liver sinusoidal EC (LSEC) are a prime model of angiodiversity. LSEC show unique molecular, phenotypic, and functional features and instruct the hepatic vascular niche by cellular interactions and angiokines. LSEC are discontinuous EC and guarantee high permeability across the sinusoidal wall by exhibiting fenestrations and absence of a basement membrane. Pathological changes of these highly specialized EC contribute to severe liver diseases ranging from alcoholic and non-alcoholic steatohepatitis to liver cirrhosis and from hepatocarcinogenesis to liver metastasis. During these disease processes, LSEC trans-differentiate towards a capillary phenotype (sinusoidal capillarization) aggravating disease progression. The molecular and signaling mechanisms driving sinusoidal capillarization, however, still await detailed analysis.
Recently, we have been able to identify the transcription factor Gata4 as molecular master regulator for LSEC differentiation. Using newly generated LSEC-specific cre-driver lines (stab2-iCre), LSEC-restricted deletion of Gata4 was shown by us to be embryonic lethal and to cause transformation of discontinuous liver sinusoids into continuous capillaries. Gata4 also controls down-stream angiocrine functions of LSEC. Hepatic angiocrine endothelial Bmp2 deficiency, for example, caused severe iron overload, while hepatic angiocrine wnt signaling controls liver growth and metabolic maturation. Preliminary results furthermore show that LSEC-specific Gata4 deficiency in adult mice engineered using novel LSEC-specific Cre driver lines causes hepatopathy and liver fibrosis.
In this project, the major aim is to study more broadly the molecular regulators of hepatic angiodiversity and to provide proof of principle that maintaining and restoring hepatic angiodiversity is a valid strategy to prevent and treat hepatic disease.