Control of hepatic stellate cells of liver health and disease

Endosialin has been identified as a marker of tumor endothelial cells (Science 289:1197,2000). Yet, detailed expression profiling analyses by our and other laboratories revealed that it is not expressed by endothelial cells. Instead, Endosialin is expressed by tumor-associated pericytes and stromal myofibroblasts, identifying it as a marker of the activated mesenchymal lineage (Am J Pathol 172:486, 2008). We consequently hypothesized that Endosialin may be functionally involved in organ fibrosis, a process critically dependent on the recruitment and proliferation of activated mesenchymal cells. In line with this hypothesis, expression profiling experiments of human liver tissue samples revealed that Endosialin expression was significantly upregulated during liver fibrosis and cirrhosis. Yet, expression did not correlate with the severity of disease suggesting that Endosialin may be an early marker of liver fibrosis. Endosialin expression was most pronounced in portal fibroblasts and hepatic stellate cells (HSC), which localized along the sinusoids in the space of Dissé and also forming scar tissue of fibrotic septa and cirrhotic nodules. To mechanistically study the role of Endosialin during liver fibrogenesis, we pursued CCl4-induced liver fibrosis experiments in wildtype and Endosialin-deficient mice. CCl4-mediated liver damage (apoptosis of hepatocytes) was similar in both genotypes. Likewise, the pattern and intensity of fibrogenesis was not different. Surprisingly though, hepatocyte proliferation during early stages of liver fibrosis (2 and 4 weeks) was significantly elevated in the absence of Endosialin. To study proliferative liver regeneration more directly, we pursued partial hepatectomy experiments and traced hepatocyte proliferation during the rapid phase of liver regeneration. Proliferation of hepatocytes during early liver regeneration was dramatically enhanced in Endosialin-deficient mice. Collectively, the experiments identified a paracrine growth regulatory interaction between HSC and hepatocytes. Definite genetic experiments showed that the activated HSC marker Endosialin plays a causal role in this interaction. Ongoing transcriptomic analyses of HSC isolated from the different genotypes under physiological and pathological conditions are aimed at unraveling the molecular nature of this regulatory circuit.