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.
