Semaphorin 3C exacerbates liver fibrosis

Background & Aims Chronic liver disease is a growing epidemic leading to fibrosis and cirrhosis. TGF-β is the pivotal pro-fibrogenic cytokine which activates hepatic stellate cells (HSC), yet, other molecules can substantially modulate TGF-β signaling in the course of liver fibrosis. Expression of the axon guidance molecules Semaphorins (SEMAs), which signal through Plexins and Neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. This study aims at determining their function in the regulation of HSCs. Approach & Results We analyzed publicly available patient databases and liver biopsies. We employed transgenic mice where genes are deleted only in activated HSCs to perform ex vivo analysis and animal models. SEMA3C is the most enriched member of the Semaphorin family in liver samples from cirrhotic patients. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis or HBV-induced hepatitis discriminates those with a more pro-fibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs upon activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-β-mediated myofibroblast activation, as shown by increased SMAD2 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained upon activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice. Conclusion SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis. ### Competing Interest Statement The authors have declared no competing interest. * CLD : chronic liver disease NASH : non-alcoholic steatohepatitis HSCs : hepatic stellate cells NRP : Neuropilin-1 SEMA : semaphorin HBV : chronic viral hepatitis B; hepatitis C HCV HFD : High-fat diet FPC : Fructose-Palmitate-Cholesterol CCl4 : carbon tetrachloride; y IVC : inferior vena cava GSEA : Gene Set Enrichment Analysis ES : enrichment plot NES : normalized enrichment score FDR : False Discovery rate ECs : endothelial cells.