Semaphorin 3C exacerbates liver fibrosis

Area of Science:

• Hepatology
• Cell Biology
• Molecular Biology

Background:

• Chronic liver disease is a global health concern, often progressing to fibrosis and cirrhosis.
• Transforming growth factor-beta (TGF-β) is a key cytokine in liver fibrosis, activating hepatic stellate cells (HSCs).
• Semaphorins (SEMA), axon guidance molecules, are implicated in liver fibrosis, particularly in hepatitis B virus (HBV)-induced chronic hepatitis.

Purpose of the Study:

• To investigate the role of semaphorins (SEMA) and their receptors, plexins and neuropilins (NRPs), in regulating HSCs during liver fibrosis.
• To determine if SEMA3C functions as a profibrotic factor in liver disease.

Main Methods:

• Analysis of patient databases and liver biopsies.
• Utilized transgenic mice with gene deletion in activated HSCs for ex vivo and in vivo studies.
• Investigated SEMA3C and NRP2 expression and function in isolated HSCs and mouse models of liver fibrosis.

Main Results:

• SEMA3C is highly expressed in cirrhotic liver samples and elevated in various liver disease models and activated HSCs.
• SEMA3C overexpression enhances TGF-β-mediated HSC activation, indicated by increased SMAD2 phosphorylation.
• Deletion of SEMA3C or its receptor NRP2 in activated HSCs significantly reduces liver fibrosis in mice.

Conclusions:

• SEMA3C is identified as a novel marker for activated HSCs.
• SEMA3C plays a critical role in the development of the myofibroblastic phenotype and liver fibrosis.
• Targeting SEMA3C or NRP2 in activated HSCs presents a potential therapeutic strategy for liver fibrosis.