The role of liver sinusoidal endothelial cells in hepatitis C virus infection

Rowe, Ian Alston Cooper (2013). The role of liver sinusoidal endothelial cells in hepatitis C virus infection. University of Birmingham. Ph.D.

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Abstract

Hepatitis C virus (HCV) infection is a major cause of global morbidity, causing chronic liver injury that can progress to cirrhosis and hepatocellular carcinoma. The liver is a large and complex organ containing multiple cell types, including hepatocytes, sinusoidal endothelial cells (LSEC), stellate cells, Kupffer cells and biliary epithelial cells. Hepatocytes are the major reservoir supporting HCV replication, however, the role of non-‐parenchymal cells in the viral lifecycle remain largely unexplored. Endothelial cell hepatocyte co-‐cultures were established to study the role of LSEC in HCV biology. Vascular endothelial growth factor (VEGF-‐A) regulated transcripts were profiled by microarray to identify factors modulating HCV replication. The initial studies indicated that rather than transmitting HCV to permissive hepatocytes LSEC were protective in HCV infection. Co-‐culture of epithelial and endothelial cell showed that LSEC limit hepatocyte permissivity to HCV infection via cell contact-‐dependent mechanisms and by the expression of soluble mediator(s) that are regulated by VEGF-‐A. Transcript analysis identified LSEC expression of bone morphogenetic protein 4 (BMP4), a novel proviral molecule that is negatively regulated by VEGF-‐A via a VEGF receptor-‐2 (VEGFR-‐2) MAPK dependent pathway. Consistent with the in vitro data I observed increased BMP4 expression and reduced VEGFR-‐2 activation in inflamed liver tissue. These studies show a novel role for LSEC and BMP4 in HCV infection and highlight BMP4 as a new therapeutic target for treating liver disease.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):