Regulation of hepatic stellate cell phenotype and cytoglobin expression by extracellular matrix proteins

Stone, Louise Catherine (2015). Regulation of hepatic stellate cell phenotype and cytoglobin expression by extracellular matrix proteins. University of Birmingham. Ph.D.

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Abstract

All chronic liver diseases can induce fibrosis and lead to liver cirrhosis. Within liver disease, hepatic stellate cells (HSC) are accepted as the major effectors of fibrogenesis and changes in the extracellular matrix (ECM). Cytoglobin (CYGB), a hexacoordinated globin, is upregulated in liver disease, and expression has been reported to be specific to HSCs in the liver, though this is disputed. Data presented in Chapter 3 of this thesis confirm upregulation of Cygb in murine models of liver disease and diseased human liver tissue. Chapter 4 shows how ECM can effect HSC morphology, behaviour and phenotype with collagen I, an important component of the hepatic scar conferring an activated HSC phenotype, and laminin, a basal protein in a normal liver, inducing a more quiescent phenotype in HSC cell lines HSC-T6 and LX-2. Chapter 5 demonstrates the novel observation of collagen I-induced downregulation, and laminin-induced upregulation, of Cygb in HSC-T6s. Chapter 6 explores the role of cell signalling through membrane receptors and regulation of Cygb expression, identifying phosphorylated focal adhesion kinase as a mechanism of signal transduction through integrin activation. These findings suggest that Cygb expression is modulated by ‘outside-in signalling’ and this is important in the activation status of HSCs.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):