Regulation of hepatic stellate cells by extracellular matrix : role of intergrin avb3

Abstract

The interaction between extracellular matrix (ECM) and hepatic stellate cells (HSC) is the major event in liver fibrosis and recovery. The integrins, as a family of cell surface adhesion molecules, mediate adhesion of HSC to ECM and regulate a variety of cellular functions. In this thesis, I have examined the hypothesis that the ECM regulated HSC phenotype in liver fibrosis and recovery is mediated by integrins; and that integrin a_vb₃ plays a role in HSC activation, proliferation and apoptosis. These were examined by 1) investigating the correlations of ECM remodelling with HSC activation, proliferation or apoptosis in-vivo and in-vitro; 2) evaluating the regulation of integrin expression and adhesion affinities by different substrata in-vitro; 3) investigating the function of integrin a_vb₃ on extracellular and intracellular signalling mechanisms that regulate cell survival or apoptosis. To do so, rat CCl₄ liver fibrosis/recovery models and human liver biopsies were employed. In-vitro substrata-HSC cell models, integrin a_vb₃ agonists (vitronectin, fibronectin, collagen I), and antagonists (matrigel, echistatin and integrin specific antibodies), and various biochemical techniques were used.

In-vivo studies demonstrated that as fibrosis progressed in liver, collagen I, MMP-2, MT1-MMP, TIMP-1, CTGF, TGF-b1 expression were increased and collagenase activity was suppressed. As spontaneous recovery occurred, the expression of these fibrotic effectors declined and returned to normal, whereas collagenase activity was increased to normal. The change of a-SMA expression, a HSC activation marker, was associated with fibrogenesis or spontaneous recovery, indicating HSC as a key cell in liver fibrosis.

In-vitro studies using substrata-HSC cell models demonstrated that substrata in ECM regulate HSC activation, proliferation, arrest and apoptosis, which were associated with cell morphology change and altered integrin expression. This study is first reporting that integrin a_vb₃ is expressed by activated HSC and involved in HSC proliferation and survival in a fibrotic microenvironment.

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