Topic 2 : CYTOSKELETON - PORTAL HYPERTENSION

Topics - overview

Title

Project leader

Hendrik Reynaert MD, PhD

PhD Project -finalized in 2014

Elke van Rossen

 

 

Functional characterization of the hepatic stellate cell cytoskeleton
Pathogenesis of portal hypertension

In normal liver, intrahepatic resistance changes with variations in portal blood flow, thereby keeping portal pressure within normal limits. In cirrhosis however, both intrahepatic resistance and splanchnic blood flow are increased, resulting in portal hypertension. Although structural changes, e.g. fibrotic nodules, contribute most to the increased intrahepatic vascular resistance, it has become clear that not only fixed, but also dynamic factors add significantly to the increased resistance (1). This dynamic part is caused by active contraction of septal and/or portal myofibroblasts, activated hepatic stellate cells and portal venules. The anatomical location of stellate cells and their capacity to contract or relax in response to various vasoactive mediators give away that these cells play a role in modulating intra-hepatic vascular resistance and blood flow at the sinusoidal level (2). Hepatic stellate cells are currently regarded as target cells for treating portal hypertension. We have demonstrated that somatostatin, a drug used to treat portal hypertension, induces relaxation of HSC via somatostatin receptor subtype 1 (3). In order to transmit contractile forces, cells need a firm cytoskeleton and anchoring in the extracellular matrix. In the past decade, the CYTO lab has extensively studied the stellate cell cytoskeleton (4-7) and continues to contribute to a better understanding of its contractile forces with the intention of relieving hypertension in fibrotic patients.

References
1.Bhathal, P. S. & Grossman, H. J. J Hepatol 1, 325-37 (1985). 2.Reynaert, H., Thompson, M. G., Thomas, T. & Geerts, A. Gut 50, 571-81 (2002) 3.Reynaert, H. et al. Gastroenterology 121, 915-30 (2001). 4.Niki, T. et al. Hepatology 23, 1538-45 (1996). 5.Niki, T. et al. Hepatology 29, 520-7 (1999). 6.Geerts, A. et al. Hepatology 33, 177-88 (2001). 7.Uyama, N. et al. Gut 55, 1276-1289 (2006)

The cytoskeleton of hepatic stellate cells: role in cellular contraction and relaxation

Hepatic stellate cells (HSCs) are important in several (patho)physiological conditions. In response to chronic injury, HSCs are activated and change from quiescent to myofibroblast-like cells with contractile properties. This makes HSCs an interesting target in the study of portal hypertension. The shift in phenotype is accompanied by a change in expression of intermediate filament proteins (IFs). In contrast to most differentiated cell types, HSCs express a broad but variable spectrum of IFs. The goal of our project is to understand the role of these intermediate filament proteins in the contraction of hepatic stellate cells.


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