Cytokine and growth factor mediated regulation of cell polarity in liver regeneration and fibrosis

Project objectives

The ability of the liver to fully regenerate after injury is unique and as a tissue it therefore differs greatly from other tissues in the body which heal with a scar. This ability is founded on the livers central role in controlling whole organism metabolism and its role in compound detoxification, any injuries incurred must be repaired efficiently to maintain the organs functionality. However, during chronic injury (viral hepatitis or long-term alcohol abuse) epithelia can be replaced with non-functional connective tissue, leading to fibrosis, cirrhosis and possibly liver failure. This project aims to examine the roles of cytokine and growth factor secretion on tissue regeneration and how ‘Tight Junction’ mediated cell polarity effects fibrotic development.

Research impact

Many organ systems exhibit significant age-related deficits, but based on studies in old rodents and elderly humans, the liver appears to be relatively protected from such changes. Reports suggest that ageing compromises the liver’s regenerative capacity, both in the rate and to the extent the organ’s original volume is restored. Therefore, with an ageing population and a steady increase in people suffering with liver disorders including viral hepatitis, alcohol-related liver disease, cirrhosis and cancer; geriatricians are frequently managing older patients with chronic liver diseases.

This work will focus on the understanding the role(s) of cytokines and growth factors which are known to control distinct phases of the livers regeneration; including activation, proliferation and migration of cells required for tissue repair. Excessive cytokine and growth factor activity has also been linked with fibrosis in the liver so understanding the physiological conditions required for effective tissue regeneration will be critical.

This study will also examine the importance of hepatocyte (primary liver cell type) polarity in responses to liver injury, repair and cytokines/growth factors. This is because the establishment and maintenance of polarized plasma membrane domains is essential for cellular function and development. The ability of cells to maintain distinct and separate regions impacts area’s such as cell fate, cell movement, cell signalling and protein trafficking. Cellular specification through polarization occurs in almost all cell types and it has been observed that a loss of cell polarity and/or the components involved in cell polarity leads to a number of disease conditions including viral hepatitis and cancer.

Understanding these effects on the liver will hopefully help give insight into the fundamental cellular and molecular mechanisms involved in this organ’s unique regenerative abilities and how they are then subverted in age-related liver disorders such that novel therapies can be applied to their treatment.