Liver research at the Perkins is focussed on the biology of the liver progenitor cell (LPC) called an “oval cell” which describes its shape. Our long-term vision is to use human LPCs to treat liver cancer, especially end-stage liver cancer for which organ transplant is the only possible solution. To do this we have to understand mechanisms underlying the differentiation of LPCs as opposed to their transformation into liver cancer.
As a result, one objective of our research is to document molecular and cellular differences between tumorigenic and non-tumorigenic LPCs and to show which of these are causal and which are consequential in regards to transformation. Causal changes can form the basis of prevention strategies and unique characteristics of tumorigenic LPCs can be used to selectively target liver cancer cells which develop from LPCs.
[Image]: BMEL TAT LPCs cell lines which have been differentiated to form ducts (a), hepatocytes (b) and ducts and hepatocytes (c). X-gal staining reveals LPCs expressing the beta-gal reporter which have differentiated into mature hepatocytes.
To utilise LPCs we must identify and understand the action of growth factors and cytokines, which influence them. To accomplish this, we have determined the pattern of growth factors and cytokines in pre-clinical models with liver disease that induces the appearance of LPCs. The importance of these factors has been confirmed by showing that they affect cultured LPCs. These studies indicate that IL6, TNF alpha, Interferon alpha and gamma and lymphotoxin beta are important LPC regulatory factors. To effectively use LPCs as vehicles for cell therapy we need to define conditions which enhance their growth and differentiation. Knowledge of cytokines which enhance LPC proliferation can be used to increase their contribution to liver regeneration in humans which can lead to positive outcomes for liver disease patients.
Recent research breakthroughs in this area include:
- Establishment of LPCs from a transgenic model which expresses a liver specific reporter (see image)
- Acquisition of the Cellscreen instrument which allows for progressive, accurate, high throughput and comparative growth characteristic of multiple cell cultures
- Establishment of specific phenotypic differences in mitochondria between normal and transformed LPCs
Current research projects will further investigate these new developments and they are designed to increase our understanding of LPCs and establish their utility for treating liver disease.