Liver Disease and Carcinogenesis

This research group focuses on the biology of the liver progenitor cell (LPC) called an "oval cell" which describes its shape. We envisage an enormous potential for this cell as the vehicle for cell and gene therapy to treat liver disease. We propose it is superior to other cell types such as the hepatocyte and the embryonic (ESC) or adult stem cell (ASC) for several reasons. In particular, it is robust and simple to freeze and store, then thaw and grow by in vitro culture for use as required. It can be rapidly differentiated into either hepatocytes or cholangiocytes (bile duct cells) when maintained under appropriate conditions; therefore it is more versatile than the hepatocyte.

Our long-term vision is to hasten the day when human LPCs are utilised to treat liver disease, especially end-stage liver disease for which currently organ transplant is the only solution. To do this we have to understand mechanisms underlying the differentiation of LPCs as opposed to their transformation into liver cancer. Therefore 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 a consequential in respect of 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.

Senior Research Staff

Professor George Yeoh Head, Liver Disease Research: hepatocyte development; liver progenitor cells

Research Details

Our research group focuses on the biology of the LPC called an "oval cell" in rodents as this describes its shape. We envisage an enormous potential for this cell as the vehicle for cell and gene therapy to treat liver disease. We propose it is superior to other cell types such as the hepatocyte and the embryonic (ESC) or adult stem cell (ASC) for many reasons. In particular, it is robust and simple to freeze and store, then thaw and grow by in vitro culture when required. It can be easily differentiated into either hepatocytes or cholangiocytes (bile duct cells) quite rapidly when maintained under appropriate conditions, therefore it is more versatile than the hepatocyte. Most importantly, the LPC is developmentally close to the hepatocyte and the cholangiocyte in contrast to the ESC or ASC, which will require many more cell divisions and developmental steps to produce useful cells for liver therapy. Such cells can also be used to populate bioartifical chambers which can then function as external liver assist devices as well as devices which can be implanted.

Our long-term vision is to hasten the day when human LPCs are utilised to treat liver disease, especially end-stage liver disease for which currently organ transplant is the only solution. A realistic expectation in the short term is to use LPCs to "bridge" patients thereby extending their survival and enhances their probability of finding a suitable organ donor. A more ambitious and longer-term aim is to use these cells to circumvent the requirement for organ transplant. This may be possible with some liver diseases.

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 mice 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 developments in our laboratory which underpin our current research are:

1. Isolation of LPCs from human fetal liver
2. Establishment of LPCs from a transgenic mouse which expresses a liver specific reporter (see Figure 1)
3. Acquisition of the Cellscreen instrument which allows for progressive, accurate, high throughput and comparative growth characteristic of multiple cell cultures
4. Establishment of specific phenotypic differences in mitochondria between normal and transformed LPCs

Current research projects will exploit these new developments and they are designed to increase our understanding of LPCs and establish their utility for treating liver disease.