Liver Disease and Carcinogenesis
Professor George Yeoh
Liver Disease and Carcinogenesis
Professor George Yeoh
Emeritus Professor George Yeoh BsC, PhD received his PhD in Biochemistry from UWA in 1972. Shortly after he was awarded the CJ Martin Overseas Research Fellow (NH&MRC) and studied at the University of Pennsylvania USA and the Beatson Institute for Cancer Research, Glasgow, Scotland. He filled many roles as Visiting Scientist at a number of prestigious universities in the USA and in Europe. Following his return to Australia he was successful in obtaining an NHMRC Fellowship and achieved successive renewals to the level of Principal Research Fellow. He was the Associate Dean, Research in the UWA Faculty of Medicine, Dentistry and Health Sciences, and is currently a Professor of Biochemistry & Molecular Biology.
He has an extensive and protracted interest in liver progenitor cells (LPCs). LPCs are induced in liver when rodents are placed on a diet, which results in fat accumulation that damages the liver. His laboratory showed that LPCs are bipotential cells; able to generate hepatocytes as well as bile duct cells; and was the first to report their existence in a rat model of alcoholic liver disease and in mouse hepatitis induced by cytomegalovirus. The Yeoh lab was also the first to demonstrate the presence of LPCs in human liver diseases, namely, chronic alcoholic liver disease, hemochromatosis and hepatitis C. These findings suggest that LPCs may play an important role in liver regeneration in liver pathologies, especially when damage is prolonged. The majority of publications in the last ten years have focused on this topic for which his laboratory has now an established international reputation. The group reported the involvement of macrophages and more specifically TNFalpha and TWEAK in the LPC response. His international reputation is founded on the quality of his publications, collaborations and participation in meetings as a keynote speaker and reviewing for the leading hepatology journals.
Our 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 LPCs as the vehicle for cell and gene therapy to treat liver disease. Liver progenitor cells are superior to other cells such as hepatocytes and embryonic (ESC) or adult stem cells (ASC) for many reasons. In particular, LPCs are robust and simple to freeze and store, they can then be thawed and grown by in vitro culture when required. They are more versatile than hepatocytes as they are easily and rapidly differentiated into either hepatocytes or cholangiocytes (bile duct cells) when maintained under appropriate conditions. 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 steps and much coaxing to produce useful cells for liver therapy. Our long-term vision is to hasten the day when human LPCs are used 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 by extending their survival and enhancing their chances 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.
Urea synthesis defect resulting from OTC deficiency Ornithine transcarbamylase (OTC) is a urea cycle enzyme that is mutated in individuals with a metabolic disorder – OTC deficiency. The consequence of accumulating ammonia affects many tissues, and the liver in particular is damaged. The condition affects young children with neurologic consequences, hence liver organ transplant is necessary to treat those severely affected. Cell therapy using normal hepatocytes may also be possible, but hepatocytes are difficult to maintain and store; and once transplanted may not survive for very long. In contrast LPCs are robust and have the added advantage of long-term survival and the ability to proliferate and continue to generate hepatocytes in situ means they have the potential to confer sustained benefits following transplant. We have access to the Spf-ash mouse model of human OTC deficiency through our collaboration with Professor Ian Alexander of the Childrens’ Medical Research Institute in Sydney. This group also has expertise in ESC and iPSC technology and this allows us to test our LPC lines and LPCs generated from ESCs and iPSCs in these mice.
1. Holtzer H, Biehl J, Yeoh G, Meganathan R, Kaji A. 1975. Effect of oncogenic virus on muscle differentiation. Proc Natl Acad Sci USA 72:4051-4055. [PNAS USA]
2. Newman SA, Birnbaum J, Yeoh GC. 1976. Loss of a non-histone chromatin protein parallels in vitro differentiation of cartilage. Nature 259:417-418. [Nature]
3. Yeoh GC, Bennett FA, Oliver IT. 1979. Hepatocyte differentiation in culture. Appearance of tyrosine aminotransferase. Biochem J 180:153-160. [Biochem J]
4. Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. 1999. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol 154:537-41. [NCBI PubMed Entry]
5. Knight B, Yeoh GC, Husk KL, Ly T, Abraham LJ, Yu C, Rhim JA, Fausto N. 2000. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J Exp Med 192:1809-18. [NCBI PubMed Entry]
6. Shelly LL, Tynan W, Schmid W, Schutz G, Yeoh GC. 1989. Hepatocyte differentiation in vitro: initiation of tyrosine aminotransferase expression in cultured fetal rat hepatocytes. J Cell Biol 109:3403-3410. [NCBI PubMed Entry]
7. Akhurst B, Croager EJ, Farley-Roche CA, Ong JK, Dumble ML, Knight B, Yeoh GC. 2001. A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology 34:519-22. [NCBI PubMed Entry]
8. Dumble ML, Croager EJ, Yeoh GCT, Quail EA. 2002. Generation and characterisation of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis 23:435-45. [NCBI PubMed Entry]
9. Olynyk JK, Yeoh GC, Ramm GA, Clarke SL, Hall PM, Britton RS, Bacon BR, Tracy TF. 1998. Gadolinium chloride suppresses hepatic oval cell proliferation in rats with biliary obstruction. Am J Pathol 152:347-52. [NCBI PubMed Entry]
10. Smith PG, Tee LB, Yeoh GC. 1996. Appearance of oval cells in the liver of rats after long-term exposure to ethanol. Hepatology 23:145-54. [NCBI PubMed Entry]