Dr. Xin Wang is an assistant professor in the Medical School's Department of Laboratory Medicine and Pathology and a faculty member of Stem Cell Institute. Wang received his Ph.D. in 1998 from State University of New York at Buffalo. His Ph.D. research project in the laboratory of Dr. Stanley Halvorsen focused on reciprocal regulation of ciliary neurotrophic factors (CNTF) and acetylcholine receptors during synaptogenesis in embryonic chick atria. He then did post-doctoral research in the laboratory of Dr. Markus Grompe at Oregon Health & Science University where he began studies on liver gene therapy, liver stem cells and liver cell transplantation in a murine model of human Hereditary Tyrosinemia Type I.
Dr. Wang's lab is interested in the nature of stem cells, the mechanism of their differentiation and the methods to induce them into the differentiated cells that are transplantable for curing diseases.
Particularly, one research project focuses on how stem cell can differentiate to liver cells and how to use stem cells for curing liver diseases. Liver organ transplantation has been known useful for the treatment of end-stage liver diseases. However, such surgery is expensive, associated with significant morbidity and mortality, and not readily available due to shortage of donor organs. Cell therapy is a promising alternative to liver organ transplantation. Hepatocyte (main functional cells in liver) transplantation can result in significant repopulation of donor cells in recipient liver. In order to make hepatocyte transplantation available for large numbers of patients in future, generating sufficient numbers of hepatocytes will be required. In addition, generating large numbers of hepatocytes would also allow for the development of bioartifical liver (BAL). Several kinds of stem cells are studied for inducing liver cell differentiation in my lab. One of them is embryonic stem (ES) cell. ES cells have the ability to form all differentiated somatic cells. We are studying how ES cells can be induced to differentiate to transplantable hepatocytes. When enough differentiated cells can be obtained, we will prove the function of ES cell derived hepatocytes by using liver transplantation assay in a mouse model of hereditary tyrosinemia Type I (HT I). HTI mouse has a liver disease that is caused by mutant of an enzyme fumarylacetoacetate dehydroxylase (FAH) in the tyrosine catabolic pathway. HT1 mouse is used as a robust model for liver transplantation assay to analyze the liver repopulating cells (see the figure1, 2, 3).
In addition, we are developing methods for purification of transplantable hepatocytes from other cells. For example, the in vitro induced hepatocytes from ES cells may be mixed with undifferentiated ES cells. Contaminated ES cells at un-differentiation state may induce tumors after transplantation. We will purify the induced hepatocytes by their cellular characteristics, such the pattern of membrane protein expression. One method is by using fluorescence activated cell sorting (FACS).
Further more, we are studying the mechanism for the stem cell derived liver cells both in vivo and in vitro. We hope to determine the key growth factors that control the process of hepatocyte differentiation. We are also interested in the lineage commitment from ES cells to mature hepatocytes. The information will greatly help us to efficiently manipulate the process of hepatocyte differentiation from ES cells.
Wang X and Halvorsen S W (1998) Reciprocal regulation of ciliary neurotrophic factors and acetylcholine receptors during synaptogenesis in embryonic chick atria J. Neurosci. 18(18), 7372-7380.
Wang X and Halvorsen S W (1998) Retinoic acid up-regulates ciliary neurotrophic factor receptors in cultured chick neurons and cardiomyocytes Neurosci. Lett. 240, 9-12.
Lagasse E, Connors H Al-Dhalimy, M Reitsma, Dohse, M, Osborne L, Wang X, Finegold M., Weissman IL and Grompe M. (2000) Purified Hematopoietic Stem Cells Can Differentiate into Hepatocytes In Vivo. Nature Medicine 6(11), 1229-1234.
Wang X, Al-Dhalimy, M, Lagasse, E, Finegold, M, Grompe, M (2001) Liver repopulation and correction of metabolic liver disease by transplanted adult mouse pancreatic cell. The American Journal of Pathology 158(2), 571- 579.
Wang X, Montini, E, M Al-Dhalimy, M Lagasse, E, Finegold and M Grompe (2002) Kinetics of liver repopulation by bone marrow transplantation. The American Journal of Pathology 161(2), 565-574.
Wang X, Willenbring, H, Akkari, Y, Torimaru, Y, Foster, M, Al-Dhalimy, M, Lagasse, E, Finegold, F, Olson, S, and Markus Grompe. (2003) Cell fusion is the principal source of bone-marrow derived hepatocytes. Nature, Advanced online publication, March 30, 2003.
Wang X, Al-Dhalimy, M, Foster, M, Lagasse, E, Finegold, M, Grompe, M Mouse oval cells are not derived from hepatocytes but can be used for efficient liver repopulation. (In press).