Hepatocytes derived by cell fusion of transplanted bone marrow cells have the capacity to proliferate and completely restore abnormal liver function in an animal model of metabolic liver disease, the fumarylacetoacetate hydrolase (Fah) knockout mouse. However, spontaneous fusion is a very rare event and remains far below the threshold required for therapeutic utility unless the fusion products have a strong selective growth advantage. Furthermore, basic properties of fusion-derived hepatocytes such as genomic stability, centrosome number and efficiency of nuclear reprogramming are unknown. The overall goal of this application is to determine whether in vivo cell fusion could be a viable therapeutic strategy. To achieve this goal we will clarify some of the basic processes that lead to cell fusion in the liver. We will also delineate the properties of early and late fusion products. Finally, methods to enhance the efficiency of cell fusion in vivo will be studied.
Aim 1 : To elucidate details of the intrahepatic fusion process.
Aim 2 : To determine relevant properties of fusion-derived hepatocytes.
Aim 3 : To enhance in vivo cell fusion by expression of fusogenic viral envelope proteins. ? ? ?
| Duncan, Andrew W; Hanlon Newell, Amy E; Bi, Weimin et al. (2012) Aneuploidy as a mechanism for stress-induced liver adaptation. J Clin Invest 122:3307-15 |
| Duncan, Andrew W; Hanlon Newell, Amy E; Smith, Leslie et al. (2012) Frequent aneuploidy among normal human hepatocytes. Gastroenterology 142:25-8 |
| Duncan, Andrew W; Taylor, Matthew H; Hickey, Raymond D et al. (2010) The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 467:707-10 |
| Duncan, Andrew W; Hickey, Raymond D; Paulk, Nicole K et al. (2009) Ploidy reductions in murine fusion-derived hepatocytes. PLoS Genet 5:e1000385 |
| Duncan, Andrew W; Dorrell, Craig; Grompe, Markus (2009) Stem cells and liver regeneration. Gastroenterology 137:466-81 |
