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 is viable as a therapeutic strategy. The application has 3 specific aims.
In aim 1 we will elucidate details of how intrahepatic fusion happens. We will determine which bone marrow derived cell type is fusing with hepatocytes, and the frequencies of cell fusion and reprogramming to the hepatocyte fate will be compared. The effects of different kinds of hepatic injury on fusion and reprogramming frequency will also be evaluated.
In aim 2 we will study the properties of fusion derived hepatocytes, especially their cytogenetic properties and their propensity to form tumors.
Aim 3 is geared toward enhancing the efficiency of in vivo fusion and thereby increasing the number of bone marrow derived hepatocytes. Fusogenic viral envelope proteins will be used to artificially induce cell fusion.
| 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 |
| Willenbring, Holger; Bailey, Alexis S; Foster, Mark et al. (2004) Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 10:744-8 |
