Tyrosinemia type I (HT) is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Its main clinical features include progressive liver failure, renal tubular damage and liver cancer. Recently we have created a murine model of FAH deficiency by gene knock-out in embryonic stem cells. Affected animals display a complex phenotype of hepatic dysfunction and neonatal death. The drug NTBC corrects liver dysfunction and neonatal lethality and withdrawal of this medication at a later age gives rise to a phenotype similar to human HT 1. FAH deficiency induces progressive hepatocellular damage and we have recently shown that metabolically corrected hepatocytes have a strong selective growth advantage over deficient cells. Because of this in vivo selection, transplantation of wild-type hepatocytes can lead to a complete repopulation of FAH deficient liver. This repopulation is clonal and nodular and can be affected by as few as 1,000 donor cells. We will use this repopulation assay to determine the nature of the repopulating cells (number, size, differentiation phenotype) in mouse liver. The effects of liver injury and developmental stages (fetal, newborn, adult) on the repopulating cells will be determined. FAH deficient hepatocytes, which have been transduced with a FAH expressing retrovirus have the same selective advantage as transplanted wild-type cells. We will use retroviral marking to trace the lineage and regenerative potential of infected liver cells. By crossbreeding to SCID mice, we will also create an immune deficient FAH mutant mouse. These animals will be used to develop an analogous liver repopulation assay for xenogeneic donor hepatocytes from rat, primates and humans.
| Li, Bin; Dorrell, Craig; Canaday, Pamela S et al. (2017) Adult Mouse Liver Contains Two Distinct Populations of Cholangiocytes. Stem Cell Reports 9:478-489 |
| Kopp, Janel L; Grompe, Markus; Sander, Maike (2016) Stem cells versus plasticity in liver and pancreas regeneration. Nat Cell Biol 18:238-45 |
| Naugler, Willscott E; Tarlow, Branden D; Fedorov, Lev M et al. (2015) Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers. Gastroenterology 149:728-40.e15 |
| Tarlow, Branden D; Finegold, Milton J; Grompe, Markus (2014) Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60:278-89 |
| Tarlow, Branden D; Pelz, Carl; Naugler, Willscott E et al. (2014) Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15:605-18 |
| Dorrell, Craig; Tarlow, Branden; Wang, Yuhan et al. (2014) The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar. Stem Cell Res 13:275-83 |
| Gramignoli, Roberto; Tahan, Veysel; Dorko, Kenneth et al. (2013) New potential cell source for hepatocyte transplantation: discarded livers from metabolic disease liver transplants. Stem Cell Res 11:563-73 |
| Grompe, Markus; Strom, Stephen (2013) Mice with human livers. Gastroenterology 145:1209-14 |
| Huch, Meritxell; Dorrell, Craig; Boj, Sylvia F et al. (2013) In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494:247-50 |
| Vaughan, Ashley M; Mikolajczak, Sebastian A; Wilson, Elizabeth M et al. (2012) Complete Plasmodium falciparum liver-stage development in liver-chimeric mice. J Clin Invest 122:3618-28 |
Showing the most recent 10 out of 18 publications
