Therapeutic liver repopulation (TLR) is a process similar to bone marrow transplantation (BMT) resulting in replacement of >90% of hepatocytes in the recipient liver by transplanted donor cells. Although TLR to date has been achieved experimentally only in animal models, spontaneous liver repopulation is known to occur in humans. Therefore the procedure holds great promise for the treatment of human liver diseases, particularly hepatic enzyme deficiencies. Currently, the only cell source available for clinical liver cell therapy are hepatocytes isolated from the livers of beating-heart donors, the same source used to procure whole organs for orthotopic liver transplantation. However, liver stem cells may provide an alternative, more readily available source of hepatocytes. Our findings from the previous funding period make it unlikely that hematopoietic stem cells can be used for liver repopulation anytime soon. For this reason, we will refocus our efforts on the intrahepatic stem cell itself. Preliminary data indicate that hepatic progenitor cells are ischemia resistant and can survive for many hours after death. Cadaveric donors therefore may a useful source of liver repopulating cells. We have developed novel cell surface antibodies for the isolation of hepatocyte precursors from adult mice. The properties of these adult progenitors will be ascertained in vitro (gene expression profiles, clonogenicity, and expandability) and in vivo (repopulation ability) in our Fah knock-out liver repopulating assay.
In Aim 1, we will study the oval cell response as a system to elucidate factors which control hepatic progenitor activation and then test these signals for their ability to expand progenitors from normal mouse liver in Aim 2. To translate insights gained by studying murine progenitor cells to clinical relevance, a robust system for xenogeneic repopulation of mouse liver with human hepatocytes is needed.
In Aim 3, we will validate the Fah knockout model as a user-friendly system for this purpose. Relevance to public health: The studies proposed here will explore intrahepatic stem cells obtained from cadaveric donors as a potential cell source for liver cell therapy. These animal experiments will pave the way for the use of cadaveric human liver progenitors. In addition, the creation of a widely usable murine model for repopulation with human hepatocytes will facilitate translational studies in all areas of liver biology.
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| 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 |
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