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Originally published online as doi:10.2353/ajpath.2009.090117 on August 28, 2009

Published online before print August 28, 2009
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(American Journal of Pathology. 2009;175:1483-1492.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090117

Repopulation Efficiencies of Adult Hepatocytes, Fetal Liver Progenitor Cells, and Embryonic Stem Cell-Derived Hepatic Cells in Albumin-Promoter-Enhancer Urokinase-Type Plasminogen Activator Mice

Dhivya Haridass*, Qinggong Yuan*, Pablo D. Becker{dagger}, Tobias Cantz{ddagger}, Marcus Iken*, Michael Rothe*, Nidhi Narain*, Michael Bock*, Miriam Nörder{dagger}, Nicolas Legrand§, Heiner Wedemeyer*, Kees Weijer§, Hergen Spits§, Michael P. Manns*, Jun Cai, Hongkui Deng, James P. Di Santo||**, Carlos A. Guzman{dagger} and Michael Ott*

From the Department of Gastroenterology, Hepatology, and Endocrinology,* Hannover Medical School and Twincore Centre of Experimental and Clinical Infection Research, Hannover, Germany; the Department of Vaccinology and Applied Microbiology,{dagger} Helmholtz Center for Infection Research, Braunschweig, Germany; the Junior Research Group,{ddagger} "Stem Cell Biology," Cluster-of-Excellence REBIRTH, Hannover Medical School, Hannover, Germany; the Department of Cell Biology and Histology,§ Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands; the Department of Cell Biology and Genetics, College of Life Sciences, Beijing University, Beijing, China; and the Cytokines and Lymphoid Development Unit,|| Immunology Department, Institut Pasteur, Paris, France; and Inserm U668,** Paris, France

Fetal liver progenitor cell suspensions (FLPC) and hepatic precursor cells derived from embryonic stem cells (ES-HPC) represent a potential source for liver cell therapy. However, the relative capacity of these cell types to engraft and repopulate a recipient liver compared with adult hepatocytes (HC) has not been comprehensively assessed. We transplanted mouse and human HC, FLPC, and ES-HPC into a new immunodeficient mouse strain (Alb-uPAtg(+/–)Rag2(–/–){gamma}c(–/–) mice) and estimated the percentages of HC after 3 months. Adult mouse HC repopulated approximately half of the liver mass (46.6 ± 8.0%, 1 x 106 transplanted cells), whereas mouse FLPC derived from day 13.5 and 11.5 post conception embryos generated only 12.1 ± 3.0% and 5.1 ± 1.1%, respectively, of the recipient liver and smaller cell clusters. Adult human HC and FLPC generated overall less liver tissue than mouse cells and repopulated 10.0 ± 3.9% and 2.7 ± 1.1% of the recipient livers, respectively. Mouse and human ES-HPC did not generate HC clusters in our animal model. We conclude that, in contrast to expectations, adult HC of human and mouse origin generate liver tissue more efficiently than cells derived from fetal tissue or embryonic stem cells in a highly immunodeficient Alb-uPA transgenic mouse model system. These results have important implications in the context of selecting the optimal strategy for human liver cell therapies.






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