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

• Published in: The American journal of pathology Vol. 175; no. 4; pp. 1483 - 1492
• Main Authors: Haridass, Dhivya, Yuan, Qinggong, Becker, Pablo D, Cantz, Tobias, Iken, Marcus, Rothe, Michael, Narain, Nidhi, Bock, Michael, Nörder, Miriam, Legrand, Nicolas, Wedemeyer, Heiner, Weijer, Kees, Spits, Hergen, Manns, Michael P, Cai, Jun, Deng, Hongkui, Di Santo, James P, Guzman, Carlos A, Ott, Michael
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.10.2009; ASIP; American Society for Investigative Pathology
• Subjects: Adult; Albumins - genetics; alpha-Fetoproteins - metabolism; Animals; Biological and medical sciences; Cell Movement; Cell Proliferation; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Enhancer Elements, Genetic - genetics; Fetus - cytology; Hepatocytes - cytology; Hepatocytes - metabolism; Hepatocytes - transplantation; Humans; Investigative techniques, diagnostic techniques (general aspects); Liver - cytology; Liver - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Stem Cell Transplantation; Urokinase-Type Plasminogen Activator - metabolism; Human; u-Plasminogen activator; Serine endopeptidases; Digestive system; Enzyme; Stem cell; Liver; Rodentia; Albumin; Promoter; Peptidases; Vertebrata; Anatomic pathology; Mammalia; Fetal cell; Hepatocyte; Mouse; Embryonic cell; Efficiency; Animal; Hydrolases; Adult; Progenitor cell
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.090117

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(−/−) γc(−/−) 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 × 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.