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.
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-uPA(tg(+/-))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 10(6) 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.
Haridass
Dhivya
D
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School and Twincore Centre for Experimental and Clinical Infection Research, Hannover 30625, Germany.
Yuan
Qinggong
Q
Becker
Pablo D
PD
Cantz
Tobias
T
Iken
Marcus
M
Rothe
Michael
M
Narain
Nidhi
N
Bock
Michael
M
Nörder
Miriam
M
Legrand
Nicolas
N
Wedemeyer
Heiner
H
Weijer
Kees
K
Spits
Hergen
H
Manns
Michael P
MP
Cai
Jun
J
Deng
Hongkui
H
Di Santo
James P
JP
Guzman
Carlos A
CA
Ott
Michael
M
D000328:Adult; D000418:Albumins / Q000235:genetics*; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005333:Fetus / Q000166:cytology*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D033581:Stem Cell Transplantation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000378:metabolism
D000418:Albumins; D000509:alpha-Fetoproteins; D014568:Urokinase-Type Plasminogen Activator