GH enhances proliferation of human hepatocytes grafted into immunodeficient mice with damaged liver.
We investigated effects of human (h) GH on the proliferation of h-hepatocytes that had been engrafted in the liver of albumin enhancer/promoter driven-urokinase plasminogen activator transgenic/severe combined immunodeficiency disease (uPA/SCID) mice (chimeric mice). The h-hepatocytes therein were considered to be deficient in GH, because hGH receptor (hGHR) is unresponsive to mouse GH. Actually, hIGF-1 was undetectable in chimeric mouse sera. The uPA/SCID mice were transplanted with h-hepatocytes from a 6-year (6Y)-old donor, and were injected with recombinant hGH (rhGH). rhGH stimulated the repopulation speed of h-hepatocytes; and up-regulated hIGF-1, human signal transducers and activators of transcription (hSTAT) 3, and cell cycle regulatory genes such as human forkhead box M1, human cell division cycle 25A, and human cyclin D1. To confirm the reproducibility of these effects of rhGH, similar experiments were run using h-hepatocytes from a 46-year (46Y)-old donor. rhGH similarly enhanced their repopulation speed and up-regulated the expression of the above-tested genes, especially hIGF-1 and hSTAT1. The extent of the enhancement by rhGH was much less than that in 6Y-hepatocyte-chimeric mice most probably due to the difference in GHR expression levels between the two donors. In conclusion, this study clearly demonstrated that rhGH stimulates the proliferation of h-hepatocytes in vivo.
Masumoto
Norio
N
Yoshizato Project, Cooperative Link of Unique Science and Technology for Economy Revitalization, Hiroshima Prefectural Institute of Industrial Science and Technology, Higashihiroshima, Hiroshima 739-0046, Japan.
Tateno
Chise
C
Tachibana
Asato
A
Utoh
Rie
R
Morikawa
Yoshio
Y
Shimada
Takashi
T
Momisako
Hiroyuki
H
Itamoto
Toshiyuki
T
Asahara
Toshimasa
T
Yoshizato
Katsutoshi
K
D000418:Albumins / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002678:Chimera; D004742:Enhancer Elements, Genetic; D022781:Hepatocytes / Q000637:transplantation*; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000627:therapeutic use; D013268:Stimulation, Chemical; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D000418:Albumins; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D014568:Urokinase-Type Plasminogen Activator