Hepatic hyperplasia associated with discordant xenogeneic parenchymal-nonparenchymal interactions in human hepatocyte-repopulated mice.
Liver mass is optimized in relation to body mass. Rat (r) and human (h) hepatocytes were transplanted into liver-injured immunodeficient mice and allowed to proliferate for 3 or 11 weeks, respectively, when the transplants stopped proliferating. Liver/body weight ratio was normal throughout in r-hepatocyte-bearing mice (r-hep-mice), but increased continuously in h-hepatocyte-bearing mice (h-hep-mice), until reaching approximately three times the normal m-liver size, which was considered to be hyperplasia of h-hepatocytes because there were no significant differences in cell size among host (mouse [m-]) and donor (r- and h-) hepatocytes. Transforming growth factor-beta (TGF-beta) type I receptor, TGF-beta type II receptor, and activin A type IIA receptor mRNAs in proliferating r-hepatocytes of r-hep-mice were lower than in resting r-hepatocytes (normal levels) and increased to normal levels during the termination phase. Concomitantly, m-hepatic stellate cells began to express TGF-beta proteins. In stark contrast, TGF-beta type II receptor and activin A type IIA receptor mRNAs in h-hepatocytes remained low throughout and m-hepatic stellate cells did not express TGF-beta in h-hep-mice. As expected, Smad2 and 3 translocated into nuclei in r-hep-mice but not in h-hep-mice. Histological analysis showed a paucity of m-stellate cells in h-hepatocyte colonies of h-hep-mouse liver. We conclude that m-stellate cells are able to normally interact with concordant r-hepatocytes but not with discordant h-hepatocytes, which seems to be at least partly responsible for the failure of the liver size optimization in h-hep-mice.
Utoh
Rie
R
Yoshizato Project, Cooperative Link of Unique Science and Technology for Economy Revitalization, Hiroshima Prefectural Institute of Industrial Science and Technology, Hiroshima, Japan.
Tateno
Chise
C
Kataoka
Miho
M
Tachibana
Asato
A
Masumoto
Norio
N
Yamasaki
Chihiro
C
Shimada
Takashi
T
Itamoto
Toshiyuki
T
Asahara
Toshimasa
T
Yoshizato
Katsutoshi
K
D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology*; D007223:Infant; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030301:Activin Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625843:Tgfbr1 protein, rat; C425585:activin receptor type II-A