Hepatic stellate cells' involvement in progenitor-mediated liver regeneration.
Earlier studies conducted by our laboratory have shown that suppression of transforming growth factor-beta (TGFbeta)-mediated upregulation of connective tissue growth factor (CTGF) by iloprost resulted in a greatly diminished oval cell response to 2-acetylaminofluorene/partial hepatectomy (2AAF/PH) in rats. We hypothesized that this effect is due to decreased activation of hepatic stellate cells. To test this hypothesis, we maintained rats on a diet supplemented with 2% L-cysteine as a means of inhibiting stellate cell activation during the oval cell response to 2AAF/PH. In vitro experiments show that L-cysteine did, indeed, prevent the activation of stellate cells while exerting no direct effect on oval cells. Desmin immunostaining of liver sections from 2AAF/PH animals indicated that maintenance on the L-cysteine diet resulted in an 11.1-fold decrease in the number of activated stellate cells within the periportal zones. The total number of cells proliferating in the periportal zones of livers from animals treated with L-cysteine was drastically reduced. Further analyses showed a greater than fourfold decrease in the magnitude of the oval cell response in animals maintained on the L-cysteine diet as determined by immunostaining for both OV6 and alpha-fetoprotein (AFP). Global liver expression of AFP as measured by real-time PCR was shown to be decreased 4.7-fold in the L-cysteine-treated animals. These data indicate that the activation of hepatic stellate cells is required for an appropriate oval cell response to 2AAF/PH.
Pintilie
Dana G
DG
Department of Pathology, Immunology and Laboratory Medicine, Program for Stem Cell Biology and Regenerative Medicine, University of Florida College of Medicine, Gainesville, FL 32610-0275, USA.
Shupe
Thomas D
TD
Oh
Seh-hoon
SH
Salganik
Susan V
SV
Darwiche
Houda
H
Petersen
Bryon E
BE
D015073:2-Acetylaminofluorene / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D055513:Connective Tissue Growth Factor; D003545:Cysteine / Q000378:metabolism / Q000494:pharmacology; D006498:Hepatectomy; D055166:Hepatic Stellate Cells / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D000509:alpha-Fetoproteins / Q000378:metabolism / Q000494:pharmacology
D016212:Transforming Growth Factor beta; D000509:alpha-Fetoproteins; D055513:Connective Tissue Growth Factor; D015073:2-Acetylaminofluorene; D003545:Cysteine