These authors contributed equally to the manuscript for this article.
Article first published online: 21 DEC 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 1, pages 209–221, January 2012
How to Cite
Meng, F., Francis, H., Glaser, S., Han, Y., DeMorrow, S., Stokes, A., Staloch, D., Venter, J., White, M., Ueno, Y., Reid, L. M. and Alpini, G. (2012), Role of stem cell factor and granulocyte colony-stimulating factor in remodeling during liver regeneration. Hepatology, 55: 209–221. doi: 10.1002/hep.24673
Potential conflict of interest: Nothing to report.
This study was supported by the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White, a Veterans Affairs Research Career Scientist Award, a Veterans Award Merit Award, and National Institutes of Health grants DK58411 and DK76898 (to G.A.).
- Issue published online: 21 DEC 2011
- Article first published online: 21 DEC 2011
- Accepted manuscript online: 19 SEP 2011 09:04AM EST
- Manuscript Accepted: 30 AUG 2011
- Manuscript Received: 30 JUN 2011
- Veterans Affairs Research Career Scientist Award
- National Institutes of Health. Grant Numbers: DK58411, DK76898
Functional pluripotent characteristics have been observed in specific subpopulations of hepatic cells that express some of the known cholangiocyte markers. Although evidence indicates that specific cytokines, granulocyte macrophage colony-stimulating factors (GM-CSFs), and stem cell factors (SCFs) may be candidate treatments for liver injury, the role of these cytokines in intrahepatic biliary epithelium remodeling is unknown. Thus, our aim was to characterize the specific cytokines that regulate the remodeling potentials of cholangiocytes after 70% partial hepatectomy (PH). The expression of the cytokines and their downstream signaling molecules was studied in rats after 70% PH by immunoblotting and in small and large murine cholangiocyte cultures (SMCCs and LMCCs) by immunocytochemistry and real-time polymerase chain reaction (PCR). There was a significant, stable increase in SCF and GM-CSF levels until 7 days after PH. Real-time PCR analysis revealed significant increases of key remodeling molecules, such as S100 calcium-binding protein A4 (S100A4) and miR-181b, after SCF plus GM-CSF administration in SMCCs. SMCCs produced significant amounts of soluble and bound SCFs and GM-CSFs in response to transforming growth factor-beta (TGF-β). When SMCCs were incubated with TGF-β plus anti-SCF+GM-CSF antibodies, there was a significant decrease in S100A4 expression. Furthermore, treatment of SMCCs with SCF+GM-CSF significantly increased matrix metalloproteinases (MMP-2 and MMP-9) messenger RNA as well as miR-181b expression, along with a reduction of metalloproteinase inhibitor 3. Levels of MMP-2, MMP-9, and miR-181b were also up-regulated in rat liver and isolated cholangiocytes after PH. Conclusion: Our data suggest that altered expression of SCF+GM-CSF after PH can contribute to biliary remodeling (e.g., post-transplantation) by functional deregulation of the activity of key signaling intermediates involved in cell expansion and multipotent differentiation. (HEPATOLOGY 2012;;55:209–221)