title: Role of stem cell factor and granulocyte colony-stimulating factor in remodeling during liver regeneration.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX 76504, USA.
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Han
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.forename: Allison
authors.initials: A
authors.lastname: Stokes
authors.forename: Dustin
authors.initials: D
authors.lastname: Staloch
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Melanie
authors.initials: M
authors.lastname: White
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.forename: Lola M
authors.initials: LM
authors.lastname: Reid
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D016207:Cytokines / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019089:Stem Cell Factor / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016207:Cytokines; D035683:MicroRNAs; D016184:Receptors, Colony-Stimulating Factor; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; D016179:Granulocyte Colony-Stimulating Factor; D019278:Matrix Metalloproteinase 3