Stem cell factor and its receptor, c-kit, are important for hepatocyte proliferation in wild-type and tumor necrosis factor receptor-1 knockout mice after 70% hepatectomy

Surgery. 2008 Jun;143(6):790-802. doi: 10.1016/j.surg.2008.03.021.

Abstract

Background: Stem cell factor (SCF) has well-known proliferative effects on hematopoietic cells. SCF also has effects on differentiation and proliferation in other cell types. Interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha have proliferative effects in the liver. Recent studies in our laboratory have linked SCF's hepatoproliferative actions to those of IL-6, demonstrating that IL-6-induced hepatocyte proliferation depends, at least in part, on SCF. We now hypothesize that TNF-alpha's hepatoproliferative effects are also dependent on SCF.

Methods and results: In vitro studies using primary mouse hepatocytes show that SCF is induced by TNF-alpha; anti-SCF antibody treatment in this system inhibits TNF-alpha-induced hepatocyte proliferation, suggesting that TNF-alpha-induced hepatocyte proliferation is also SCF dependent. Additional in vivo experiments were performed in which wild type and/or TNF-alpha receptor-1 knockout mice (TNFR1(-/-)) were subjected to 70% hepatectomy or sham laparotomy. TNFR1(-/-) mice are known to have delayed hepatic regeneration after partial hepatectomy. Initial experiments demonstrated that the SCF receptor, c-kit, is upregulated after partial hepatectomy in wild-type mice, further emphasizing the importance of this system in the restoration of hepatic mass. SCF administration to TNFR1(-/-) mice in the context of partial hepatectomy restores hepatocyte proliferation to normal. Further, SCF administration to TNFR1(-/-) mice before hepatectomy increases phosphotyrosine signal transducer and activator (p-stat-3) levels, suggesting that SCF-induced increases in hepatocyte proliferation may also be stat-3 mediated.

Conclusions: These data suggest that TNF-alpha-induced hepatocyte proliferation depends, at least in part, on SCF and that SCF and its receptor, c-kit, are important for the liver's regenerative processes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Hepatectomy*
  • Hepatocyte Growth Factor / metabolism
  • Hepatocytes / cytology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Interleukin-6 / metabolism
  • Liver / cytology
  • Liver / metabolism
  • Liver / surgery
  • Liver Regeneration / physiology
  • Male
  • Mice
  • Mice, Inbred CBA
  • Mice, Knockout
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / physiology
  • Stem Cell Factor / metabolism*
  • Stem Cell Factor / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Interleukin-6
  • Receptors, Tumor Necrosis Factor, Type I
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Stem Cell Factor
  • Tumor Necrosis Factor-alpha
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-kit