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

• Published in: Surgery 2008-06, Vol.143 (6), p.790-802
• Main Authors: Ren, Xiaodan, MD, Hu, Bin, MD, PhD, Colletti, Lisa, MD
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Proliferation - drug effects; Cells, Cultured; General aspects; Hepatectomy; Hepatocyte Growth Factor - metabolism; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Interleukin-6 - metabolism; Liver - cytology; Liver - metabolism; Liver - surgery; Liver Regeneration - physiology; Liver, biliary tract, pancreas, portal circulation, spleen; Male; Medical sciences; 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; Signal Transduction - physiology; STAT3 Transcription Factor - metabolism; Stem Cell Factor - metabolism; Stem Cell Factor - pharmacology; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/j.surg.2008.03.021

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)-α 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-α'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-α; anti-SCF antibody treatment in this system inhibits TNF-α–induced hepatocyte proliferation, suggesting that TNF-α–induced hepatocyte proliferation is also SCF dependent. Additional in vivo experiments were performed in which wild type and/or TNF-α 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-α–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.