Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy
Xiaodan Ren, Cory Hogaboam, Audra Carpenter, Lisa Colletti
Xiaodan Ren, Cory Hogaboam, Audra Carpenter, Lisa Colletti
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Article Hepatology

Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy

Abstract

Stem cell factor (SCF) is a molecule with known proliferative effects on hematopoietic cells. More recent studies suggest that this molecule may also have effects on cellular differentiation and proliferation in other types of cells. The current investigations demonstrate that there is a large reservoir of SCF in the liver, that hepatic SCF levels change dramatically following partial hepatectomy in mice, and that SCF blockade, either by administration of anti-SCF antibodies or by using genetically altered, SCF-deficient mice, inhibits hepatocyte proliferation after partial hepatectomy; if SCF is replaced in the genetically SCF-deficient mice after partial hepatectomy, hepatocyte proliferation is restored to that seen in WT animals. Furthermore, SCF administration to IL-6 knockout mice also restores hepatocyte proliferation to normal. In vitro studies using primary mouse hepatocytes demonstrate that SCF causes hepatocyte proliferation and is induced by IL-6 and that treatment with anti-SCF antibodies inhibits IL-6–induced hepatocyte proliferation. Further in vivo studies in IL-6 knockout mice demonstrate that SCF administration to these animals increases p-stat3 levels, suggesting that the SCF-induced increase in hepatocyte proliferation in this system is stat3-mediated.

Authors

Xiaodan Ren, Cory Hogaboam, Audra Carpenter, Lisa Colletti

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Representative Western blot and associated densitometric analysis for cy...
Representative Western blot and associated densitometric analysis for cytosolic p-stat3 levels in WT and IL-6 knockout mice undergoing hepatectomy with and without SCF treatment. The Western blot is a single representative blot from one group of animals. The graph demonstrates densitometric analysis of three separate Western blots from three groups of animals. The maximum OD for each well was normalized to the maximum OD for the same well for GAPDH to correct for slightly unequal protein loading. The mean and standard errors were then calculated for each group and statistical analysis was performed. These experiments demonstrated that there is a significant decrease in cytosolic p-stat3 levels in IL-6 knockout mice treated with vehicle at 1 and 3 hours after hepatectomy compared with WT animals undergoing hepatectomy and treatment with vehicle (*P < 0.05, IL-6 knockout mice + vehicle vs. all other treatment groups at that timepoint). Furthermore, treatment of IL-6 knockout mice with SCF restores cytosolic p-stat3 levels to those of WT animals treated with vehicle, that is, there was no significant difference between cytosolic p-stat3 levels in IL-6 knockout mice receiving SCF after hepatectomy vs. WT animals undergoing hepatectomy; p-stat3 levels in IL-6 knockout mice receiving SCF and hepatectomy were significantly increased compared with IL-6 knockout mice undergoing hepatectomy alone. In addition, treatment of WT mice with SCF in the setting of partial hepatectomy significantly increased cytosolic p-stat3 levels in these animals compared with WT animals undergoing hepatectomy alone. #P < 0.05, WT + SCF vs. WT + vehicle at the same timepoint.