Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy
Xiaodan Ren, … , Audra Carpenter, Lisa Colletti
Xiaodan Ren, … , Audra Carpenter, Lisa Colletti
Published November 1, 2003
Citation Information: J Clin Invest. 2003;112(9):1407-1418. https://doi.org/10.1172/JCI17391.
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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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Liver weight/total body weight ratios and BrdU staining in WT and IL-6 k...
Liver weight/total body weight ratios and BrdU staining in WT and IL-6 knockout mice after 70% hepatectomy with and without SCF treatment. Liver weight/total body weight ratios and BrdU staining as an estimate of hepatocyte proliferation were measured in mice over time. Four treatment groups were studied: WT + vehicle, WT + SCF, IL-6 knockout + vehicle, and IL-6 knockout + SCF. (a) Beginning 72 hours after hepatectomy, liver weight/total body weight ratios in IL-6 knockout mice treated with vehicle are significantly decreased compared with the other three treatment groups, and this difference continues to 120 hours. *P < 0.05, IL-6 knockout + vehicle vs. all other groups. There was no significant difference noted between IL-6 knockout mice treated with SCF and WT animals treated with vehicle or SCF. Data are expressed as mean ± SEM. (b) At 36 hours after hepatectomy, there was a significant increase in hepatocyte proliferation in IL-6 knockout animals treated with SCF (#P < 0.05 vs. all other treatment groups). At 48 hours of incubation, the proliferation measured in IL-6 knockout animals treated with vehicle was significantly decreased compared with all other treatment groups (*P < 0.01 vs. all other groups). By 60 hours after hepatectomy, proliferation in IL-6 knockout mice treated with vehicle was still significantly decreased compared with WT animals treated with vehicle or SCF (**P < 0.05 vs. WT + vehicle and WT + SCF); however, there was no longer a difference between IL-6 knockout mice treated with vehicle and IL-6 knockout mice treated with SCF.