Liver Regeneration is Impaired in Macrophage Colony Stimulating Factor Deficient Mice After Partial Hepatectomy: The Role of M-CSF-Induced Macrophages
Liver Regeneration is Impaired in Macrophage Colony Stimulating Factor Deficient Mice After Partial Hepatectomy: The Role of M-CSF-Induced Macrophages
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DOI：
10.1016/j.jss.2009.08.008
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发表时间：
2011-01-01
影响因子：
2.2
通讯作者：
Fujii, Hideki
中科院分区：
文献类型：
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作者：
Amemiya, Hidetake;Kono, Hiroshi;Fujii, Hideki
巨噬细胞集落刺激因子（M-CSF）诱导巨噬细胞成熟，在肝脏中显著表达。因此，本研究的具体目的是研究M-CSF在部分肝切除术（PH）后肝再生中的作用。骨硬化（OP/OP）小鼠，遗传缺乏功能性M-CSF，或其同窝小鼠经历70% PH。动物在PH后的指定时间点处死，并收获残余肝组织用于进一步研究。以BrdU表达和肝体质量比评价肝细胞增殖。测量TNF-α和IL-6的mRNA表达水平以及磷酸化（p）STAT 3的蛋白表达水平。免疫组化法测定枯否细胞（KCs）的数量。此外，从op/op小鼠或同窝小鼠分离KC，并在用LPS刺激后评估TNF-α和IL-6的mRNA表达水平。在同窝小鼠中，观察到稳定的肝再生。与先前报道的同窝小鼠相比，OP/OP小鼠中的KC数量显著减少约60%。此外，这些细胞在形态上较小且不成熟。在同窝小鼠中，在PH后1h观察到TNF-α和IL-6在肝脏中的峰值表达水平，这与先前报道的数据一致。相反，在op/op小鼠中，PH后3 h观察到峰值表达水平，并且与同窝小鼠相比显著较低。结果，肝细胞的增殖在op/op小鼠中显著受损。与同窝小鼠相比，LPS刺激后，OP/OP小鼠分离的KC中IL-6的mRNA表达水平显著降低，但TNF-α的mRNA表达水平没有显著降低，这表明OP/OP小鼠和同窝小鼠的KC的功能不同。为了阐明M-CSF在肝再生中的作用，op/op小鼠在PH前2d腹腔内接受小鼠重组M-CSF，并评估肝再生。结果，在用M-CSF处理的op/op小鼠中，枯否细胞数量和肝再生恢复到与其同窝小鼠相似的程度。因此，M-CSF诱导的肝巨噬细胞在PH后的肝再生中起重要作用。（C）2011 Elsevier Inc. All rights reserved.
Macrophage colony stimulating factor (M-CSF), which induces maturation of macrophages, is notably expressed in the liver. Thus, the specific purpose of this study was to investigate the role of M-CSF in liver regeneration after partial hepatectomy (PH). Osteopetrotic (op/op) mice, genetically lacking functional M-CSF, or their littermate mice underwent 70% PH. Animals were sacrificed at the designated time points after PH, and remnant liver tissues were harvested for further investigations. Proliferation of hepatocytes was evaluated by the expression of BrdU and the liver-body weight ratio. The mRNA expression levels of TNF-alpha and IL-6 and protein expression levels of phosphorylated (p) STAT3 were measured. The number of Kupffer cells (KCs) was determined by immunohistochemistry. Furthermore, KCs were isolated from op/op mice or littermate mice, and mRNA expression levels of TNF-a and IL-6 were assessed after stimulation with LPS. In littermate mice, steady liver regeneration was observed. The number of KCs reduced markedly by about 60% in the op/op mice compared with littermates as reported previously. Furthermore, these cells were morphologically small and immature. In littermate mice, the peak expression levels of TNF-a and IL-6 in the liver was observed 1h after PH, which was consistent with data in previous reports. In contrast, in op/op mice, the peak expression levels were observed 3 h after PH and were significantly lower compared with littermate mice. As a result, the proliferation of hepatocytes was significantly impaired in op/op mice. The mRNA expression level of IL-6, but not TNF-a, was significantly reduced in isolated KCs from op/op mice compared with the litter-mates after stimulation with LPS, suggesting that the function of KCs is different between op/op mice and littermate mice. To clarify the role of M-CSF in liver regeneration, op/op mice received intraperitoneally, mouse recombinant M-CSF 2 d before PH, and liver regeneration was also assessed. As a result, the numbers of Kupffer cells and liver regeneration were recovered in the op/op mice treated with M-CSF to a similar extent to those in their littermates. Thus, M-CSF-induced hepatic macrophages play an important role in liver regeneration after PH. (C) 2011 Elsevier Inc. All rights reserved.