Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes
Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes
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DOI：
10.1007/s00441-005-0077-0
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发表时间：
2006-02-01
影响因子：
3.6
通讯作者：
Okita, K
中科院分区：
文献类型：
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作者：
Ishikawa, T;Terai, S;Okita, K
我们已经开发了一种体内小鼠模型，即绿色荧光蛋白（GFP）/四氯化碳（CCl4）模型，并且先前已经报道了移植的GFP阳性骨髓细胞（BMC）通过成肝细胞中间体分化为肝细胞。在这里，我们研究了与移植的BMCs分化为肝细胞密切相关的生长因子，以及特定生长因子影响GFP/CCl4模型中分化过程的方式。我们进行了免疫组织化学分析，以确定一个重要的生长因子在我们的模型，即，成纤维细胞生长因子（FGF）。在肝脏样本中，与其他因素相比，骨髓移植（BMT）后，FGF1和FGF2以及FGF受体（FGFRs; FGFR1，FGFR2）的表达随着时间的推移而显著升高，并且可以检测到GFP和FGF或FGFRs的共表达。然后，我们通过免疫组织化学、免疫印迹和微阵列分析来分析FGF信号传导对BMC向肝细胞分化的促进作用和分子机制。重组FGF（rFGF），特别是rFGF 2的治疗，提高了GFP阳性细胞在肝脏中的再增殖率，并显着增加Liv2（肝细胞标志物）和白蛋白（肝细胞标志物）的表达。在BMT中施用rFGF2还提高血清白蛋白水平并改善存活率。移植具有rFGF 2的BMC特异性激活肿瘤坏死因子-α（TNF-α）信号传导。因此，FGF2通过激活TNF-α信号传导促进移植的BMC经由Liv2阳性成肝细胞中间体分化为产生白蛋白的肝细胞。FGF2与BMT联合给药可改善CCl4诱导的肝损伤小鼠的肝功能和预后
We have developed an in vivo mouse model, the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model, and have previously reported that transplanted GFP-positive bone marrow cells (BMCs) differentiate into hepatocytes via hepatoblast intermediates. Here, we have investigated the growth factors that are closely related to the differentiation of transplanted BMCs into hepatocytes, and the way that a specific growth factor affects the differentiation process in the GFP/CCl4 model. We performed immunohistochemical analysis to identify an important growth factor in our model, viz., fibroblast growth factor (FGF). In liver samples, the expression of FGF1 and FGF2 and of FGF receptors (FGFRs; FGFR1, FGFR2) was significantly elevated with time after bone marrow transplantation (BMT) compared with other factors, and co-expression of GFP and FGFs or FGFRs could be detected. We then analyzed the effect and molecular mechanism of FGF signaling on the enhancement of BMC differentiation into hepatocytes by immunohistochemistry, immunoblotting, and microarray analysis. Treatment with recombinant FGF (rFGF), especially rFGF2, elevated the repopulation rate of GFP-positive cells in the liver and significantly increased the expression of both Liv2 (hepatoblast marker) and albumin (hepatocyte marker). Administration of rFGF2 at BMT also raised serum albumin levels and improved the survival rate. Transplantation of BMCs with rFGF2 specifically activated tumor necrosis factor-alpha (TNF-alpha) signaling. Thus, FGF2 facilitates the differentiation of transplanted BMCs into albumin-producing hepatocytes via Liv2-positive hepatoblast intermediates through the activation of TNF-alpha signaling. Administration of FGF2 in combination with BMT improves the liver function and prognosis of mice with CCl4-induced liver damage.