Heparan sulfates expressed in the distal lung are required for Fgf10 binding to the epithelium and for airway branching
Heparan sulfates expressed in the distal lung are required for Fgf10 binding to the epithelium and for airway branching
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DOI：
10.1152/ajplung.00081.2003
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发表时间：
2003-10-01
影响因子：
4.9
通讯作者：
Cardoso, WV
中科院分区：
文献类型：
--
作者：
Izvolsky, KI;Zhong, L;Cardoso, WV
成纤维细胞生长因子（Fgf）10是肺形态发生过程中芽形成的关键调节因子。fgf 10在远端肺间充质中从最早发育阶段的预期出芽位点表达，并通过其上皮受体Fgfr 2b发出信号。在完整肺器官培养物中的实验表明，Fgf 10是远端上皮细胞的趋化因子，但不是近端上皮细胞的趋化因子。这种不同的反应表明参与了调节Fgf 10-Fgfr 2b相互作用的额外机制，因为Fgfr 2b在整个呼吸道中均匀表达。在这里，我们使用一种基于荧光化学的结合试验，以表明O-硫酸乙酰肝素硫酸盐（HS）是Fgf 10结合到远端上皮细胞的关键。我们表明，在肺器官培养物中，用氯酸钠或过度硫酸化的合成肝素改变HS硫酸化的内源性梯度可显着降低Fgf 10结合。此外，我们表明，在这些条件下，上皮细胞的结合并没有通过提供外源性FGF 10得到改善。我们的数据表明，不仅配体的可用性，但也存在特定模式的HS修改在远端肺上皮细胞的Fgf 10结合上皮细胞和信号的关键决定因素。
Fibroblast growth factor (Fgf) 10 is a critical regulator of bud formation during lung morphogenesis. fgf10 is expressed in distal lung mesenchyme at sites of prospective budding from the earliest developmental stages and signals through its epithelial receptor Fgfr2b. Experiments in intact lung organ cultures demonstrate that Fgf10 is a chemotactic factor for distal, but not for proximal, epithelium. This differential response suggests the involvement of an additional mechanism regulating Fgf10-Fgfr2b interactions, because Fgfr2b is uniformly expressed throughout the respiratory tract. Here we use an immunohistochemistry-based binding assay to show that O-sulfated heparan sulfates (HS) are critical for Fgf10 binding to the distal epithelium. We show that altering endogenous gradients of HS sulfation with sodium chlorate or over-O-sulfated synthetic heparin in lung organ cultures dramatically decreases Fgf10 binding. Moreover, we show that under these conditions epithelial binding is not improved by providing exogenous FGF10. Our data suggest that, not only ligand availability, but also the presence of specific patterns of HS modification in the distal lung epithelium are critical determinants of Fgf10 binding to the epithelium and signaling.