Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1
Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1
复制标题
DOI：
10.1074/jbc.m109.052530
复制
发表时间：
2009-10-09
影响因子：
4.8
通讯作者：
Liu, Lin
中科院分区：
文献类型：
--
作者：
Weng, Tingting;Gao, Li;Liu, Lin
本研究探讨了多营养素在胎肺发育中的作用。我们发现，多营养素及其受体蛋白酪氨酸磷酸酶受体β/Zeta分别在胎肺间充质细胞和上皮细胞中高表达。利用分离的胎儿肺泡II型上皮细胞，我们证明了多营养素促进了胎儿II型细胞的增殖，并抑制了II型细胞向I型肺泡上皮细胞的转分化。Pleiotroin还可促进损伤的II型细胞单层的伤口愈合。在胎肺器官培养模型中，抑制多营养素影响肺分支形态发生。增殖素促进β-连环蛋白酪氨酸磷酸化，促进β-连环蛋白转位到细胞核内，并激活T细胞因子/淋巴增强因子转录因子。Diu是一种启动Notch信号通路的膜配体，通过内源性dlk1表达、启动子分析和染色质免疫沉淀被鉴定为多营养素/β-连环蛋白通路的下游靶点。这些结果表明，多营养素通过整合多种信号通路，包括多营养素、β-连环蛋白和Notch通路来调节胎儿II型细胞的增殖和分化。
The role of pleiotrophin in fetal lung development was investigated. We found that pleiotrophin and its receptor, protein-tyrosine phosphatase receptor beta/zeta, were highly expressed in mesenchymal and epithelial cells of the fetal lungs, respectively. Using isolated fetal alveolar epithelial type II cells, we demonstrated that pleiotrophin promoted fetal type II cell proliferation and arrested type II cell trans-differentiation into alveolar epithelial type I cells. Pleiotrophin also increased wound healing of injured type II cell monolayer. Knockdown of pleiotrophin influenced lung branching morphogenesis in a fetal lung organ culture model. Pleiotrophin increased the tyrosine phosphorylation of beta-catenin, promoted beta-catenin translocation into the nucleus, and activated T cell factor/lymphoid enhancer factor transcription factors. DIU, a membrane ligand that initiates the Notch signaling pathway, was identified as a downstream target of the pleiotrophin/beta-catenin pathway by endogenous dlk1 expression, promoter assay, and chromatin immunoprecipitation. These results provide evidence that pleiotrophin regulates fetal type II cell proliferation and differentiation via integration of multiple signaling pathways including pleiotrophin, beta-catenin, and Notch pathways.