ARDS时Wnt/β-catenin-p130/E2F4调控细胞周期影响MSC向肺泡上皮分化的机制研究

项目名称： ARDS时Wnt/β-catenin-p130/E2F4调控细胞周期影响MSC向肺泡上皮分化的机制研究

项目编号： No.81471843

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 郭凤梅

作者单位： 东南大学

项目金额： 75万元

中文摘要： 弥漫性肺泡上皮损伤是ARDS的基本病理改变，有效修复损伤肺泡上皮对治疗ARDS具有关键作用。我们前期实验已证实Wnt经典通路能促进外源性MSC向ARDS小鼠损伤肺组织归巢并分化为肺上皮细胞。细胞周期在MSC定向分化中发挥关键作用，p130/E2F4是调控细胞周期的重要途径，而Wnt经典通路能调节p130/E2F4，推测Wnt经典通路通过p130/E2F4途径调控MSC的细胞周期促进其向肺泡上皮细胞定向分化。本研究基于MSC和肺上皮细胞共培养模型，通过基因转染调控p130/E2F4途径，明确Wnt经典通路通过p130/E2F4调节细胞周期而促进MSC向肺泡上皮细胞定向分化；通过复制小鼠ARDS模型，给予p130/E2F4基因转染的MSC，观察其对MSC在肺内归巢、分化及肺上皮修复的影响，证实Wnt经典通路促进MSC分化通过p130/E2F4实现，为提高MSC对ARDS肺上皮修复提供新的依据。

中文关键词： 骨髓间充质干细胞；急性呼吸窘迫综合征；肺泡上皮分化；p130/E2F4；Wnt经典通路

英文摘要： Diffuse alveolar epithelial cells injury is the major pathology of ARDS. Effective repair of damage alveolar epithelial has a key role to the treatment and the improvement the prognosis of ARDS. Our previous experiments have confirmed the activation of canonical Wnt pathway promoted exogenous mesenchymal stem cells (MSC) to homing into lung tissue and differentiation into lung epithelial cells in acute respiratory distress syndrome (ARDS) mice. Many studies found that the cell cycle involved in differentiation of MSC, and the canonical Wnt pathway can regulate the p130/E2F4 patheway which is the key regulators of the cell cycle. We hypothesize that canonical Wnt pathway promotes the differentiation of MSC into lung epithelial cells through regulation of p130/E2F4 pathway. In this study, MSC is co-cultured with lung epithelial cells injured by lipopolysaccharide, and the p130/E2F4 pathway is regulated through gene modification mediated by lentivirus transfection, then to assay the effect of the p130/E2F4 pathway on the differentiation of MSC into lung epithelial cells.In addition ,we assay the effect of p130/E2F4 pathway on the homing and differentiation of MSC into lung epithelial cells , and the lung injury repair after LPS challenged in mice.It may illustrate that the effect of activation of canonical Wnt pathway on promotion of differentiation of MSC into lung epithelial cells is achieved by regulating the cell cycle through regulation of the p130/E2F4 pathway. This study may provide an evidence for lung epithelium repair in ARDS and facilitate the further improvement of MSC-based treatment for ARDS.

英文关键词： mesenchymal stem cells;acute respiratory distress syndrome;differentiation of mesenchymal stem cells into alveolar epithelialcells;p130/E2F4;canonical Wnt signaling