Role of IL-17 in Recruitment of Adult Stem Cells to Lung

描述(申请人提供)：从成年小鼠骨髓中获取的干细胞在移植后可以定位于受体小鼠的肺，并获得分化的肺上皮细胞和间质细胞的表型和功能特征。这些发现提出了一种可能性，即异常的肺上皮可以被骨髓来源的正常功能细胞取代或重新种植。这为囊性纤维化等多种肺部疾病提供了一种新的潜在的治疗方法。 然而，现有的数据大多是描述性的；骨髓来源的细胞被招募到肺并参与肺重塑的机制尚不清楚。肺损伤增加了骨髓来源的细胞向肺内募集的数量，这些细胞可以参与损伤后的肺重塑。这提示肺损伤或修复所释放的物质可能有助于将骨髓来源的干细胞招募到肺内，并进一步诱导表型转化为上皮细胞或间质细胞。 我们推测，呼吸道上皮细胞释放的可溶性因子作用于向肺招募成人骨髓干细胞，并诱导表型转化为呼吸道上皮细胞。此外，在肺损伤的背景下，潜在的可溶性介质的释放将会增加。在初步研究中，我们发现IL-17是一种已知的影响中性粒细胞趋化的炎性细胞因子，在原代培养中可能介导间充质干细胞(MSC)向小鼠呼吸道上皮细胞迁移。我们建议通过在上皮细胞中定向过度表达IL-17或通过中和抗体或从IL-17受体敲除小鼠获得的MSC计时来进一步表征IL-17对成年MSC募集和表型转换的影响。我们还建议调查假设，IL-17的释放增加，在CF上皮细胞，这增加了MSC招募和表型转换。这些研究将为更详细地研究成人骨髓干细胞向呼吸道上皮细胞的招募和表型转换机制奠定基础。

DESCRIPTION (provided by applicant): Stem cells obtained from bone marrow of adult mice can, following transplantation, localize to lungs of recipient mice and acquire phenotypic and functional characteristics of differentiated lung epithelial and interstitial cells. These findings raise the possibility that abnormal lung epithelium can be replaced or repopulated with normal functioning cells of bone marrow origin. This offers a new potential therapeutic approach for a variety of lung diseases including cystic fibrosis. However, the available data is mostly descriptive; the mechanisms by which marrow-derived cells are recruited to lung and participate in lung remodeling remain unclear. Lung injury increases the number of marrow-derived cells recruited to lung and these cells can participate in lung remodeling after injury. This suggests that substances released by injured or repairing lung may serve to recruit marrow-derived stem cells to lung and further induce phenotypic conversion into epithelial or interstitial cells. We postulate that soluble factors released by airway epithelial cells act to recruit adult marrow stem cells to lung and induce phenotypic conversion to airway epithelial cells. Further, release of potential soluble mediators will be increased in the setting of lung injury. In preliminary studies, we have found that IL-17, an inflammatory cytokine known to influence neutrophil chemotaxis, may mediate migration of mesenchymal stem cells (MSC) towards mouse airway epithelial cells in primary culture. We propose to further characterize the effects of IL-17 on recruitment and phenotypic conversion of adult MSC using targeted IL-17 over-expression in epithelial cells or by clocking IL-17 effects using either neutralizing antibody or MSC obtained from IL-17 receptor knockout mice. We also propose to investigate the hypothesis that IL-17 release is increased in CF epithelial cells and that this increases MSC recruitment and phenotypic conversion. These studies will serve as a basis for more detailed investigations into mechanisms of recruitment and phenotypic conversion of adult marrow stem cells into airway epithelial cells.