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

描述（由申请人提供）：从成年小鼠骨髓中获得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。这些发现提高了异常肺上皮细胞可以被骨髓来源的正常功能细胞替代或重新填充的可能性。这为包括囊性纤维化在内的各种肺部疾病提供了一种新的潜在治疗方法。 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仍不清楚。肺损伤增加了骨髓源性细胞向肺募集的数量，这些细胞可以参与损伤后的肺重塑。这表明，损伤或修复肺释放的物质可能有助于将骨髓源性干细胞募集到肺中，并进一步诱导表型转化为上皮细胞或间质细胞。 我们推测，气道上皮细胞释放的可溶性因子的作用是招募成人骨髓干细胞到肺，并诱导表型转化为气道上皮细胞。此外，在肺损伤的情况下，潜在的可溶性介质的释放将增加。在初步研究中，我们发现，IL-17，一种已知影响中性粒细胞趋化性的炎性细胞因子，可以介导间充质干细胞（MSC）向小鼠气道上皮细胞的迁移。我们建议使用靶向IL-17在上皮细胞中的过表达或通过使用中和抗体或从IL-17受体敲除小鼠获得的MSC计时IL-17效应来进一步表征IL-17对成人MSC的募集和表型转化的影响。我们还建议调查的假设，IL-17的释放增加CF上皮细胞，这增加了MSC的招聘和表型转换。这些研究将作为基础，更详细的调查机制的招募和表型转换成人骨髓干细胞成气道上皮细胞。

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.