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.
