Lung transplantation is often the only viable therapeutic option for end-stage pulmonary disorders. Unfortunately, lung transplantation is associated with numerous serious complications including acute rejection and bronchiolitis obliterans syndrome (BOS). Studies have indicated that immune-mediated injury and loss of airway epithelial cells is critical in the pathogenesis of BOS. Targeting this biology could therefore provide a major breakthrough for developing new therapeutic strategies for preventing rejection in lung transplantation. We have identified circulating epithelial progenitor cells (CEPC) that are recruited to the injured airway and aid in repair of the epithelium. These cells express cytokeratin 5, a marker of progenitor basal epithelial cells in the airway, and traffic via the CXCR4/CXCL12 biological axis. Consistent with the importance of CEPC in airway repair, blocking the recruitment of CEPC with neutralizing antibodies to CXCL12 resulted in the phenotype of squamous metaplasia. This implies that the interaction between circulating and resident progenitor epithelial cells in the airway niche is critical for normal airway repair. We hypothesize that enhancing engraftment of recipient CEPC into donor airway epithelium after lung transplantation will improve epithelial repair, result in less allo-recognition of the donor lung and ultimately reduce BOS. The goal of this proposal is to: 1) investigate the role of resident and circulating epithelial progenitor cell populations in the development of BOS by selectively eliminating these cell populations, 2) examine the effect of enhanced mobilization of CEPC on the development of BOS and 3) use patient lung transplant blood samples to determine whether CEPC correlate with patient outcome. The proposed studies will allow further understanding of the role of epithelial progenitor cells in the airway and will enable the harnessing of the therapeutic potential of CEPC. PUBLIC HEALTH RELEVANCE: Adult stem cells hold great promise for repair of the lungs and we have discovered adult stem cells in the blood that contribute to repair of the lungs. Lung transplants are performed for many patients with end stage lung diseases, but are associated with many complications. We hypothesize that mobilizing adult stem cells after lung transplantation will improve the repair of the injured donor lungs and reduce the complications of lung transplantation. We plan to test this hypothesis in preclinical models and in lung transplant patient samples.