This research is designed to test the central hypothesis that bone marrow-derived stromal stem cells engraft in the lung and differentiate to alveolar and airway epithelial and mesenchymal cells, consequently ameliorating or exacerbating the progression of fibroproliferative lung disease. Two well-characterized models of lung injury will be used: 1) Brief exposure to inhaled asbestos fibers rapidly causes injury of the bronchiolar-alveolar epithelium and a fibroproliferative lesion at the alveolar duct bifurcations. Studies were carried out in female rats that have undergone whole bone marrow transplantation from male green fluorescent protein (GFP)-transgenic syngeneic rats. The Preliminary Data shown here demonstrate that there are significantly increased numbers of GFP-positive, Y chromosome-positive bone marrow-derived cells in the asbestotic lesions compared with surrounding, uninjured tissues and with lungs from unexposed rats. Furthermore, the GFP-positive cells in the lung had both epithelial and mesenchymal phenotypes. Studies were also carried out in female rats injected intravascularly with 5 x 10[6] marrow stromal stem cells isolated from male GFP-transgenic rats. Our Preliminary Data demonstrate putative stem cells apparently attached to alveolar duct walls. Here we propose to define the subpopulations of stem cells that engraft and differentiate in injured lung and the effect they have on progression of asbestos-induced fibroproliferative lesions. 2) Denuded rat tracheae grafted into nude mice provide a milieu in which an epithelial lining can be reestablished, the characteristics of which is primarily determined by the differentiation potential of the inoculated cells. Our Preliminary Data show that purified populations of airway epithelial cells mixed with bone marrow-derived cells form a differentiated epithelium in the tracheal graft system. Furthermore the bone marrow-derived cells in the graft appear to differentiate into epithelial cells, as well as endothelial cells that participate in revascularization of the grafts. Some stem cells appear to differentiate as mesenchymal cells. This system will be ideal for testing the postulate since varying numbers of specific stem cell subpopulations in different stages of differentiation can be studied in combination with varying numbers and types of epithelial cells. There are no data available which allow us to predict whether or not the stem cells will play any role in the degree of lesion development or participate in populating the tracheo-bronchial and bronchiolar-alveolar duct walls. These studies will provide opportunities to develop therapeutic approaches through the use of adult bone marrow-derived stem cells because we know the precise anatomic and temporal distribution of the developing lesions. The stem cells will be characterized in, and we will be using the same populations of cells employed by investigators in the other projects. This will be a clear advantage for the final data analysis.
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