Mechanisms of Marrow-Derived Stem Cell Remodeling of Aged Emphysematous Lungs

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Adult marrow-derived cells participate in lung remodeling after injury. This suggests an exciting potential therapeutic approach for lung diseases including emphysema, a devastating and highly prevalent lung disease for which there remains no cure. However, emphysema is predominantly a disease of older patients. Studies evaluating repopulation of lung epithelium have been conducted in young mice. It is unknown whether lung remodeling with marrow-derived cells occurs in older lungs, particularly older diseased lungs. Soluble mediators released by lung epithelial cells play an important role in recruitment of adult marrow-derived cells to lung. However, little is known about whether this process is altered with aging. We hypothesize that release of mediators by epithelial cells and/or response to the mediators by the adult marrow-derived cells decreases with aging. This is a critical consideration if adult marrow- derived cells are to be utilized for emphysema. The current proposal will assess this hypothesis in vitro using primary cultures of lung epithelial cells and marrow-derived cells obtained from young and aged mice and in vivo assessing transplantation of adult marrow-derived cells in a mouse model of emphysema. Evaluations will include state of the art assessments of marrow-derived cell lung remodeling including sophisticated functional measurements of potential physiologic effects of lung remodeling by the marrow-derived cells. Our overall goal is to establish a scientific basis for the potential therapeutic use of marrow-derived cells for lung disease associated with aging and emphysema. (Lay Statement): Use of adult marrow-derived cells is a potential therapeutic approach for a number of lung diseases including emphysema. The proposed studies will investigate mechanisms by which adult marrow-derived cells might participate in repair of emphysematous lungs and provide important basic scientific information and a firm scientific basis for which to design future clinical trials.