Chronic Obstructive Pulmonary Disease (Chronic Bronchitis & Emphysema) ranks 4th among the leading causes of mortality in the United States. Emphysema is manifest histologically as the destruction of alveolar walls without significant fibrosis. Restoration of respiratory function in the emphysematous lung may be possible by expanding alveolar surface area through the use of adult bone marrow-derived stromal cells for tissue regeneration in the distal lung. Injury appears to increase the prevalence of marrow stromal cells (MSCs) in the lung after systemic administration. However, unenhancecl lung engraftment of MSCs is limited, making significant tissue regeneration unlikely at current levels of engraftment. Therefore, before the utility of MSCs can be fully tested, we need to evaluate mechanisms by which MSCs are recruited to, and engraft in, the injured lung. Our Hypothesis is that a specific subpopulation of MSCs will optimally engraft in the emphysematous lung via a multi-step process involving both vascular adhesion and chemotaxis.
The Specific Aims of this application are:
Specific Aim 1 : To compare engraftment of MSC subpopulations in the elastase model of emphysema and to evaluate the implantation process.
Specific Aim 2 : To investigate the role of endothelial adhesion in MSC homing to the lung.
Specific Aim 3 : To evaluate the hypothesis that augmenting chemokine-directed MSC migration will increase engraftment in the lung.
Specific Aim 4 : To determine the morphological and functional outcomes of optimized MSC delivery to the emphysematous lung. The lung engraftment potential of different MSC subpopulations identified will be tested in the in vivo elastase model of emphysema. Differentiation of engrafted cells will be determined and the role of cell fusion defined. Integrin- & selectin-mediated vascular adhesion, chemokine signaling pathways and mechanics of engraftment will be explored in order to augment MSC delivery to the lung. We will then evaluate the morphologic and functional impact of optimized delivery of bone marrow-derived stromal cells to the alveolar wall in the emphysematous lung. These studies will expand our understanding of the biology of MSCs & methods to improve recruitment to the lung, hopefully leading to novel therapies for emphysema.
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