Growing evidence supports the potential use of stem cells in the repair and regeneration of injured or diseased human lungs. While both embryonic and adult tissue-derived stem cells can be induced to express phenotypic markers of ainway or alveolar epithelial cells as well as pulmonary vascular cells, the magnitude of engraftment and the determinants of expansion and differentiation of these progenitor cells have yet to be rigorously determined. Progenitor cell therapy is most readily administered intravenously and, thus, future clinical trials of stem cell therapy for pulmonary diseases will require an effective method for promoting the recruitment, retention, proliferation, and differentiation of systemically administered progenitor cells in the lung. To this end, we propose to study the use of a novel nanoglycan technology for the intra-alveolar delivery and peri-alveolar retention of growth factors believed to be important for recruitment, clonal expansion, and differentiation of pulmonary progenitor cells in well-established rodent models of human lung diseases. To achieve this goal, we propose three specific aims. We will first synthesize nanoglycan complexes bearing specific growth factors (vascular endothelial growth factor, palifermin, and repifermin) or a chemokine (stromal cell-derived factor-1) each chosen for its unique effects in lung repair and regeneration. The synthesis of these nanoglycan complexes exploits the heparin-binding sites contained in these proteins to facilitate their association with and stabilization by polyanionic glycosaminoglycan components ofthe complex. We will then monitor the time course of their retention and distribution in the lung. Next, we will study the effects of these aerosolized nanoglycan complexes on human progenitor cell recruitment to and retention in the lung after their systemic (intravenous) administration. Finally, we will assess the consequences of this nanoglycan-guided progenitor cell therapy on lung repair and regeneration in hwo rat models of human pulmonary disease, elastase-induced emphysema and monocrotaline-induced pulmonary hypertension. This assessment will include morphological and molecular analyses of engraftment and regeneration of alveolo-vascular structures, as well as serial hyperpolarized noble gas magnetic resonance imaging of time-dependent changes in lung structure and function. Taken together, these studies will be used to demonstrate the feasibility of this unique approach to stem cell therapy for human pulmonary diseases, as well as its potentially beneficial structural and functional consequences.
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