The signaling role of alveolar type 1 cell-derived Wnt ligands during alveologenesis

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PROJECT SUMMARY Although surfactant producing alveolar type 2 cells have been the focus for many years, the alveolar type 1 (AT1) cells are the neighboring lung epithelial cells that cover >90% gas exchange surface area. We found AT1 cells are more than a passive structure because they express VEGFA and signal to the vasculature. We also found AT1 cells express Wnt ligands. Interestingly, cultured lung fibroblasts proliferate upon WNT3A stimulation and lung myofibroblasts express widely canonical Wnt target gene, Axin2. This led to our hypothesis that AT1 cells signal lung myofibroblasts via Wnt ligands. We will investigate the requirement of AT1-derived Wnt ligands for lung myofibroblasts during alveologenesis (aim 1), the epithelial-mesenchymal signaling mechanism (aim 2), and the Wnt-mediated crosstalk between AT1 and lung myofibroblasts in an experimental BPD models (aim 3). Successful completion of this study will reveal a new signaling role of AT1 cells and elucidate lung mesenchymal cell types, thereby representing a first step toward our long-term goal of unraveling epithelial-mesenchymal crosstalk during alveologenesis and BPD pathogenesis.