Ancillary Studies of Lung Stem/Progenitor Cell Epithelial-Mesenchymal Signaling

Ancillary Studies of Lung Stem/Progenitor Cell Epithelial-Mesenchymal Signaling Abstract: Epithelial-mesenchymal signaling is essential for organogenesis and adult tissue maintenance but is poorly understood in lung repair and regeneration. This proposal exploits timely advances by Consortium investigators and the additional skills and resources of collaborating scientists to identify the critical mesenchymal and epithelial stem/progenitor cell populations that mediate lung regeneration and identify the key signaling factors that operate in lung bronchi, bronchioles, and alveoli. Sorted epithelial and mesenchymal cell populations will be scrutinized for evidence of signaling cascade activation separately in both epithelium and mesenchyme. Using murine genetic models and co-cultures of epithelial and mesenchymal cells, prioritized pathways, initially Sonic hedgehog (Shh), will be modulated to establish the role of pathway activation or dysfunction in airway homeostasis and during regeneration. Parallel in vitro models for primary human lung cells will be developed. Additionally, normal and pathologic pathway activation will be assessed in human lung tissue by in situ hybridization and immunohistochemistry. The Aims are: 1) To lineage trace and sort region-specific epithelial progenitor cells and mesenchyme to identify candidate signaling pathways mediating epithelial-mesenchymal crosstalk; 2) To define the role of Shh signaling in epithelial and niche interactions in airway homeostasis and after lung injury; and 3) To employ novel human lung cell in vitro coculture models to test the function of candidate epithelial-mesenchymal signaling pathways identified in mice and to examine expression of cognate molecules in normal and diseased human lung tissues. These studies will exploit the skills, knowledge and tools of the Progenitor Cell Biology Consortium and this Ancillary team and will leverage these assets to enhance our understanding of lung regenerative biology. The information gained will be invaluable for defining mechanisms of normal lung repair and pathologic lung disease development, which lag behind our understanding in cardiac and bone marrow biology and disease. click for more info on lungs repair and regeneration