Extracellular matrix composition directs airway epithelial branching through focal adhesion kinase
James Spurlin a, Celeste Nelson a
a Chemical & Biological Engineering, Princeton University, 315 Hoyt Laboratory William St, Princeton, 08544, United States
b Molecular Biology, Princeton University, 315 Hoyt Laboratory William St, Princeton, 08544, United States
Proceedings of New Advances in Probing Cell-ECM Interactions (CellMatrix)
Berlin, Germany, 2016 October 20th - 21st
Organizers: Ovijit Chaudhuri, Allen Liu and Sapun Parekh
Oral, James Spurlin, presentation 024
Publication date: 25th July 2016

The extracellular matrix (ECM) within developing tissues modulates biomechanical cues necessary for organogenesis. During the airway branching program of the embryonic lung, basement membrane (BM) proteins are depleted from the distal tips of extending branches, which is assumed to promote branch growth. While reduction of the BM may facilitate branch extension, it is unclear whether BM turnover is required for branch initiation. To elucidate the role of BM during airway epithelial branching, we characterized the distribution of BM proteins in embryonic chicken lungs prior to and during branching initiation. We found a correlation between branch extension and BM depletion at branch tips, but that BM distribution does not predict future branch sites. Culturing lung explants revealed that matrix metalloproteinase activity is not required for branch initiation, suggesting that BM thinning occurs during branch extension. Since BM protein distribution is modified at the tips of elongating branches, we sought to determine how branch extension directs the ECM composition in the surrounding pulmonary mesenchyme. To address this, we investigated the spatiotemporal distribution tenascin-C (TNC), which we found is localized in the BM adjacent to the airway epithelium and becomes enhanced in both epithelial and mesenchymal cells at the tips of growing branches. In these regions, mesenchymal cells are more elongated then those surrounding non-branching regions of the lung epithelium. These data suggest that local deformation of the mesenchyme may influence ECM composition surrounding the developing airways. To determine if mechanical cues could direct local accumulation of TNC, we cultured lung explants with an inhibitor of focal adhesion kinase (FAK). In FAK-inhibited explants, TNC expression and branch initiation are both significantly reduced, and elongating branches assume a wedge-shape morphology distinct from control lungs. Our data suggest that as the airway epithelium extends a branch, it thins the proximal BM and deforms the adjacent mesenchymal cells, activating FAK, which induces the expression of TNC. Therefore, ECM composition is regulated via mechanotransduction to influence the airway branching program.



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