Branching Morphogenesis and the impact of Canonical WNT on Mechanical and Dynamic properties of the Lung Mesenchyme.

Abstract

Congenital lung disorders are a leading cause of infant mortality and cause high morbidity in adults. A better understanding of lung morphogenesis is key to improving current treatment options and will pave the way for future tissue engineering applications. Branching morphogenesis of the mammalian lung is tightly controlled by a feedback loop of coupled interactions between the airway epithelium and surrounding mesenchymal and mesothelial tissues. Patterning of the mesenchyme is of particular interest given its critical role in sculpting the epithelium. Fibronectin deposition and airway smooth-muscle differentiation at mesenchymal cleft sites act as a physical barrier to induce terminal bifurcation of growing branches. While research suggests that canonical WNT signaling plays an important role during lung development, its precise function in the mesenchyme during terminal bifurcation of epithelial branches is still under investigation. This study seeks to investigate how canonical WNT influences branching through changes in the mechanical and dynamic properties of the embryonic pulmonary mesenchyme. By modulating canonical WNT using pharmacological inhibitors and activators, we show that canonical WNT signaling plays an important role in the differentiation and localization of airway smooth muscle around the epithelium. This project also hints at the redundancy of mechanisms by which mesenchymal WNT signaling regulates branching through FN and Actin remodeling.