Determining How FGF-10 Signaling and Mechanical Forces Are Integrated to Regulate Airway Branching Morphogenesis

Abstract

Understanding how the development of the lung airway occurs is a fundamental question that can help improve understanding and treatment of congenital lung malformations, guide tissue engineering strategies for building branched epithelial networks, and give insight into potentially conserved mechanisms of development in other branched organs. In the mammalian lung, the embryonic airway epithelium starts out as a simple, wishbone-shaped tube, which undergoes multiple rounds of branching to form the bronchial tree in a process collectively known as branching morphogenesis. This branched network is built by distinct branching modes: lateral branching and bifurcations. New daughter branches form via lateral branching by emerging along the length of the parent bronchi, and bifurcations cause the tip of a branch to split. Throughout lung development, there is a complex network of signaling pathways present, but fibroblast growth factor-10 (FGF-10) is thought to serve as the master regulator of airway branching. FGF-10 is hypothesized to be expressed in a focal pattern within the pulmonary mesenchyme, the tissue surrounding the epithelial airway, and provide a biochemical template where a single source of growth factor stimulates the formation of an individual branch, possibly through localized proliferation and chemotaxis. However, several recent studies have also indicated mechanical forces can sculpt the branching of the lung airway. Here, we are interested in studying the interplay between FGF-10 signaling and mechanical cues, including fluid pressure and tissue stiffness, that initiate new epithelial branches. Taken together, these data will help elucidate how biochemical and mechanical cues work in concert to give rise to the macroscopic changes in tissue form that build branched epithelial networks.