Exploiting mechanisms for hierarchical branching structure of lung airway

Abstract

The lung airways exhibit distinct features with long, wide proximal branches and short, thin distal branches, crucial for optimal respiratory function. In this study, we investigated the mechanism behind this hierarchical structure through experiments and modeling, focusing on the regulation of branch length and width during the pseudoglandular stage. To evaluate the response of mouse lung epithelium to fibroblast growth factor 10 (FGF10), we monitored the activity of extracellular signal-regulated kinase (ERK). ERK activity exhibited an increase dependent on the curvature of the epithelial tissue, which gradually decreased with the progression of development. We then constructed a computational model that incorporates curvature-dependent growth to predict its impact on branch formation. It was demonstrated that branch length is determined by the curvature dependence of growth. Next, in exploring branch width regulation, we considered the effect of apical constriction, a mechanism we had previously proposed to be regulated by Wnt signaling. Analysis of a mathematical model representing apical constriction showed that branch width is determined by cell shape. Finally, we constructed an integrated computational model that includes curvature-dependent growth and cell shape controls, confirming their coordination in regulating branch formation. This study proposed that changes in the autonomous property of the epithelium may be responsible for the progressive branch morphology.