Computational Modeling of FGF10 Mediated Buckling Morphogenesis Within the Embryonic Airway Epithelium
Abstract
Abstract
The embryonic lung is an excellent model system to study mechanisms of branching
morphogenesis, since the embryonic airways undergo a series of recursive branching events to
build the bronchial tree. This process involves reciprocal signaling interactions between the
branching airway epithelium and a surrounding layer of pulmonary mesenchyme. Focal regions of
fibroblast growth factor (FGF10) expression within the pulmonary mesenchyme are thought to
provide a biochemical template for the overall airway branching pattern. Recent work, however,
has shown that mechanical forces can also impact this process, and it remains unclear how patterns
of FGF10 expression interact with biophysical cues in the developing lung to sculpt incipient
branches. This is, in part, owing a lack of computational models that incorporate both growth-factor diffusion and the mechanics of growth and remodeling. Several previous studies have used
computational modeling to suggest how specific spatial patterns of FGF10 expression might arise
spontaneously within the pulmonary mesenchyme, while others have used continuum mechanics
to identify the forces involved in bud initiation, but no computational framework has been
developed which unite these different approaches. Here, we developed a finite-element model in COMSOL Multiphysics, which couples growth-factor diffusion to the mechanics of epithelial morphogenesis. We first consider the axial growth
of a constrained bar, in which the components of the growth tensor depend on the local
concentration of a diffusible molecule. This framework is then extended to determine how growth
factor diffusion from a focal source within the pulmonary mesenchyme elicits patterns of epithelial
growth and budding morphogenesis along the embryonic airway epithelium. This work highlights
the importance of both mechanical forces and growth factor diffusion during airway branching
morphogenesis.