Mesenchymal cell motility is required for sacculation during lung development

During the final stages of embryonic lung development, the distal tips of the epithelial airways expand into the surrounding mesenchyme to generate multiple small sacs called saccules, which form the gas-exchange surfaces of the neonatal mouse lung. The cellular mechanisms that drive the dramatic changes in tissue morphology that accompany sacculation, including epithelial expansion and mesenchymal thinning, are poorly understood. Using tissue-specific knockout mice, we found experimentally that proteins associated with cell motility are required in the mesenchyme for normal lung sacculation. In this study, we build a computational model of sacculation to test our hypothesis that mesenchymal cell motility is required for epithelial expansion and mesenchymal thinning. By independently tuning both luminal pressure and mesenchymal motility, we show that the sacculation process requires mesenchymal cells to undergo neighbor exchanges. Despite the simplicity of the model, our numerical results recapitulate the morphologies of saccules observed in our wild-type embryos (high luminal pressure and high mesenchymal motility) and mutant embryos (high luminal pressure and low mesenchymal motility). The latter indicates that normal lung sacculation requires a motile, and thus more fluid population of mesenchymal cells surrounding the epithelium.