The Biomechanical Basis of Biased Epithelial Tube Elongation

Abstract

During lung development, epithelial branches expand preferentially in longitudinal direction. This bias in outgrowth has been linked to a bias in cell shape and in the cell division plane. How such bias arises is unknown. Here, we show that biased epithelial outgrowth occurs independent of the surrounding mesenchyme. Biased outgrowth is also not the consequence of a growth factor gradient, as biased outgrowth is obtained with uniform growth factor cultures, and in the presence of the FGFR inhibitor SU5402. Furthermore, we note that epithelial tubes are largely closed during early lung and kidney development. By simulating the reported fluid flow inside segmented narrow epithelial tubes, we show that the shear stress levels on the apical surface are sufficient to explain the reported bias in cell shape and outgrowth. We use a cell-based vertex model to confirm that apical shear forces, unlike constricting forces, can give rise to both the observed bias in cell shapes and tube elongation. We conclude that shear stress may be a more general driver of biased tube elongation beyond its established role in angiogenesis.