Patterned smooth muscle constrains and constricts the airway epithelium during branching morphogenesis

During branching morphogenesis, a simple tube of cells gives rise to an arborized epithelial network. In the mouse lung, the airway epithelium develops concomitantly with a layer of smooth muscle, which is derived from the surrounding mesenchyme and wraps circumferentially around the airways. We examined the role of smooth muscle in shaping domain branches that establish the underlying architecture of the lung. We found that branches begin as wide buds that thin at their bases as they extend. At the same time, there is an increase in the amount of smooth muscle wrapped around the parent bronchus at the base of each nascent domain branch. Perturbing the pattern of smooth muscle differentiation causes abnormal epithelial branching. Loss of smooth muscle results in ectopic branching events and slows branch thinning. Enhanced smooth muscle differentiation suppresses branch initiation and extension. Combining experiments with computational modeling revealed that patterned smooth muscle wrapping constrains and constricts the growing epithelium to properly position and physically sculpt domain branches.