Abstract

Branching morphogenesis transforms simple tubes of cells into vast, tree-like networks essential for organ function. In the embryonic mouse lung, smooth muscle differentiation around the airway epithelium physically shapes emerging branches. Here, we delved into the behavior of the sculptor itself, airway smooth muscle, and examined how it influences cell fate patterns within the underlying sculpture, the airway epithelial tree. Using genetic perturbations and single-cell bioinformatics, we demonstrate phenotypic plasticity in airway smooth muscle that ensures robust branching morphogenesis. Then, using genetic and mechanical perturbations of epithelial fate and form, we show that patterns of epithelial cell fate depend on the physical signals imposed by branching morphogenesis and airway smooth muscle wrapping.