Plasticity in airway smooth muscle differentiation during mouse lung development

Summary Smooth muscle differentiation has been proposed to sculpt airway epithelial branches in mammalian lungs. Serum response factor (SRF) acts with its cofactor myocardin to promote the expression of contractile smooth muscle markers. However, smooth muscle cells exhibit a variety of phenotypes beyond contractile that are independent of SRF/myocardin-induced transcription. To determine whether airway smooth muscle exhibits phenotypic plasticity during embryonic development, we deleted Srf from the pulmonary mesenchyme. Srf -mutant lungs branch normally, and the mesenchyme exhibits normal cytoskeletal features and patterning. scRNA-seq revealed an Srf -null smooth muscle cluster wrapping the airways of mutant lungs that lacks contractile smooth muscle markers but retains many features of control smooth muscle. Srf- null airway smooth muscle exhibits a synthetic phenotype, compared to the contractile phenotype of mature wildtype airway smooth muscle. Our findings reveal plasticity in airway smooth muscle differentiation and demonstrate that a synthetic smooth muscle layer is sufficient for airway branching morphogenesis.