Airway Smooth Muscle Differentiation is Essential for Promoting Airway Size, Tracheal Cartilage Segmentation, But Dispensable for Epithelial Branching

Airway smooth muscle is best known for its role as an airway constrictor in the pathogenesis of lung diseases such as asthma. However, its function in lung development is poorly understood. A prevalent model, supported by in vitro data, posits that airway smooth muscle promotes lung branching through peristalsis and pushing intraluminal fluid to the tips of the branching epithelium. Here, we test this model in vivo by inactivating Myocardin in the lung mesenchyme, thereby preventing airway smooth muscle cell differentiation. We found that Myocardin mutants show normal branching, despite absence of peristalsis. In contrast, tracheal cartilage, vasculature, and neural innervation patterns were all disrupted in the mutant. Furthermore, airway diameter is reduced in the mutant, counter to the expectation that the absence of smooth muscle constriction would lead to a more relaxed and thereby wider airway. These findings together demonstrate that during development, while airway smooth muscle is dispensable for epithelial branching, it is integral for building the tracheal architecture and promoting airway growth.