Alveolar epithelium propagates mechanical signals that control multi-cellular homeostasis in the lung

Respiratory motion imposes a constant mechanical strain that has important but poorly defined impact on tissue niches in the lung. We developed a reversible bronchial ligation model to induce and reverse unilateral blockade of lung mechanical motion in vivo and show that this leads to transcriptomic changes in multiple cell lineages that are not normalized upon reinitiation of respiratory motion. Perturbation of mechanosignaling specifically in alveolar epithelial type I (AT1) cells alters the transcriptomic state and fate of their niche neighbors, demonstrating that AT1 cells act as a node that propagates a mechanical cascade throughout the lung alveolus. Mechanically perturbed AT1 cells induce a distinct capillary endothelial cell state that persists after reactivation of respiratory motion, which is mediated by an integrin/TGF-β network within the alveolus that is vulnerable to pharmacological intervention. Importantly, AT1 mechanosignaling and intercellular communication are altered in chronic human lung diseases, highlighting the critical role of an AT1-driven mechanosensing network in lung disease biology. Thus, mechanosensing cells propagate biophysical signals that regulate tissue function and program tissue responses in disease.