Cytoskeletal-nuclear control of alveolar fibroblast identity directs lung regeneration

Respiratory mechanics direct cell fate in the lung, but the mechanisms by which these mechanical signals are sensed and transmitted to the nucleus to control cell state remain unclear. We paired in vivo perturbations of respiratory mechanics with single-cell genomics and found that alveolar fibroblasts are highly sensitive to physical changes in their microenvironment, exhibiting persistent shifts in their transcriptional identity after injury. Surprisingly, transmission of these signals through the nuclear envelope was not essential for maintaining transcriptional or epigenetic stability during homeostasis. However, severing mechanical-nuclear signaling promoted the normalization of alveolar fibroblast identity after acute injury, resulting in improved epithelial regeneration and reduced dysplastic remodeling. These studies reveal the importance of mechanical-nuclear signaling in the regulation of alveolar cell identity and function and reveal that targeting this complex can enhance tissue regeneration.