Age-dependent alveolar epithelial plasticity orchestrates lung homeostasis and regeneration

Regeneration of the architecturally complex alveolar niche of the lung requires precise temporal and spatial control of epithelial cell behavior. Injury can lead to a permanent reduction in gas exchange surface area and respiratory function. Using mouse models, we show that alveolar type 1 (AT1) cell plasticity is a major and unappreciated mechanism that drives regeneration, beginning in the early postnatal period during alveolar maturation. Upon acute neonatal lung injury, AT1 cells reprogram into alveolar type 2 (AT2) cells, promoting alveolar regeneration. In contrast, the ability of AT2 cells to regenerate AT1 cells is restricted to the mature lung. Unbiased genomic assessment reveals that this previously unappreciated level of plasticity is governed by the preferential activity of Hippo signaling in the AT1 cell lineage. Thus, cellular plasticity is a temporally acquired trait of the alveolar epithelium and presents an alternative mode of tissue regeneration in the postnatal lung. [Display omitted] •Alveolar type 1 cells exhibit plasticity after neonatal and adult hyperoxic injury•YAP/TAZ actively maintain alveolar type 1 cell identity•Ectopic nuclear YAP is insufficient to induce type 2 to type 1 cell differentiation Penkala et al. investigate the effects of acute hyperoxic lung injury in neonatal and adult mice and demonstrate distinct, age-specific repair processes. They show that YAP/TAZ constrain type 1 cell identity and that the loss of these factors precipitates extensive alveolar type 1 to type 2 cell reprogramming.