Release of Notch signaling coordinated by inflammation confers cross-compartment differentiation plasticity during alveolar regeneration

While the acquisition of cellular plasticity in adult stem cells is essential for rapid restoration after tissue injury, little is known about the underlying molecular mechanisms governing this process. Here, we reveal that Notch signaling is a pivotal determinant conferring cross-compartment differentiation plasticity of airway secretory cells. Temporal Notch inhibition in secretory cells is required for alveolar differentiation upon injury, which is mediated by IL-1ß-dependent modulation of Jag1/2 expression in ciliated cells. We also identify Fosl2/Fra2 as an essential transcription factor responsible for the regeneration of secretory cell-derived alveolar type 2 (sAT2) cells retaining distinct genetic/epigenetic features. We furthermore reveal that KDR/FLK-1+ human secretory cells display a conserved capacity to generate AT2 cells via Notch inhibition. Our results demonstrate that Notch signaling acts as a functional rheostat for fate decision of secretory cells during injury repair, proposing a new potential therapeutic target for human lung alveolar regeneration. Overall design: ATAC-seq was performed for secretory cells, AT2 cells derived from seceretory cells, and resident AT2 cells isolated from Scgb1a1-CreTM;R26RfGFP;Sftpc-dsRedIRES-DTR mice. RNA-seq was performed with samples from feeder free-cultured organoids of secretory cells with or without DAPT treatment, and AT2 cells.