Emergence of Wnt signaling during lung alveologenesis expands and maintains the type 2 alveolar epithelial cell population. Mus musculus

Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface. Using a novel Wnt signaling reporter system, we have identified a Wnt-responsive alveolar epithelial sublineage arising during alveologenesis called the axin2+ alveolar type 2 cell or AT2Aaxin2. The number of AT2Aaxin2 sublineage cells increases substantially during late lung development, revealing a wave of Wnt signaling during alveologenesis. Transcriptome analysis, in vivo clonal analysis, and ex vivo lung organoid assays reveal that AT2sAaxin2s promote enhanced AT2 cellalveolar growth during generation of the alveolus compared to the overall AT2 population. Activating Wnt signaling in the AT2 lineage results in expansion of the AT2axin2 sublineageAT2s whereas inhibition of Wnt signaling inhibits AT2 cell development and shunts alveolar epithelial development towards the AT1 cell lineage. These findings reveal a novel epithelial sublineage that coordinates Wnt-dependent alveolar growthAT2 expansion required for lung alveologenesis Overall design: Five samples each from FACS-based isolation of total primary type 2 alveolar epithelial cells from SftpcCreERT2-R26REYFP postnatal day 4 mice after 24 hour lineage tracing and primary type 2 alveolar epithelial cells from postnatal day 4 Axin2CreERT2-TdTomato mice