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

ABSTRACT: 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-1β-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE153677 | GEO | 2021/09/08

REPOSITORIES: GEO

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

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