Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states

Functional regeneration of the lung’s gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using single-cell transcriptomics combined with lineage tracing of proliferating progenitors, we examined mouse lung regeneration after influenza injury, demonstrating an asynchronously phased response across different cellular compartments. This longitudinal atlas of injury responses has produced a catalog of transient and persistent transcriptional alterations in cells as they transit across axes of differentiation. These cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares hallmarks with developing lung endothelium and endothelial aberrations found in degenerative human lung diseases. This dataset provides a foundational resource to understand the complexity of cellular and molecular responses to injury and correlations to responses found in human development and disease. [Display omitted] •Single-cell sequencing atlas of the lung’s response to influenza infection•Proliferation after viral injury is asynchronous across compartments of the lung•Intermediate states in myeloid and epithelial compartments resolve over time•A dysplastic endothelial cell state is found in the lung 1 year post-infection Niethamer, Morrisey, and colleagues delineate the temporal sequence of mouse lung regeneration in a single-cell RNA-sequencing atlas detailing each cellular compartment’s response to influenza infection. Transient and lasting cell states arise during tissue repair, including an aberrant endothelial cell state that persists 1 year after infection.