Temporal single-cell profiling of distinct mesenchymal, epithelial, endothelial, and immune cell lineages in the lung after injury

Upon severe injury to the lungs, a poorly understood multistep process results in either euplastic regeneration or dysplastic repair which leads to a loss of functional gas-exchanging alveolar tissue. We show that the dysplastic repair process consists of an injury-induced tissue niche (iTCH) containing Keratin 5+ epithelial cells and Pdgfra-derived Pdgfrb+ mesenchymal cells, which proliferate and transit across multiple cells states before localizing to dysplastic regions. Temporal and spatial single cell analysis reveals that Pdgfra-derived Pdgfrb+ cells communicate via Notch signaling to dysplastic keratinized epithelium. Inactivation of proliferation and Notch signaling in these Pdgfra+ progenitor mesenchymal cells prevents the establishment of iTCHs. Mesenchymal Notch signaling in iTCHs suppresses Wnt and Fgf signaling, whereas loss of Notch rewires alveolar signaling patterns to promote euplastic regeneration and restore functional gas exchange in the lung. iTCH presence and signaling patterns can be used to differentially phenotype fibrotic from degenerative chronic lung disease, with associated apposing flows of FGF and WNT signaling discriminating these disease states. These data reveal the emergence of an injury and disease associated niche in the lung, its regulation by mesenchymal Notch signaling, and the impact these cellular decisions have on discriminating the choice between dysplastic repair or euplastic regeneration.