Abstract
The lung epithelium forms the first barrier against respiratory pathogens and noxious chemicals; however, little is known about how >90% of this barrier - made of alveolar type 1 (AT1) cells - responds to injury. Using Sendai virus to model natural infection in mice, we find evidence that AT1 cells have an intermediary role by persisting in areas depleted of alveolar type 2 (AT2) cells, upregulating interferon responsive genes, and receding from invading airway cells. Sendai virus infection mobilizes airway cells to form alveolar SOX2+ clusters without differentiating into AT1 or AT2 cells. Large AT2-cell-depleted areas remain covered by AT1 cells, which we name "AT2-less regions", and are replaced by SOX2+ clusters spreading both basally and luminally. AT2 cell proliferation and differentiation are largely confined to topologically distal regions and form de novo alveolar surface, with limited contribution to in situ repair of AT2-less regions. Time-course single-cell RNA-seq profiling and RNAscope validation suggest enhanced immune responses and altered growth signals in AT1 cells. Our comprehensive spatiotemporal and genome-wide study highlights the hitherto unappreciated role of AT1 cells in lung injury-repair.
Original language | English (US) |
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Journal | American journal of respiratory cell and molecular biology |
DOIs | |
State | E-pub ahead of print - Jun 9 2022 |
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