GSE129584
Transcriptional control of lung alveolar type 1 cell development and maintenance by NK Homeobox 2-1 [scRNA-Seq]
The extraordinarily thin alveolar type 1 (AT1) cell constitutes nearly the entire gas exchange surface and allows passive diffusion of oxygen into the blood stream. Despite such an essential role, the transcriptional network controlling AT1 cells remains unclear. Using cell-specific knockout mouse models, genomic profiling, and three-dimensional imaging, we found that NK Homeobox 2-1 (NKX2-1) is expressed in AT1 cells and is required for the development and maintenance of AT1 cells. Without Nkx2-1, developing AT1 cells lose three defining features — molecular markers, expansive morphology, and cellular quiescence — leading to alveolar simplification and lethality. NKX2-1 is also cell-autonomously required for the same three defining features in mature AT1 cells. Intriguingly, Nkx2-1 mutant AT1 cells activate gastrointestinal genes and form dense microvilli-like structures apically. Single cell RNA-seq and whole lung ChIP-seq show NKX2-1 binding to 68% of genes that are downregulated upon Nkx2-1 deletion including 93% of known AT1 genes, but near-background binding to upregulated genes. Our results identify a key node in the AT1 cell transcriptional network and demonstrate remarkable plasticity of an otherwise terminally differentiated cell type. Overall design: FACS-purified lung epithelial, immune, endothelial, and mesenchymal cells were processed through the Chromium Single Cell Gene Expression Solution Platform (10X Genomics)