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Transcriptional control of lung alveolar type 1 cell development and maintenance by NK Homeobox 2-1 [scRNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE129584 | GEO | 2019/09/29

REPOSITORIES: GEO

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Project description:Lung epithelial regeneration after acute injury requires coordination of complex cellular and molecular processes required for progenitor proliferation and differentiation of specialized alveolar cells to pattern the morphologically complex alveolar gas exchange surface. During regeneration, specialized Wnt-responsive alveolar epithelial progenitor (AEP) subset of alveolar type 2 (AT2) cells transition to alveolar type 1 (AT1) cells through specialized progenitor states, though the precise molecular and epigenetic determinants of these processes remain unclear. Here, we report a refined primary murine alveolar organoid assay which recapitulates critical aspects of in vivo regeneration, providing a tractable model to dissect these key regenerative processes. Clonal expansion of single AEPs generated complex alveolar organoids with extensive structural maturation and organization. These organoids contain properly patterned AT1 and AT2 cells surrounding numerous alveolar-like cavities with minimal structural contribution from mesenchymal cells, implying extensive cell autonomous regenerative function encoded in adult AEPs. Leveraging a time series of paired scRNAseq and scATACseq analysis, we identified the AEP state at single cell resolution and defined two distinct AEP to AT1 intermediate states: a widely reported transitional state defined by cell stress markers and a second state defined by differential activation of signaling pathways mediating AT1 cell differentiation. Transcriptional regulatory network (TRN) analysis demonstrates that these AT1 transition states are driven by distinct regulatory networks controlled in part by differential activity of the lung master regulatory factor Nkx2-1. Genetic ablation of Nkx2-1 in AEP-derived organoids is sufficient to cause irreversible transition to a proliferative stressed transitional state characterized by disorganized, uncontrolled growth. Finally, AEP-specific deletion of Nkx2-1 in adult mice leads to rapid loss of AEP state, clonal expansion, and disorganization of alveolar structure, implying a continuous requirement for Nkx2-1 in maintenance and function of adult lung progenitors. Together, these data provide new insight into lineage hierarchies in lung regeneration and implicate dynamic epigenetic maintenance via lineage transcription factors as central to control of facultative progenitor activity in AEPs.

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Transcriptional control of lung alveolar type 1 cell development and maintenance by NK Homeobox 2-1 [scRNA-Seq]

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