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ScRNA-seq nased characrization of Cdh16-expression alveolar epithelial progenitor during mouse lung development

ABSTRACT: We have employed a single cell sequencing approach using 10x Genomics scRNAseq to study Cdh16-expression alveolar epithelial progenitor during mouse lung development. Alveolar morphogenesis and regeneration rely on progenitors to replenish alveolar epithelia. Cdh16 positive cells constitute an epithelial progenitor pool capable of differentiating into both AT2 and AT1 cells.In this study, we present the first scRNA-seq analysis on of Cdh16 lineage traced cells during mouse lung alveologenesis, revealing their plasticity with a dynamic differentiation trajetory along with the embryonic stages as well as the postnatal days. Overall, our study elucidates the crucial role of the Cdh16 lineage as alveolar epithelial progenitors in lung development and regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE287546 | GEO | 2025/04/01

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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ScRNA-seq nased characrization of Cdh16-expression alveolar epithelial progenitor during mouse lung development

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