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Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration.

ABSTRACT: Lung epithelial regeneration after acute injury requires coordination cellular coordination to pattern the morphologically complex alveolar gas exchange surface. During adult lung regeneration, Wnt-responsive alveolar epithelial progenitor (AEP) cells, a subset of alveolar type 2 (AT2) cells, proliferate and transition to alveolar type 1 (AT1) cells. Here, we report a refined primary murine alveolar organoid, which recapitulates critical aspects of in vivo regeneration. Paired scRNAseq and scATACseq followed by transcriptional regulatory network (TRN) analysis identified two AT1 transition states driven by distinct regulatory networks controlled in part by differential activity of Nkx2-1. Genetic ablation of Nkx2-1 in AEP-derived organoids was sufficient to cause transition to a proliferative stressed Krt8⁺ state, and AEP-specific deletion of Nkx2-1 in adult mice led to rapid loss of progenitor state and uncontrolled growth of Krt8⁺ cells. Together, these data implicate dynamic epigenetic maintenance via Nkx2-1 as central to the control of facultative progenitor activity in AEPs.

SUBMITTER: Toth A

PROVIDER: S-EPMC10775890 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration.

Toth Andrea A Kannan Paranthaman P Snowball John J Kofron Matthew M Wayman Joseph A JA Bridges James P JP Miraldi Emily R ER Swarr Daniel D Zacharias William J WJ

Nature communications 20231219 1

Lung epithelial regeneration after acute injury requires coordination cellular coordination to pattern the morphologically complex alveolar gas exchange surface. During adult lung regeneration, Wnt-responsive alveolar epithelial progenitor (AEP) cells, a subset of alveolar type 2 (AT2) cells, proliferate and transition to alveolar type 1 (AT1) cells. Here, we report a refined primary murine alveolar organoid, which recapitulates critical aspects of in vivo regeneration. Paired scRNAseq and scATA ...[more]

PMID: 38114516

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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.

Dataset Information

Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration.

Publications

Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration.

Similar Datasets

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