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Impact of Pclaf/Paf knock-out on murine lung regeneration (scRNA-seq)

ABSTRACT: The spatiotemporal orchestration of lung stem/progenitor cells is essential for lung regeneration, of which failure leads to lung disease, including fibrosis. We sought to identify mechanisms controlling lung stem/progenitor cells during lung regeneration. We previously found that PCLAF/PAF/KIAA0101 remodels the DREAM complex for cell quiescence exit and cell proliferation. PCLAF is expressed explicitly in the pulmonary proliferative cells (PPC), along with the DREAM target genes. Pclaf expression and Pclaf-expressing cells were acutely increased upon lung injury. Intriguingly, Pclaf knock-out mice exhibited lung fibrosis with impaired alveolar regeneration, resulting from the loss of alveolar type I cells. The single-cell transcriptome and organoid analyses showed that Pclaf transactivated the DREAM target gene expression for alveolar type I cells repopulation from alveolar type 2 cells. Additionally, pharmacological mimicking of the Pclaf-mediated transcriptome markedly increased alveolar regeneration in vitro and in vivo, without neoplasia. Together, our study unveiled the pivotal roles of the PCLAF-DREAM axis in controlling stem/progenitor cell activation and cell lineage, further proposing the potentially viable option for lung regenerative medicine.

ORGANISM(S): Mus musculus

PROVIDER: GSE205815 | GEO | 2024/05/31

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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Impact of Pclaf/Paf knock-out on murine lung regeneration (scRNA-seq)

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