Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA326167 | ENA |
REPOSITORIES: ENA
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Project description:Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
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Project description:Mouse pooled LNEPs, pre- and post-influenza - Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
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Project description:Alveolar epithelial cell fate decisions drive lung development and regeneration. Using transcriptomic and epigenetic profiling coupled with genetic mouse and organoid models, we identified Klf5 as a critical regulator of alveolar epithelial cell fate across the lifespan. During prenatal lung development and alveologenesis, Klf5 enforces alveolar epithelial type 1 (AT1) cell lineage fidelity. While it is dispensable for both adult AT1 and alveolar epithelial type 2 (AT2) cell homeostasis, Klf5 regulates AT2 cell plasticity after injury. Klf5 represses AT2 cell proliferation and enhances AT2-AT1 cell differentiation in a spatially restricted manner in both infectious and non-infectious models of acute respiratory distress syndrome. Moreover, ex vivo organoid assays reveal that Klf5 modulates AT2 cell fate decisions through reducing AT2 cell sensitivity to inflammatory signaling. These data highlight a major transcriptional regulator of AT1 cell lineage commitment and of the AT2 cell response to inflammatory crosstalk during lung regeneration.
2022-06-08 | GSE190676 | GEO
Project description:Alveolar type 2 (AT2) are part of the stem cell niche of the lung and their differentiation is required for pulmonary homeostasis and tissue regeneration. A disturbed crosstalk between fibroblasts and epithelial cells contributes to the loss of lung structure in chronic lung diseases. We used single cell RNA sequencing to analyze the interaction of human fibroblasts and the alveolar epithelium modelled in organoid cultures.
2024-02-19 | GSE254441 | GEO
Project description:Alveolar epithelial type 2 (AT2) cells are facultative progenitor cells that drive adult alveolar regeneration after acute lung injury. Using transcriptomic analyses from in vivo mouse injury models, we define the role of Tfcp2l1 in regulating AT2 cell behavior during lung regeneration.
2023-09-12 | GSE204786 | GEO
Project description:Alveolar epithelial type 2 (AT2) cells are facultative progenitor cells that drive adult alveolar regeneration after acute lung injury. Using transcriptomic analyses from in vivo mouse injury models, we define the role of Tfcp2l1 in regulating AT2 cell behavior during lung regeneration.
2023-09-12 | GSE204784 | GEO
Project description:Alveolar epithelial regeneration is critical for normal lung function and becomes dysregulated in disease. While alveolar type 2 (AT2) and club cells are known distal lung epithelial progenitors, determining if alveolar epithelial type 1 (AT1) cells also contribute to alveolar regeneration has been hampered by lack of highly specific mouse models labeling AT1 cells. To address this, the Gramd2CreERT2 transgenic strain was generated and crossed to ROSAmTmG mice. Extensive cellular characterization, including distal lung immunofluorescence and cytospin staining, confirmed that GRAMD2+ AT1 cells are highly enriched for green fluoresecent protein (GFP). Interestingly, Gramd2CreERT2 GFP+ cells were able to form colonies in organoid co-culture with Mlg fibroblasts. Temporal scRNAseq revealed that Gramd2+ AT1 cells transition through numerous intermediate lung epithelial cell states including basal, secretory and AT2 cell in organoids while acquiring proliferative capacity. Our results indicate that Gramd2+ AT1 cells are highly plastic suggesting they may contribute to alveolar regeneration.
2023-10-04 | GSE235217 | GEO
Project description:Idiopathic Pulmonary Fibrosis (IPF) is a progressive and often fatal chronic respiratory disease thought to result from repetitive injury and failed repair of the lung alveoli, and recent studies have identified a number of disease-emergent intermediate/transitional cell states in the IPF lung supporting this concept. In this study, we found that persistent activation of hypoxia-inducible factor (HIF)-signaling in airway-derived, repair-associated cell types/states is a hallmark of dysfunctional epithelial repair in the IPF lung epithelium and experimental models of recurrent lung epithelial injury. Disrupting Hif-signaling attenuated experimental lung fibrosis, reduced mucous-secretory cell polarization, and promoted functional alveolar regeneration following repetitive injury. Mouse and human organoid studies demonstrated that small-molecule-based HIF2 inhibition promoted alveolar epithelial cell proliferation and maturation while preventing the emergence of maladaptive intermediate/transitional states analogous to those in IPF. Together, these studies indicate that targeted HIF2-inhibition represents a novel and effective therapeutic strategy to promote functional lung regeneration, and could be readily translated into human studies of IPF and other chronic interstitial lung diseases with disease modifying effect.
2023-09-18 | GSE243252 | GEO
Project description:Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here, we leveraged single-cell RNA sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, Damage-Associated Transient Progenitors (DATPs), that arises during alveolar regeneration. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this step-wise mapping to cell fate transitions shows how an inflammatory niche impairs alveolar regeneration by controlling stem cell fate and behavior.
2020-08-03 | GSE144598 | GEO
Project description:Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here, we leveraged single-cell RNA sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, Damage-Associated Transient Progenitors (DATPs), that arises during alveolar regeneration. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this step-wise mapping to cell fate transitions shows how an inflammatory niche impairs alveolar regeneration by controlling stem cell fate and behavior.
2020-08-03 | GSE145031 | GEO