Single cell transcriptome analysis of distal adult human lung airway cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130076 | GEO | 2021/12/10
REPOSITORIES: GEO
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Project description:To comprehensively study the heterogeneity within distal airway epithelium, we performed single cell transcriptomic analysis of the naive lung samples. Our analysis reveals that distal lung airway epithelial cells are highly heterogenous. We employed supervised clustering to identify a rare group of cells with transcriptional similiarities to embryonic distal lung bud tip progenitors. This approach identified a quiescent progenitor population of airway cells that accounted for all in vitro regenerative activity. Furthermore, these cells were also required for in vivo transplantation, reconstitution of alveoli, and functional recovery of injured mice. These findings indicate that small subpopulations of specialized stem/progenitors are required for effective lung regeneration and could potentially be used as therapeutic adjuncts after major lung injury.
2020-01-23 | GSE129937 | GEO
Project description:To comprehensively study the heterogeneity within distal airway epithelium, we performed single cell transcriptomic analysis of the naive lung samples. Our analysis reveals that distal lung airway epithelial cells are highly heterogenous. We employed supervised clustering to identify a rare group of cells with transcriptional similiarities to embryonic distal lung bud tip progenitors. This approach identified a quiescent progenitor population of airway cells that accounted for all in vitro regenerative activity. Furthermore, these cells were also required for in vivo transplantation, reconstitution of alveoli, and functional recovery of injured mice. These findings indicate that small subpopulations of specialized stem/progenitors are required for effective lung regeneration and could potentially be used as therapeutic adjuncts after major lung injury.
2020-01-23 | GSE130077 | GEO
Project description:Gene expression patterns of bronchiolar progenitors and club cells in mouse lung were examined by microarray experiments. Although it has not yet been fully characterized, a subset of epithelial cells lining bronchioles are best understood as bronchiolar progenitors that self-renew over the long term and that can differentiate into more differentiated club cells and ciliated cells. The bronchiolar progenitors are distinct from club cells and characteristically express the alveolar type 2 cell marker, prosurfactant protein C, with lower levels of club cell secretory protein/Scgb1a1. There are also functional differences between them; while club cells can be depleted by naphthalene because of the abundance of cytochrome P450 enzyme Cyp2f2, bronchiolar progenitors are resistant to naphthalene-induced depletion because of defects in the enzyme.
2016-02-17 | E-MTAB-4460 | biostudies-arrayexpress
Project description:The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate investigation of pathologies including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. We generated long-term feeder-free, chemically-defined culture of distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids exhibited AT1 transdifferentiation potential while basal cell organoids developed lumens lined by differentiated club and ciliated cells. Single cell analysis of basal organoid KRT5+ cells revealed a distinct ITGA6+ITGB4+ mitotic population whose proliferation further segregated to a TNFRSF12Ahi subfraction comprising ~10% of KRT5+ basal cells, residing in clusters within terminal bronchioles and exhibiting enriched clonogenic organoid growth activity. Distal lung organoids were created with apical-out polarity to display ACE2 on the exposed external surface, facilitating SARS-CoV-2 infection of AT2 and basal cultures and identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and establishes a facile in vitro organoid model for human distal lung infections including COVID-19-associated pneumonia.
2020-11-01 | GSE106850 | 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:Lung injury activates potential stem cells or progenitors for alveolar repair and regeneration. However, the activation program and source of injury-induced facultative progenitors remain incompletely known. Here, we find that lung injury induces emergence of p63-expressing progenitors, which rapidly proliferate and differentiate into alveolar type-1 (AT1) and type-2 (AT2) cells. scRNA-seq analysis uncovers that a subset of p63+ progenitors exhibit two distinct parallele transient stages before differentiation into mature AT1 and AT2 cells, respectively. Dual recombinases-mediated sequential genetic tracing reveals that facultative p63+ progenitors originate from the distal airway secretory cells and subsequently regenerate alveoli. Functioanlly, secretory cell-specific knockout of p63 significantly impairs their contribution to alveolar epithelium during lung regeneration. Our study identified secretory cell-derived facultative p63+ progenitors that contribute to alveolar regeneration, indicating a potential therapeutic target for lung treatment after injuires.
2023-02-20 | GSE225187 | GEO
Project description:The human lung differs substantially from its murine counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas exchange niche, forming an anatomical structure known as the respiratory airways. Due to the lack of a murine counterpart, the cellular and molecular characterization of the respiratory airways in the human lung remains an enigma. We show that human respiratory airways contain a unique secretory cell population that is distinct from cells in larger proximal airways. Stem cell modeling reveal that these respiratory airway secretory cells (RASCs) act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RASC lineage differentiation into AT2 cells is regulated, in part, by Notch signaling. In COPD, RASCs are altered transcriptionally, corresponding to abnormal AT2 cell states. These data identify a distinct progenitor in a region of the human lung not found in mouse that plays a critical role in maintaining the gas exchange compartment and is altered in chronic lung disease.
2021-12-09 | GSE168191 | GEO
Project description:The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel findings that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease. 3 colonies fron control and H1N1 influenza treated lungs (12 dpi) ,each were picked for whole genome microarray analysis
2011-11-01 | E-GEOD-32600 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE32600: Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection (colony) GSE32602: Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection (LCM_Four populations of cells) GSE32604: Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection (stem cell clones NESC,TASC,DASC) Refer to individual Series
2011-11-01 | E-GEOD-32606 | biostudies-arrayexpress
Project description:Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors) signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny. Immuno-localization revealed high expression levels of Igf1r (Insulin-like Growth Factor 1 Receptor) in lung epithelial cells, alveolar macrophages and smooth muscle. To further understand the role of Igf1r in pulmonary homeostasis, two distinct lung epithelial-specific Igf1r mutant mice were generated and studied. The lack of Igf1r disturbed airway epithelial differentiation in adult mice revealed enhanced proliferation and altered morphology in distal airway club cells. During recovery after naphthalene-induced club cell injury, the kinetics of terminal bronchiolar epithelium regeneration was hindered in Igf1r mutants, revealing increased proliferation and delayed differentiation of club and ciliated cells. Amid airway restoration, lungs of Igf1r deficient mice showed increased levels of Igf1, Insr, Igfbp3 and epithelial precursor markers, reduced amounts of Scgb1a1 protein, and alterations in IGF signaling mediators. These results support the role of Igf1r in controlling the kinetics of cell proliferation and differentiation during pulmonary airway epithelial regeneration after injury.
2017-02-09 | GSE88836 | GEO