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An inflammatory memory of COVID-19 in airway basal stem cells impairs mucociliary differentiation (ATAC-Seq)

ABSTRACT: Airway basal stem cells (BSCs) in chronic lung diseases accumulate memories to promote disease-specific pathogenesis. Whether acute lung infection also endows BSCs with an inflammatory memory to impair epithelial regeneration is unknown. Here, we derived multiple BSC lines from patients with and without COVID-19 (CoV19) using tracheal aspirate (TA) as a viable source of bronchial BSCs. While tested negative for SARS-CoV-2, BSC lines from CoV19 patients bore a proinflammatory gene signature, exhibited early cell cycle exist, and displayed goblet cell hypoplasia following differentiation in air-liquid interface (ALI). These phenotypes reproduced, at least partially, changes in BSCs in patients with CoV19 assessed by bioinformatic analysis of preexisting single cell transcriptomes of BSCs and by staining of lung sections for select markers. Such a memory in BSCs previously exposed to CoV19 was mediated by increases in chromosomal accessibility at key inflammatory gene loci associated with gene dysregulation and sustained STAT3 activation. Blockade of STAT3 hyperactivation in CoV19-exposed BSCs restored mucociliary differentiation in ALI. Taken together, BSCs acquire an epigenetic memory of CoV19 to impair epithelial regeneration. BSC derivation from TA provides a versatile approach to model airway epithelium in health and lung diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212410 | GEO | 2023/06/01

REPOSITORIES: GEO

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An inflammatory memory of COVID-19 in airway basal stem cells impairs mucociliary differentiation (RNA-Seq)

Project description:Airway basal stem cells (BSCs) in chronic lung diseases accumulate memories to promote disease-specific pathogenesis. Whether acute lung infection also endows BSCs with an inflammatory memory to impair epithelial regeneration is unknown. Here, we derived multiple BSC lines from patients with and without COVID-19 (CoV19) using tracheal aspirate (TA) as a viable source of bronchial BSCs. While tested negative for SARS-CoV-2, BSC lines from CoV19 patients bore a proinflammatory gene signature, exhibited early cell cycle exist, and displayed goblet cell hypoplasia following differentiation in air-liquid interface (ALI). These phenotypes reproduced, at least partially, changes in BSCs in patients with CoV19 assessed by bioinformatic analysis of preexisting single cell transcriptomes of BSCs and by staining of lung sections for select markers. Such a memory in BSCs previously exposed to CoV19 was mediated by increases in chromosomal accessibility at key inflammatory gene loci associated with gene dysregulation and sustained STAT3 activation. Blockade of STAT3 hyperactivation in CoV19-exposed BSCs restored mucociliary differentiation in ALI. Taken together, BSCs acquire an epigenetic memory of CoV19 to impair epithelial regeneration. BSC derivation from TA provides a versatile approach to model airway epithelium in health and lung diseases.

2023-06-01 | GSE212411 | GEO

MicroRNA signature during the time course of regeneration of the human airway mucociliary epithelium

Project description:The regeneration of the airway mucociliary epithelium involves several sequential events including migration, proliferation, polarization and final differentiation (i.e ciliogenesis). The airway mucociliary epithelium is consituted of three main cell types : ciliated cells, secretory cells and basal cells. We used microRNA microrrays to investigate the signature of microRNA during the four step of regeneration of the airway epithelium. Four time points (ALI-D0, ALI-D7, ALI-D14, ALI-D21) of regeneration of the airway epithelium for 3 donors.

2011-06-06 | E-GEOD-22141 | biostudies-arrayexpress

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2011-06-06 | E-GEOD-22144 | biostudies-arrayexpress

Transcriptome analysis during the time course of regeneration of the human airway mucociliary epithelium

Project description:The regeneration of the airway mucociliary epithelium involves several sequential events including migration, proliferation, polarization and final differentiation (i.e ciliogenesis). We used microarrays to detail the global programme of gene expression that occurs during regeneration and ciliogenesis of the human airway mucociliary epithelium. The four time points of regeneration of the airway epithelium (ALI-D0 which corresponds to the end of proliferation step; ALI-D7 which corresponds to the polarization step; ALI-D14 which corresponds to the onset of ciliogenesis and ALI-D21 corresponding to the terminal differentiation step) for RNA extraction and hybridization on Affymetrix microarrays.

2011-06-06 | E-GEOD-22142 | biostudies-arrayexpress

Gene expression of healthy airway epithelium and p.Sdel560 STAT3-epithelium (Job Syndrome patient) in homeostasis and after 1 hour infection with pseudomonas aeruginosa

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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. The long-term self-renewal potential of the putative human stem cell clones (NESC,TASC,DASC) allowed us to isolate independent pedigrees for the analysis of the progeny of a single cell. Expansion of these lines yielded abundant immature cells of known pedigree for a range of differentiation assays to assess lineage potential. All stem cells were grown on feeder layer (3T3).NESC were differentiated using Air liquid interface system (ALI), 3D matrigel system (MAT) and Self assembling sphere culture(SAS). The differentiation potential of TASC and DASC were studied using ALI and MAT systems.

2011-11-01 | E-GEOD-32604 | biostudies-arrayexpress

Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection

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2011-11-01 | E-GEOD-32606 | biostudies-arrayexpress

Do Airway Epithelium Air-liquid Cultures Represent the In Vivo Airway Epithelium Transcriptome?

Project description:Human airway epithelial cells cultured in vitro at air-liquid interface (ALI) form a pseudostratified epithelium that forms tight junctions and cilia, and produces mucin, and are widely used as a model of differentiation, injury, and repair. To assess how closely the transcriptome of ALI epithelium matches that of in vivo airway epithelial cells, we used microarrays to compare the transcriptome of human large airway epithelial cells cultured at ALI with the transcriptome of large airway epithelium obtained via bronchoscopy and brushing. Gene expression profiling showed global gene expression correlated well between ALI cells and brushed cells, but there were some differences. Gene expression patterns mirrored differences in proportions of cell types (ALI have higher percentages of basal cells, brushed cells have higher percentages of ciliated cells), with ALI cells expressing higher levels of basal cell-related genes and brushed cells expressing higher levels of cilia-related genes. Pathway analysis showed ALI cells had increased expression of cell cycle and proliferation genes, while brushed cells had increased expression of cytoskeletal organization and humoral immune response genes. Overall, ALI cells are a good representation of the in vivo airway epithelial transcriptome, but for some biologic questions, the differences in the in vitro vs in vivo environments need to be considered. Affymetrix arrays were used to assess the gene expression of large airway cells cultured in vitro at air-liquid interface (12 samples) and large airway epithelial cells obtained by fiberoptic bronchoscopy of 20 healthy nonsmokers. *** Air-liquid interface Samples not provided in this Series. ***

2010-07-07 | E-GEOD-18637 | biostudies-arrayexpress

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Project description:Normal human bronchial epithelial (NHBE) cells cultured in an air-liquid interface (ALI) system form a polarized, pseudostratified epithelium composed of basal, ciliated and goblet cells that closely resemble the in vivo airway epithelium structure. ALI cultures of NHBE cells provide a unique in vitro system to investigate airway epithelial biology, including developmental, structural and physiologic aspects. In this study, we wanted to investigate mRNA expression patterns during airway epithelium differentiation. By using microarrays, we studied the changes in expression of mRNAs in normal human bronchial epithelial cells as they differentiate from an undifferentiated monolayer to a differentiated pseudostratified epithelium after 28 days of air-liquid interface (ALI) culture, when epithelial cells differentially express basal, ciliated and goblet cell markers. Normal human bronchial epithelial cells were cultured in an air-liquid interface (ALI) system and harvested at three different time-points: subconfluent, confluent and day 28 of ALI. Samples were processed for total RNA extraction and hybridization on Affymetrix microarrays. All the experiments were performed by triplicate.

2012-10-01 | E-GEOD-39059 | biostudies-arrayexpress

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Project description:Biological soil crusts (BSCs) are cyanobacteria-dominated microbial communities that cover extensive portions of the world’s arid and semi-arid deserts. The infrequent periods of hydration are often too short to allow for dormancy strategies based on sporulation; consequently, survival is based on the unique capabilities of vegetative cells to resuscitate from and re-enter a stress resistant dormant state, one of which is migration within the crust layers in response to hydration. In this study, we sought to characterize the events that govern the emergence of the dominant cyanobacterium from dormancy, its subsequent growth, and the events triggered by re-desiccation and a transition back to dormant state. We performed a 48 hour laboratory wetting experiment of a desert BSC and tracked the response of Microcoleus vaginatus using a whole genome transcriptional time-course including night/day periods. This allowed the identification of genes with a diel expression pattern, genes involved uniquely in the signaling after hydration and those that contribute primarily to desiccation preparation. Desert BSC samples collected from Moab, UT, were hydrated over a period of 48 hours followed by drying induced by removal of water. At periodic times soil samples were harvested and used for RNA extraction and whole genome expression analysis using an expression array representing genes from two strains of M. vaginatus (PCC 9802 and FGP-2)

2012-10-30 | E-GEOD-40188 | biostudies-arrayexpress

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