Transcriptional analysis of injured airway epithelial cells in Mmp7-null and wildtype mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE38513 | GEO | 2012/11/01
SECONDARY ACCESSION(S): PRJNA168165
REPOSITORIES: GEO
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Project description:Matrix metalloproteinase 7 (MMP7) is expressed at low levels in intact, normal airways by non-mucous-producing cells, including ciliated cells. In response to injury and infection, MMP7 expression is quickly and markedly upregulated and functions to regulate wound repair and various mucosal immune processes. We evaluated the global transcriptional response of airway epithelial cells from wild type and Mmp7-null mice cultured at an air-liquid interface. A common injury response was seen in both genotypes with up-regulation of genes associated with proliferation and migration. Analysis of differentially expressed genes between genotypes after injury revealed enrichment of functional categories associated with inflammation, cilia and differentiation. Because these analyses suggested MMP7 regulated ciliogenesis, we evaluated the recovery of the airway epithelium in wild type and Mmp7-null mice in vivo after naphthalene injury. These studies identified a new role for MMP7 in attenuating ciliogenesis during wound repair. A total of 16 air-liquid interface cultures of mouse airway epithelial cells were studied under four conditions: 1. Mmp7-null, no injury (n = 4); 2. Mmp7-null, scratch injury (n = 4); 3. Wildtype, no injury (n =4); 4. Wiltype, scratch injury (n = 4).
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Project description:Background: High mobility group AT-hook1 (HMGA1) is essential for airway basal cell mucociliary differentiation, barrier integrity and wound repair. HMGA1 expression suppresses the abnormal basal cell differentiation to squamous, inflammatory and epithelial-mesenchymal transition phenotype commonly observed in association with cigarette smoking and chronic obstructive pulmonary disease (COPD). Results: HMGA1 knockdown experiments indicate that when HMGA1 expression is suppressed, the airway basal cells cannot normally differentiate into a mucociliary epithelium, form an intact barrier, and repair following injury. Instead, airway basal cell differentiation was skewed to an abnormal squamous EMT-like phenotype associated with airway remodeling in COPD. This study demonstrates that HMGA1 plays a key role in normal airway differentiation, regeneration of the normal airway epithelium following injury, and suppression of expression of genes related to squamous metaplasia, EMT and inflammation.
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Project description:Defective epithelial repair in the setting of chronic lung disease has been suggested to contribute to uncontrolled extracellular matrix (ECM) deposition and development of fibrosis. We sought to directly test this hypothesis through gene expression profiling of total lung RNA isolated from mouse models of selective epithelial cell injury that are associated with either productive or abortive repair. Analysis of gene expression in repairing lungs of naphthalene-exposed mice revealed prominent clusters of up-regulated genes with putative roles in regulation of the extracellular matrix and cellular proliferation. Further analysis of tenascin C (Tnc), a representative matrix protein, in total lung RNA revealed a transient 4.5-fold increase in mRNA abundance 1 day after injury and a return to steady-state levels by Recovery Day 3. Tnc was deposited by the peribronchiolar mesenchyme immediately after injury and was remodeled to basement membrane subtending the bronchiolar epithelium during epithelial repair. Epithelial restitution was accompanied by a decrease in Tnc mRNA and protein expression to steady-state levels. In contrast, abortive repair using a transgenic model allowing ablation of all reparative cells led to a progressive increase in Tnc mRNA within lung tissue and accumulation of its gene product within the subepithelial mesenchyme of both conducting airways and alveoli. These data demonstrate that the ECM is dynamically remodeled in response to selective epithelial cell injury and that this process is activated without resolution in the setting of defective airway epithelial repair. Bronchiolar Clara cells undergo phenotypic changes during development and in disease. These changes are poorly described due to a paucity of molecular markers. We used chemical and transgenic approaches to ablate Clara cells, allowing identification of their unique gene expression profile. Flavin monooxygenase 3 (Fmo3), paraoxonase 1 (Pon1), aldehyde oxidase 3 (Aox3), and claudin 10 (Cldn10) were identified as novel Clara cell markers. New and existing Clara cell marker genes were categorized into three classes based on their unique developmental expression pattern. Cldn10 was uniformly expressed in the epithelium at Embryonic Day (E)14.5 and became restricted to secretory cells at E18.5. This transition was defined by induction of Clara Cell Secretory Protein (CCSP). Maturation of secretory cells was associated with progressive increases in the expression of Fmo3, Pon1, Aox3, and Cyp2f2 between late embryonic and postnatal periods. Messenger RNA abundance of all categories of genes was dramatically decreased after naphthalene-induced airway injury, and displayed a sequence of temporal induction during repair that suggested sequential secretory cell maturation. We have defined a broader repertoire of Clara cell-specific genes that allows staging of epithelial maturation during development and repair. 32 samples were isolated and used to screen UniSet Mouse 20K I Bioarrays (total lung RNA Mus musculus). Control RNA was isolated from uninjured mice (N = 4 mice), and RNA was also isolated from mice exposed to naphthalene and recovered for 1, 2, 3, and 6 days (N = 4 mice per timepoint). Additionally, transgenic mice expressing HSV-tk under control of the mouse CCSP promoter were exposed to Ganciclovir (GCV) and recovered for 3, 6, and 9 days (N = 4 mice per timepoint).
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Project description:Adenosine (ADO) involvement in lung injury depends on the activation of its receptors (A1, A2A, A2B, A3). The A2A receptor (A2AAR) and A2B receptor (A2BAR) are best described to have both tissue-protective and tissue-destructive processes. However, no approach has been effective in delineating the mechanism(s) involved with ADO shifting from its tissue-protective to tissue-destructive properties in chronic airway injury. Using cigarette smoke (CS) as our model of injury, we hypothesized that chronic CS exposure increases CD73-generated ADO which, activates low affinity A2BAR, subsequently impairing airway wound repair. To test this hypothesis, we chronically exposed human bronchial epithelial cell line, Nuli-1 cells, to 5% CS extract (CSE) for three years establishing a long-term CSE exposure model (LTC). We found significant morphological changes, decreased proliferation, and migration resulting in impaired airway wound closure in LTC. Further investigations showed that CSE exposure upregulates CD73 and A2BAR expression, increases ADO production, inhibits PKC alpha activity and phosphorylation of MEK, ERK, p90RSK and CREB. Moreover, when both or either of A2BAR and CD73 are knocked down in LTC, PKC alpha is activated and there is an increase in phosphorylation of MEK, ERK, p90RSK and CREB. Collectively, long-term CSE exposure upregulates CD73 expression and increases ADO production, which promotes A2BAR activation and subsequent diminution of PKC alpha activity and ERK signaling pathway, and inhibition of airway wound repair. Moreover, the data suggested that targeting both A2BAR and CD73 as potential therapeutic targets may be more efficacious in improving chronic CS impaired wound repair than either alone.
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Project description:Responses of the Human Airway Epithelium Transcriptome to In Vivo Injury; To identify genes participating in repair of the human airway epithelium following injury, we used bronchoscopy and brushing to denude the airway epithelium of healthy individuals, sequentially sampled the same region 7 and 14 days later, and assessed the recovered epithelium for relative levels of gene expression using Affymetrix high-density oligonucleotide microarrays with TaqMan PCR confirmation. Histologic assessment showed that the epithelium was denuded immediately following injury, at 7 days the epithelium was completely covered but partially de-differentiated, and by 14 days there was close to normal proportions of differentiated cells. Gene expression analysis was carried out with both the Affymetrix Microarray Suite 5.0 and Robust Multi-array Average algorithms, applying a multiple test correction to identify bona fide changes in gene expression. At day 7, there were substantial differences in the gene expression pattern compared to the resting epithelium, with a distinctive airway epithelial â??repair transcriptomeâ?? of actively proliferating cells in the process of re-differentiation. The repair transcriptome at 7 days was dominated by genes encoding proteins involved in cell cycle regulation, transcription, signal transduction, metabolism and transport. Interestingly, the majority of cell cycle genes differentially expressed at day 7 belonged to the G2 and M late phases of the cell cycle, suggesting that the proliferating cells are relatively synchronized 1 wk following injury. At 14 days post-injury, the majority of the gene expression changes observed at day 7 were no longer observed, with the expression profile similar to that of resting airway epithelium. Using a class prediction algorithm, a group of 50 genes dominated by cell cycle genes, that represent a human airway epithelial â??repair signatureâ?? was identified. These observations provide a baseline of the functional gene categories participating in the process of normal human airway epithelial repair that can be used in future studies of injury and repair in human airway epithelial diseases. Experiment Overall Design: comparison of gene expression in airway epithelial cells of the large airways, before and after mechanical injury caused by airway brushing
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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.
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Project description:Repair-supportive mesenchymal cells (RSMCs) have been recently reported in the context of naphthalene (NA)-induced airway injury and regeneration. These cells transiently express smooth muscle actin (Acta2) and are enriched with platelet-derived growth factor receptor alpha (Pdgfra) and fibroblast growth factor 10 (Fgf10) expression. Genetic deletion of Ctnnb1 (gene coding for beta catenin) or Fgf10 in these cells using the Acta2-Cre-ERT2 driver line after injury (defined as NA-Tam condition; Tam refers to tamoxifen) led to impaired repair of the airway epithelium. In this study, we demonstrate that RSMCs are mostly captured using the Acta2-Cre-ERT2 driver when labeling occurs after (NA-Tam condition) rather than before injury (Tam-NA condition), and that their expansion occurs mostly between days 3 and 7 following NA treatment. Previous studies have shown that lineage-traced peribronchial GLI1+ cells are transiently amplified after NA injury. Here, we report that Gli1 expression is enriched in RSMCs. Using lineage tracing with Gli1Cre-ERT2 mice combined with genetic inactivation of Fgf10, we show that GLI1+ cells with Fgf10 deletion fail to amplify around the injured airways, thus resulting in impaired airway epithelial repair. Interestingly, Fgf10 expression is not upregulated in GLI1+ cells following NA treatment, suggesting that epithelial repair is mostly due to the increased number of Fgf10-expressing GLI1+ cells. Co-culture of SCGB1A1+ cells with GLI1+ cells isolated from non-injured or injured lungs showed that GLI1+ cells from these two conditions are similarly capable of supporting bronchiolar organoid (or bronchiolosphere) formation. Single-cell RNA sequencing on sorted lineage-labeled cells showed that the RSMC signature resembles that of alveolar fibroblasts. Altogether, our study provides strong evidence for the involvement of mesenchymal progenitors in airway epithelial regeneration and highlights the critical role played by Fgf10-expressing GLI1+ cells in this context.
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