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. 2014 Oct 15;190(8):955-8.
doi: 10.1164/rccm.201406-1167LE.

"V体育2025版" Airway Basal stem/progenitor cells have diminished capacity to regenerate airway epithelium in chronic obstructive pulmonary disease

Michelle R Staudt  1 , Lauren J Buro-Auriemma, Matthew S Walters, Jacqueline Salit, Thomas Vincent, Renat Shaykhiev, Jason G Mezey, Ann E Tilley, Robert J Kaner, Melisa W Y Ho, Ronald G Crystal
Affiliations

Airway Basal stem/progenitor cells have diminished capacity to regenerate airway epithelium in chronic obstructive pulmonary disease

Michelle R Staudt et al. Am J Respir Crit Care Med. .
No abstract available

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Figures

Figure 1.
Figure 1.
Capacity of airway basal cells from nonsmokers, smokers, and smokers with chronic obstructive pulmonary disease (COPD) to regenerate a mucociliary epithelium. The study cohort included n = 17 healthy nonsmokers, n = 14 healthy smokers, and n = 16 COPD smokers (9 Global Initiative for Chronic Obstructive Lung Disease [GOLD] I, 6 GOLD II, 1 GOLD III). All subjects were assessed by medical history, physical exam, routine blood tests, chest X-ray, and full lung function tests (including FVC, FEV1, FEV1/FVC, TLC, and diffusing capacity of carbon monoxide). Smoking was confirmed by urine tobacco metabolite analysis. All subjects had normal α1-antitrypsin levels and were HIV-negative. Healthy nonsmokers and healthy smokers had normal chest X-ray and lung function. Purified primary basal cells (BCs) were obtained by fiberoptic bronchoscopy and brushing of the small airway epithelium (SAE; 10th- to 12th-order bronchi) and were characterized as previously described (9, 10). The purified basal cells were seeded on air–liquid interface (ALI; 3 × 105 cells/cm2, on 0.4-μm pore-sized Costar Transwell (New York, NY) insert precoated with type 4 collagen) and cultured for 28 days in medium (9, 10). Transepithelial electrical resistance was assessed at Day 10, and the ability to form a differentiated epithelium was assessed over the course of 28 days. (A) Transepithelial electrical resistance of SAE-derived BC cultured on ALI. Resistance (Ω ⋅ cm2) was measured at Day 10 of ALI culture. Data shown are the average transepithelial electrical resistance ± standard error. Significance was determined by a two-tailed t test (smokers vs. nonsmokers, P > 0.05; COPD smokers vs. nonsmokers, P < 0.003; smokers vs. COPD smokers, P > 0.3). (B) Capacity of SAE-derived BCs to regenerate a differentiated epithelium on ALI culture. Ordinate, percentage of total SAE-BC samples regenerating a differentiated epithelium on ALI culture; abscissa, time (in days) on ALI culture. Cultures that failed to fully differentiate to Day 28 on ALI exhibited spontaneous generation of holes in the cellular monolayer, followed by collapse and failure of the culture at 10–28 days. Pairwise comparison of survival curves was performed using a log-rank test (smokers vs. nonsmokers, P > 0.09; COPD smokers vs. nonsmokers, P < 0.009; smokers vs. COPD smokers, P > 0.3). To ensure that the number of samples did not affect the test statistic, an exact conditional test was used to compare the survival curves of different groups; this yielded similar P values (not shown). (C) Immunofluorescence analysis of ALI culture differentiation at Day 28. The ability of SAE-derived BC to differentiate on ALI at Day 28 was assessed by immunofluorescent staining for β-tubulin IV (ciliated cells, green), SCGB1A1 (secretory cells, red), and nuclei (blue); scale bars = 20 μm. (D) Quantification of differentiation of ALI Day 28 of SAE-BC cultures. The number of SCGB1A1-positive secretory cells from immunofluorescent staining was scored. Data are shown as percentage of total cells, average ± standard error. Statistics were calculated by two-tailed t test.
Figure 2.
Figure 2.
DNA methylation profile of small airway basal cells that could not regenerate a differentiated epithelium ex vivo compared with small airway basal cells that could regenerate a differentiated epithelium. Primary BCs from Figure 1 were assessed at time 0 before seeding on ALI culture. Genomewide DNA methylation data were assessed using the Illumina Infinium HumanMethylation 450 array. (A) Volcano plot, genomewide DNA methylation analysis of small airway epithelium (SAE)-derived basal cells (BCs) that did not have the capacity to regenerate a differentiated epithelium compared with BCs that did regenerate. Assessment was performed using logit transformed β values of more than 414,000 methylation sites and Illumina recommendations to eliminate probes with detection P < 0.01, as well as filtering out probes on X and Y chromosomes and probes not associated with genes, CpG islands, or shores. Ordinate, P value (log10); abscissa, fold change (log2). Red indicates probe sets significantly different (P < 0.05) with fold-change higher than 1.5 compared between samples that could not regenerate versus samples that could regenerate a differentiated epithelium; gray indicates nonsignificant probe sets. (B) Unsupervised hierarchical clustering, genomewide DNA methylation analysis of SAE-BC that could regenerate versus those that could not regenerate a differentiated epithelium over the course of 28 days in the ALI culture (423 probe sets, fold-change > 1.5; P < 0.05). Probe sets identifying hypermethylated regions are represented in red, hypomethylated in blue, and average in gray. Probe sets are represented horizontally and individual samples vertically. The phenotype of individual samples is shown vertically. The horizontal color legend represents the SAE-BC survival phenotype: yellow, ALI cultures that could not regenerate; green, ALI cultures that could regenerate and survive until Day 28. The smoking phenotype of samples is represented: green, healthy nonsmokers; orange, healthy smokers; red, COPD smokers. The orange horizontal line designates the major separation of clusters between SAE-BC samples that did not regenerate versus those that regenerated over the course of 28 days on ALI. (C) Functional categories of the 277 significant genes differentially methylated in SAE-BC that did not have the capacity to regenerate a differentiated epithelium versus SAE-BC that did have the capacity (fold-change > 1.5, P < 0.05). Shown are the fold-changes of the differentially methylated genes on a log2 scale. Ingenuity pathway analysis was performed on the 277 unique hyper- and hypomethylated genes.
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