Regenerative Metaplastic Clones in COPD Lung Drive Inflammation and Fibrosis.
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ABSTRACT:
SUBMITTER: Rao W
PROVIDER: S-EPMC7294989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The human airway epithelium is regenerated by basal cells. Thus, basal cell therapy has the potential to cure cystic fibrosis (CF) lung disease. We previously reported that the human basal cells repopulated the mouse airway epithelium after transplantation, and we estimated that 60 million cells would be needed to treat a human patient. To further develop cell therapy, we compared the proliferation potential of non-CF and CF tissue-derived bronchial basal cells. Three methods were used: regenerative cell frequency, burst size, and cell division frequency. Second, we used a serial passage strategy to determine if CF basal cells could be amplified to the estimated therapeutic dose. These studies evaluated that tissue-derived bronchial basal cells and the basal cells that were recovered by brushing bronchial airways or the nasal respiratory epithelium. Finally, we used the limiting dilution method to isolate non-CF and CF basal cell clones. The proliferation assays and the air-liquid-interface differentiation method were used to determine if cell amplification altered the proliferation and/or differentiation potential of clonal isolates. We demonstrate that: (a) non-CF and CF basal cell proliferation is similar, (b) CF basal cells can be amplified to a therapeutic cell dose, and (c) amplified non-CF and CF basal cell clones differentiate normally. Despite these encouraging findings, we also find that the cell amplification process depletes the regenerative basal cell pool. Analysis of basal cell clones indicates that serial passage selects for long-lived basal cells and raise the possibility that prospective isolation of these stem-like cells will improve the efficacy of cell replacement therapy. Stem Cells Translational Medicine 2019;8:225&235.
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Project description:Controlled recruitment of C-C Motif Chemokine Receptor 2 (CCR2)-positive monocytes into lung tissues is a crucial component of the host immune response to infections. Pathogenesis of cystic fibrosis (CF) lung remodeling, which ultimately leads to respiratory failure, is caused by chronic infections and neutrophilic inflammation, but the immune mechanisms are not fully understood. Here, we show that lung explants from CF patients with severe disease contain abundant CCR2-positive classical monocytes in the submucosal tissues of small airways and areas of tissue remodeling. Recapitulating human CF lung remodeling by repeatedly exposing CF mice to lipopolysaccharide (LPS), and by using genetic ablation or pharmacological inhibition of CCR2, we demonstrate that CCR2-dependent accumulation of classical monocytes and monocyte-derived macrophages drive lung neutrophilia, pathogenic Transforming Growth Factor Beta signaling and irreversible lung tissue scarring. Importantly, six weeks after cessation of LPS exposure, the lungs of CF mice still have elevated numbers of pro-inflammatory monocytes with higher expression of neutrophil chemoattractants, thus perpetuating recruitment of neutrophils and lung tissue damage. Lastly, we demonstrate that the increased accumulation of immune cells to inflamed lungs is driven by dysfunctional CF transmembrane conductance regulator (CFTR) expression in CCR2-positive cells. These studies identify uncontrolled recruitment of CCR2-positive cells as a key driver of lung remodeling, and as a novel therapeutic target for patients with CF for which lung hyper-inflammation and tissue damage remain an issue despite recent advances in CFTR-specific therapeutics. Keywords: monocytes; macrophages; neutrophils; chronic lung inflammation; lipopolysaccharide; recruitment; CC-motif chemokine receptor 2; transforming growth factor beta; lung remodeling; cystic fibrosis
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