A Developmental Role of the Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Lung Disease Pathogenesis

Huang, Elena N.; Quach, Henry; Lee, Jin-A; Dierolf, Joshua; Moraes, Theo J.; Wong, Amy P.

doi:10.3389/fcell.2021.742891

Cited by 9 publications

(5 citation statements)

References 87 publications

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“…4A ), we grouped the tissues into 3 vignettes: Early (GW10-13), Mid (GW14–16), and Late (GW17-19). The late vignette (GW17-19) marks the early canalicular stage of lung development, a period in which differentiation and emergence of many epithelial cell subtypes emerge 67 . A few noteworthy trajectories were observed.…”

Section: Resultsmentioning

confidence: 99%

Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity

Quach,

Farrell,

et al. 2024

Nat Commun

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Studying human fetal lungs can inform how developmental defects and disease states alter the function of the lungs. Here, we sequenced >150,000 single cells from 19 healthy human pseudoglandular fetal lung tissues ranging between gestational weeks 10–19. We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR). These cells give rise to multiple specialized epithelial cell types. Combined with spatial transcriptomics, we show temporal regulation of key signalling pathways that may drive the temporal and spatial emergence of specialized epithelial cells including ciliated and pulmonary neuroendocrine cells. Finally, we show that human pluripotent stem cell-derived fetal lung models contain CFTR-expressing progenitor cells that capture similar lineage developmental trajectories as identified in the native tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development and benchmarks fetal lung cultures from human pluripotent stem cell differentiations to similar developmental window.

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Section: Resultsmentioning

confidence: 99%

Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity

Quach,

Farrell,

et al. 2024

Nat Commun

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“…This enzyme mediates the hydrolysis of the cAMP and cGMP. Based on the role of cAMP and cGMP in key cellular pathways as secondary messengers [ 23 ], the enzyme plays important role in cell signaling [ 24 ], including cell inorganic ion transport process [ 25 ]. The intracellular level of cAMP is suggested to be a key factor in the osmoregulation [ 26 , 27 ].…”

Section: Resultsmentioning

confidence: 99%

Adaptive laboratory evolution of Rhodococcus rhodochrous DSM6263 for chlorophenol degradation under hypersaline condition

Zheng,

Zhang,

et al. 2023

Microb Cell Fact

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Background Normally, a salt amount greater than 3.5% (w/v) is defined as hypersaline. Large amounts of hypersaline wastewater containing organic pollutants need to be treated before it can be discharged into the environment. The most critical aspect of the biological treatment of saline wastewater is the inhibitory/toxic effect exerted on bacterial metabolism by high salt concentrations. Although efforts have been dedicated to improving the performance through the use of salt-tolerant or halophilic bacteria, the diversities of the strains and the range of substrate spectrum remain limited, especially in chlorophenol wastewater treatment. Results In this study, a salt-tolerant chlorophenol-degrading strain was generated from Rhodococcus rhodochrous DSM6263, an original aniline degrader, by adaptive laboratory evolution. The evolved strain R. rhodochrous CP-8 could tolerant 8% NaCl with 4-chlorophenol degradation capacity. The synonymous mutation in phosphodiesterase of strain CP-8 may retard the hydrolysis of cyclic adenosine monophosphate (cAMP), which is a key factor reported in the osmoregulation. The experimentally verified up-regulation of intracellular cAMP level in the evolved strain CP-8 contributes to the improvement of growth phenotype under high osmotic condition. Additionally, a point mutant of the catechol 1,2-dioxygenase, CatAN211S, was revealed to show the 1.9-fold increment on activity, which the mechanism was well explained by molecular docking analysis. Conclusions This study developed one chlorophenol-degrading strain with extraordinary capacity of salt tolerance, which showed great application potential in hypersaline chlorophenol wastewater treatment. The synonymous mutation in phosphodiesterase resulted in the change of intracellular cAMP concentration and then increase the osmotic tolerance in the evolved strain. The catechol 1,2-dioxygenase mutant with improved activity also facilitated chlorophenol removal since it is the key enzyme in the degradation pathway.

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“…The abnormal ion conductance leads to dehydration of ASL, impaired MCC, airway obstruction by viscous sputum and abnormally thick and sticky mucus promotes chronic infection and inflammation. The consequence of this cascade is inflammation and progressive chronic endobronchial bacterial infection, the hallmarks of CF lungs, resulting in permanent lung damages ( Ratjen, 2009 ; Huang et al, 2021 ). Additionally, CFTR is also expressed by immune cells, including alveolar macrophages and neutrophils, which help maintaining immunological and physiological homeostasis in the lungs and are the front line of cellular defense against pathogens that were not eliminated by the mechanical defenses of the airways ( Yoshimura et al, 1991 ).…”

Section: Challengesmentioning

confidence: 99%

Gene therapy for cystic fibrosis: Challenges and prospects

Sui

et al. 2022

Front. Pharmacol.

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Cystic fibrosis (CF) is a life-threatening autosomal-recessive disease caused by mutations in a single gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). CF effects multiple organs, and lung disease is the primary cause of mortality. The median age at death from CF is in the early forties. CF was one of the first diseases to be considered for gene therapy, and efforts focused on treating CF lung disease began shortly after the CFTR gene was identified in 1989. However, despite the quickly established proof-of-concept for CFTR gene transfer in vitro and in clinical trials in 1990s, to date, 36 CF gene therapy clinical trials involving ∼600 patients with CF have yet to achieve their desired outcomes. The long journey to pursue gene therapy as a cure for CF encountered more difficulties than originally anticipated, but immense progress has been made in the past decade in the developments of next generation airway transduction viral vectors and CF animal models that reproduced human CF disease phenotypes. In this review, we look back at the history for the lessons learned from previous clinical trials and summarize the recent advances in the research for CF gene therapy, including the emerging CRISPR-based gene editing strategies. We also discuss the airway transduction vectors, large animal CF models, the complexity of CF pathogenesis and heterogeneity of CFTR expression in airway epithelium, which are the major challenges to the implementation of a successful CF gene therapy, and highlight the future opportunities and prospects.

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A Developmental Role of the Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Lung Disease Pathogenesis

Cited by 9 publications

References 87 publications

Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity

Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity

Adaptive laboratory evolution of Rhodococcus rhodochrous DSM6263 for chlorophenol degradation under hypersaline condition

Gene therapy for cystic fibrosis: Challenges and prospects

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