Efficient generation of functional CFTR-expressing airway epithelial cells from human pluripotent stem cells

Wong, Amy P.; Chin, Stephanie; Xia, Sunny; Garner, Jodi; Bear, Christine E.; Rossant, Janet

doi:10.1038/nprot.2015.021

Cited by 73 publications

(130 citation statements)

References 49 publications

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“…10) confirmed that F508del-CFTR expression was increased after treatment with VX-661. These results recapitulate those previously published using the time-consuming iodide efflux methods using the same iPS cell line 46, 47 and show the potential utility of the ACC method for studying modulation of mutant CFTR responses in iPS cell-derived lung tissue. Taken together, CFTR function and pharmacological rescue of F508del-CFTR can be assessed using our ACC technique in lung cultures differentiated from patient-specific iPS cells.…”

Section: Resultssupporting

confidence: 86%

“…Further, in proof of concept studies, CF patient (F508del)-derived iPS cells differentiated into proximal lung have been shown to recapitulate the primary defect in the functional expression of CFTR-mediated chloride channel activity. 46, 47 Such functional studies have been performed using iodide efflux, patch clamp, or Ussing chamber studies of iPS cell-derived lung epithelium. 29, 46, 48, 49 To date, none of these functional assays in stem cell-derived tissues have been adapted to the medium-throughput format necessary for patient-specific drug profiling.…”

Section: Resultsmentioning

confidence: 99%

“…This difference is particularly relevant in measurements of CFTR function in iPS cell-derived lung cultures, as these cultures are not homogeneously differentiated. 46, 47 …”

Section: Discussionmentioning

confidence: 99%

“…More efficient protocols are being developed for the differentiation of conditionally reprogrammed nasal cells to differentiated nasal epithelium 56 or iPS cells to CF lung. 46, 47 These innovations will enable the generation of uniform cultures of patient-specific tissues on 96 transwell plates—platforms suitable for defining the best intervention for each patient.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia

et al. 2017

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Pulmonary disease is the major cause of morbidity and mortality in patients with cystic fibrosis, a disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Heterogeneity in CFTR genotype–phenotype relationships in affected individuals plus the escalation of drug discovery targeting specific mutations highlights the need to develop robust in vitro platforms with which to stratify therapeutic options using relevant tissue. Toward this goal, we adapted a fluorescence plate reader assay of apical CFTR-mediated chloride conductance to enable profiling of a panel of modulators on primary nasal epithelial cultures derived from patients bearing different CFTR mutations. This platform faithfully recapitulated patient-specific responses previously observed in the “gold-standard” but relatively low-throughput Ussing chamber. Moreover, using this approach, we identified a novel strategy with which to augment the response to an approved drug in specific patients. In proof of concept studies, we also validated the use of this platform in measuring drug responses in lung cultures differentiated from cystic fibrosis iPS cells. Taken together, we show that this medium throughput assay of CFTR activity has the potential to stratify cystic fibrosis patient-specific responses to approved drugs and investigational compounds in vitro in primary and iPS cell-derived airway cultures.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

“…This difference is particularly relevant in measurements of CFTR function in iPS cell-derived lung cultures, as these cultures are not homogeneously differentiated. 46, 47 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia

et al. 2017

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“…iPSCs derived from human dermal fibroblasts differentiate to form both proximal and distal airway epithelial cell types under culture conditions which mimic developmental processes [51][52][53][54][55].…”

Section: Recellularisation Of Bioengineered Airwaymentioning

confidence: 99%

Airway tissue engineering for congenital laryngotracheal disease

Lesage

Butler

Hynds

et al. 2016

Seminars in Pediatric Surgery

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Advanced In Vitro Lung Models for Drug and Toxicity Screening: The Promising Role of Induced Pluripotent Stem Cells

Moreira¹,

Müller

Costa³

et al. 2021

Advanced Biology

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Respiratory diseases are among the global leading causes of morbidity and mortality. Acute conditions arising from infection, such as pneumonia and tuberculosis, affect millions of people worldwide, the latter being the most common lethal infectious disease with 1.4 million annual deaths. [1] Upon infection, the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which caused a worldwide pandemic, leads to the clinical picture of the coronavirus disease-2019 (COVID-19) with possibly severe and life-threatening progression. Lung cancer is the most frequently diagnosed malignancy and the main cause of cancer-related death, [2] with markedly low survival rates especially when the diagnosis is performed at an advanced state of the disease. [3] Moreover, chronic respiratory diseases (CRDs), including chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung disease (ILD), have consistently received less attention in comparison to other non-communicable diseases, continuing to exert a considerable socioeconomic impact. [4,5] Risk factors for the development of respiratory diseases include, for example, tobacco use and second-hand smoke, as well as exposure to air-pollutants, which has been accentuated with the widespread use of fossil fuels. [4] It is clear that a great number of these risks can be mitigated by lifestyle changes, promoted by anti-tobacco campaigns already in place at a global scale and by the use of renewable, clean energy sources, and two recent studies indicate that the age-standardized incidence and prevalence of CRDs has decreased from 1990 to 2017. [4,5] However, the risk of developing CRDs, particularly COPD, appears to increase steeply with age; [4,5] most strikingly, these diseases were the third leading cause of death in 2017 [4] and potentially in 2020. [6] In addition to microbial, environmental, and lifestyle-related factors, a large number of lung diseases have a genetic origin. [7] Cystic fibrosis (CF), for example, is an incurable hereditary disorder known to originate from different mutations in the gene coding for the CF transmembrane conductance regulator (CFTR), an ion transporter, resulting in severe alterations in pulmonary physiology that culminate in impaired lung function, respiratory distress and, ultimately, death. [8,9]

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Efficient generation of functional CFTR-expressing airway epithelial cells from human pluripotent stem cells

Cited by 73 publications

References 49 publications

Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia

Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia

Airway tissue engineering for congenital laryngotracheal disease

Advanced In Vitro Lung Models for Drug and Toxicity Screening: The Promising Role of Induced Pluripotent Stem Cells

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