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Updated: Sep 3, 2025
Generation of Human Nasal Epithelial Cell Spheroids for Individualized Cystic Fibrosis Transmembrane Conductance Regulator Study
Published on: April 11, 2018
A multimodal iPSC platform for cystic fibrosis drug testing
Andrew Berical1,2, Rhianna E Lee3,4, Junjie Lu5
1Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA.
Abstract:
Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants.
Insights
Researchers developed a new stem cell model to test cystic fibrosis (CF) treatments. This model shows genotype-specific differences in CFTR function, aiding the development of therapies for CF patients with rare variants.
Area of Science:
- Cell Biology
- Genetics
- Respiratory Medicine
Background:
- Cystic fibrosis (CF) is a monogenic lung disease caused by cystic fibrosis transmembrane conductance regulator (CFTR) anion channel dysfunction.
- While CFTR modulators have advanced CF treatment, a subset of patients lack effective therapies.
- Novel therapeutic strategies are urgently needed for individuals unresponsive to current treatments.
Purpose of the Study:
- To generate induced pluripotent stem cell (iPSC)-derived airway epithelial cells from CF patients with diverse CFTR variants.
- To establish and validate in vitro assays for measuring CFTR function in these iPSC-derived cells.
- To investigate genotype-specific CFTR function and modulator response.
Main Methods:
- Generation of iPSC lines from CF patients representing common and rare CFTR variants.
- Adaptation of two in vitro assays: forskolin-induced swelling in 3-D spheroids and polarized mucociliary airway epithelial cell cultures.
- Assessment of CFTR baseline function and response to CFTR modulators.
Main Results:
- Detected genotype-specific differences in CFTR baseline function across different CFTR variant classes.
- Observed variable responses to CFTR modulators based on patient genotype.
- Demonstrated the utility of iPSC-derived airway cells in characterizing CFTR dysfunction.
Conclusions:
- Human iPSC-derived airway cells provide a valuable platform for studying CF.
- This model can accelerate the development of targeted therapies for CF, especially for patients with rare CFTR variants.
- The findings highlight the potential for personalized medicine approaches in CF treatment.
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