A functional CFTR assay using primary cystic fibrosis intestinal organoids
Abstract
We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin-induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.
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Derivation of organoids from patient material enables personalized disease modeling and drug screening.
“This enables personalized disease modeling and drug screening.8”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [8]
ASC organoids can be derived from healthy organs, from patients with Mendelian disorders such as cystic fibrosis, or directly from tumor material.
“Additionally, organoids can be derived from both healthy (i.e., wild-type) organs, but also from patients suffering from Mendelian disorders such as cystic fibrosis or directly from tumor material.”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [8]
Organoid swelling depends on the activity of the CFTR anion channel.
“Lumen formation and increased organoid size of intestinal organoids (swelling) depends on the activity of the CFTR anion channel46 (schematized in Fig. 3g) and thus can be used to measure the restoration of CFTR function after AsCas12a-crRNA+11 genome editing.”
From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [46]
Intestinal organoids from CF patients are valuable tools to evaluate CFTR channel activity and functional recovery.
“Intestinal organoids from CF patients are valuable tools to evaluate CFTR channel activity and functional recovery46–48.”
From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [46]
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- Authors
- Dekkers, J. F., Wiegerinck, C. L., de Jonge, H. R., Bronsveld, I., Janssens, H. M., de Winter-de Groot, K. M., Brandsma, A. M., de Jong, N. W. M., Bijvelds, M. J. C., Scholte, B. J., Nieuwenhuis, E. E. S., van den Brink, S., Clevers, H., van der Ent, C. K., Middendorp, S., & Beekman, J. M.
- Affiliations
- University Medical Center Utrecht (NL)
- Erasmus MC (NL)
- Corresponding author
- Clevers, Hans
- Beekman, Jeffrey M
- ORCID
- Venue
- Nature Medicine
- Published
- 2013-06-02
- Volume
- 19
- Issue
- 7
- Pages
- 939-945
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2151829259
- Cited by
- 999
- References
- 4
- Citations by year
- 2026: 55 · 2025: 70 · 2024: 60 · 2023: 71 · 2022: 93 · 2021: 111 · 2020: 120 · 2019: 82 · 2018: 100 · 2017: 77 · 2016: 69 · 2015: 44 · 2014: 35 · 2013: 10
- FWCI
- 42.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- cystic fibrosis, CFTR, intestinal organoids, F508del mutation, anion currents, CFTR correctors, CFTR potentiators, organoid expansion, personalized medicine, drug development
- MeSH terms
- Animals, Biological Assay, Cells, Cultured, Cystic Fibrosis, Female, Humans, Intestinal Mucosa, Male, Mice, Inbred C57BL, Organoids, Water, Mice, Inbred CFTR, Cystic Fibrosis Transmembrane Conductance Regulator, Mutant Proteins, Mice, HEK293 Cells, Primary Cell Culture
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