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A functional CFTR assay using primary cystic fibrosis intestinal organoids

Nature medicine, 2013-07, Vol.19 (7), p.939-945 [Peer Reviewed Journal]

COPYRIGHT 2013 Nature Publishing Group ;COPYRIGHT 2013 Nature Publishing Group ;Copyright Nature Publishing Group Jul 2013 ;ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/nm.3201 ;PMID: 23727931

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Title:
A functional CFTR assay using primary cystic fibrosis intestinal organoids
Author: Dekkers, Johanna F ; Wiegerinck, Caroline L ; de Jonge, Hugo R ; Bronsveld, Inez ; Janssens, Hettie M ; de Winter-de Groot, Karin M ; Brandsma, Arianne M ; de Jong, Nienke W M ; Bijvelds, Marcel J C ; Scholte, Bob J ; Nieuwenhuis, Edward E S ; van den Brink, Stieneke ; Clevers, Hans ; van der Ent, Cornelis K ; Middendorp, Sabine ; Beekman, Jeffrey M
Subjects: Animals ; Biological Assay - methods ; Biotechnology ; Cells, Cultured ; Cystic fibrosis ; Cystic Fibrosis - diagnosis ; Cystic Fibrosis - genetics ; Cystic Fibrosis - pathology ; Cystic Fibrosis Transmembrane Conductance Regulator - analysis ; Cystic Fibrosis Transmembrane Conductance Regulator - genetics ; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism ; Drug therapy ; Female ; HEK293 Cells ; Humans ; Intestinal Mucosa - metabolism ; Intestinal Mucosa - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CFTR ; Mutagenesis ; Mutant Proteins - analysis ; Mutant Proteins - genetics ; Mutant Proteins - metabolism ; Mutant Proteins - physiology ; Organoids - metabolism ; Organoids - pathology ; Primary Cell Culture - methods ; Technology application ; Tissues ; Water - metabolism
Is Part Of: Nature medicine, 2013-07, Vol.19 (7), p.939-945
Description: 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.
Publisher: United States: Nature Publishing Group
Language: English
Identifier: ISSN: 1078-8956
EISSN: 1546-170X
DOI: 10.1038/nm.3201
PMID: 23727931
Source: MEDLINE
ProQuest Central

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A functional CFTR assay using primary cystic fibrosis intestinal organoids

COPYRIGHT 2013 Nature Publishing Group ;COPYRIGHT 2013 Nature Publishing Group ;Copyright Nature Publishing Group Jul 2013 ;ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/nm.3201 ;PMID: 23727931

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