Gene expression profile of intestinal organoids from people with cystic fibrosis upon exposure to elexacaftor/tezacaftor/ivacaftor
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
39278758
DOI
10.1016/j.jcf.2024.09.005
PII: S1569-1993(24)01713-2
Knihovny.cz E-zdroje
- Klíčová slova
- Cystic fibrosis, Differential expression, Elexacaftor, Intestinal organoid, Ivacaftor, Tezacaftor,
- MeSH
- aktivátory chloridových kanálů farmakologie MeSH
- aminofenoly * farmakologie MeSH
- benzodioxoly * farmakologie MeSH
- chinoliny MeSH
- chinolony * farmakologie MeSH
- cystická fibróza * genetika farmakoterapie MeSH
- fixní kombinace léků MeSH
- indoly * farmakologie MeSH
- lidé MeSH
- organoidy * účinky léků metabolismus MeSH
- protein CFTR genetika MeSH
- pyrazoly MeSH
- pyridiny * farmakologie MeSH
- pyrrolidiny MeSH
- pyrroly * farmakologie MeSH
- stanovení celkové genové exprese MeSH
- thiofeny farmakologie MeSH
- transkriptom MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aktivátory chloridových kanálů MeSH
- aminofenoly * MeSH
- benzodioxoly * MeSH
- chinoliny MeSH
- chinolony * MeSH
- elexacaftor, ivacaftor, tezacaftor drug combination MeSH Prohlížeč
- elexacaftor MeSH Prohlížeč
- fixní kombinace léků MeSH
- indoly * MeSH
- ivacaftor MeSH Prohlížeč
- protein CFTR MeSH
- pyrazoly MeSH
- pyridiny * MeSH
- pyrrolidiny MeSH
- pyrroly * MeSH
- tezacaftor MeSH Prohlížeč
- thiofeny MeSH
The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.
Citace poskytuje Crossref.org
