Characterization of patient-derived intestinal organoids for modelling fibrosis in Inflammatory Bowel Disease.
Inflamm Res
; 73(8): 1359-1370, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38842554
ABSTRACT
BACKGROUND AND AIMS:
Intestinal fibrosis is a common complication of Inflammatory Bowel Disease (IBD), namely Crohn's disease (CD) and ulcerative colitis (UC), but the precise mechanism by which it occurs is incompletely understood hampering the development of effective therapeutic strategies. Here, we aimed at inducing and characterizing an inflammation-mediated fibrosis in patient-derived organoids (PDOs) issued from crypts isolated from colonic mucosal biopsies of IBD pediatric patients and age matched-control subjects (CTRLs).METHODS:
Inflammatory-driven fibrosis was induced by exposing CTRL-, CD- and UC-PDOs to the pro-inflammatory cytokine TNF-α for one day, followed by a co-treatment with TNF-α and TGF-ß1 for three days. Fibrotic response was proven by analyzing inflammatory and fibrotic markers by RT-qPCR and immunofluorescence. Transcriptomic changes were assessed by RNA-sequencing.RESULTS:
Co-treatment with TNF-α and TGF-ß1 caused in CTRL- and IBD-PDOs morphological changes towards a mesenchymal-like phenotype and up-regulation of inflammatory, mesenchymal, and fibrotic markers. Transcriptomic profiling highlighted that in all intestinal PDOs, regardless of the disease, the co-exposure to TNF-α and TGF-ß1 regulated EMT genes and specifically increased genes involved in positive regulation of cell migration. Finally, we demonstrated that CD-PDOs display a specific response to fibrosis compared to both CTRL- and UC-PDOs, mainly characterized by upregulation of nuclear factors controlling transcription.CONCLUSIONS:
This study demonstrates that intestinal PDOs may develop an inflammatory-derived fibrosis thus representing a promising tool to study fibrogenesis in IBD. Fibrotic PDOs show increased expression of EMT genes. In particular, fibrotic CD-PDOs display a specific gene expression signature compared to UC and CTRL-PDOs.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fibrose
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Organoides
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Fator de Necrose Tumoral alfa
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Fator de Crescimento Transformador beta1
Limite:
Adolescent
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Child
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article