Lewis, Amy and Humphreys, David T and Pan-Castillo, Belen and Berti, Giulio and Felice, Carla and Gordon, Hannah and Gadhok, Radha and Nijhuis, Anke and Mehta S, Shameer and Eleid, Liliane and Iqbal, Sidra and Armuzzi, Alessandro and Minicozzi, Annamaria and Giannoulatou, Eleni and ChinAleong, Joanne and Feakins, Roger and Sagi-Kiss, Virag and Barisic, Dora and Koufaki, Margarita-Ioanna and Bundy, Jacob G and Lindsay, James O and Silver, Andrew (2024) Epigenetic and Metabolic Reprogramming of Fibroblasts in Crohn’s Disease Strictures Reveals Histone Deacetylases as Therapeutic Targets. Journal of Crohn's and Colitis, 18 (6). pp.895-907. ISSN 1873-9946
Full text not available from this repository.Abstract
BACKGROUND AND AIMS: No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterized fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS: We undertook immunohistochemistry, metabolic, signalling pathway and epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/NSCD fibroblasts were cultured with TGFbeta and valproic acid [VPA]. RESULTS: Stricturing CD was characterized by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFbeta stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appeared 'metabolically primed' and responded more strongly to both TGFbeta and VPA. Treatment with VPA revealed TGFbeta-dependent and TGFbeta-independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS: Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype and metabolic priming characterize SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFbeta-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 23 Dec 2024 04:14 |
| Last Modified: | 23 Dec 2024 04:14 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1562 |
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