| Autor: |
Lewis, Amy, Humphreys, David T, Pan-Castillo, Belen, Berti, Giulio, Felice, Carla, Gordon, Hannah, Gadhok, Radha, Nijhuis, Anke, S, Shameer Mehta, Eleid, Liliane, Iqbal, Sidra, Armuzzi, Alessandro, Minicozzi, Annamaria, Giannoulatou, Eleni, ChinAleong, Joanne, Feakins, Roger, Sagi-Kiss, Virag, Barisic, Dora, Koufaki, Margarita-Ioanna, Bundy, Jacob G |
| Zdroj: |
Journal of Crohn's & Colitis; Jun2024, Vol. 18 Issue 6, p895-907, 13p |
| Abstrakt: |
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 TGFβ 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 TGFβ stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appeared 'metabolically primed' and responded more strongly to both TGFβ and VPA. Treatment with VPA revealed TGFβ-dependent and TGFβ-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 TGFβ-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis. [ABSTRACT FROM AUTHOR] |
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