Epigenetic modulation of stromal cell states underpins pathological tissue niches in Crohn’s disease
Abstract
Stromal cell states are altered in active Crohn’s disease (CD), but their origin and phenotypic stability are unknown. Using single-cell spatial transcriptomics, RNA sequencing and ATAC sequencing of ~2,500,000 cells, we map 18 distinct stromal cell states within their cellular and cytokine signaling environments in human full-thickness CD bowel. Inflammatory fibroblasts (IFs) reside in immune cell-rich mucosal ulcers and are induced through combinatorial cytokine exposure suppressing submucosal universal fibroblast programs. The IF state is stabilized through transcription factor (TF) activity of GLI3, TWIST1, ETV4, PRDM1 and RELB, and does not spontaneously revert; however, histone deacetylase inhibition destabilizes the IF state, preventing IF secretome-induced epithelial transmigration and activation of neutrophils. The IF open chromatin configuration is distinct from that of fibrotic contractile stroma, which populate adjoining immune-depleted submucosal fibrotic niches. These findings show that microenvironments in pathological tissue niches shape open chromatin configuration of stromal states that are amenable to modulation by epigenetic modifiers.
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BibTeX
@article{koplev2026epigenetic,
title = {{Epigenetic modulation of stromal cell states underpins pathological tissue niches in Crohn’s disease}},
author = {Simon Koplev and Osheen Sharma and Simon Woelfel and Ni Huang and Mathilde Pohin and Adrian Feile and Maria Warschinke and Mikel Rezola Artero and Sharujan Suthakaran and Ioannis Sarropoulos and J. Patrick Pett and Julia Nyman and Tom Thomas and Duy Pham and Bin Li and Moustafa Attar and Julia Pakpoor and Kate Milosevic-Hutton and Alistair Easton and Matt Butler and James Dunford and Martin Philpott and Mark Coles and Christopher D Buckley and Calliope Dendrou and Khalid Shamiyah and Lorenz Kretschmer and Lisa Dratva and Fadi Issa and Joanna Hester and Jens Rittscher and Alissa Walsh and Simon P Travis and Fränze Progatzky and Lukas W Unger and Mark Bignell and Katherine Baker and Bruce George and Hussein Al-Mossawi and Paul Klenerman and Alexander S Mosig and Udo Oppermann and Sarah A Teichmann and Fiona M Powrie and Matthias Friedrich},
journal = {Nature Immunology},
year = {2026},
month = aug,
doi = {10.1038/s41590-026-02617-0},
url = {https://u-bordeaux.hal.science/hal-05745717v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epigenetic modulation of stromal cell states underpins pathological tissue niches in Crohn’s disease
AU - Simon Koplev
AU - Osheen Sharma
AU - Simon Woelfel
AU - Ni Huang
AU - Mathilde Pohin
AU - Adrian Feile
AU - Maria Warschinke
AU - Mikel Rezola Artero
AU - Sharujan Suthakaran
AU - Ioannis Sarropoulos
AU - J. Patrick Pett
AU - Julia Nyman
AU - Tom Thomas
AU - Duy Pham
AU - Bin Li
AU - Moustafa Attar
AU - Julia Pakpoor
AU - Kate Milosevic-Hutton
AU - Alistair Easton
AU - Matt Butler
AU - James Dunford
AU - Martin Philpott
AU - Mark Coles
AU - Christopher D Buckley
AU - Calliope Dendrou
AU - Khalid Shamiyah
AU - Lorenz Kretschmer
AU - Lisa Dratva
AU - Fadi Issa
AU - Joanna Hester
AU - Jens Rittscher
AU - Alissa Walsh
AU - Simon P Travis
AU - Fränze Progatzky
AU - Lukas W Unger
AU - Mark Bignell
AU - Katherine Baker
AU - Bruce George
AU - Hussein Al-Mossawi
AU - Paul Klenerman
AU - Alexander S Mosig
AU - Udo Oppermann
AU - Sarah A Teichmann
AU - Fiona M Powrie
AU - Matthias Friedrich
PY - 2026
DA - 2026/08/12
JO - Nature Immunology
DO - 10.1038/s41590-026-02617-0
UR - https://u-bordeaux.hal.science/hal-05745717v1
AB - Stromal cell states are altered in active Crohn’s disease (CD), but their origin and phenotypic stability are unknown. Using single-cell spatial transcriptomics, RNA sequencing and ATAC sequencing of ~2,500,000 cells, we map 18 distinct stromal cell states within their cellular and cytokine signaling environments in human full-thickness CD bowel. Inflammatory fibroblasts (IFs) reside in immune cell-rich mucosal ulcers and are induced through combinatorial cytokine exposure suppressing submucosal universal fibroblast programs. The IF state is stabilized through transcription factor (TF) activity of GLI3, TWIST1, ETV4, PRDM1 and RELB, and does not spontaneously revert; however, histone deacetylase inhibition destabilizes the IF state, preventing IF secretome-induced epithelial transmigration and activation of neutrophils. The IF open chromatin configuration is distinct from that of fibrotic contractile stroma, which populate adjoining immune-depleted submucosal fibrotic niches. These findings show that microenvironments in pathological tissue niches shape open chromatin configuration of stromal states that are amenable to modulation by epigenetic modifiers.
SN - 1529-2908
SN - 1529-2916
ER -