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Background <p>Intestinal epithelial stem cells (SCs) and their transit-amplifying (TA) progeny are critical for mucosal repair and regeneration. However, their behaviour under chronic inflammatory conditions, such as those observed in Inflammatory Bowel Disease (IBD), remains incompletely understood.</p> Methods <p>We investigated the impact of chronic inflammation on intestinal stem/progenitor cells by integrating bulk RNA sequencing from the largest IBD biopsy cohort to date with single-cell transcriptomic analysis and experimental assays using patient-derived intestinal organoids.</p> Results <p>Active inflammation was associated with a reduction in canonical LGR5⁺ intestinal stem cells and a concurrent expansion of OLFM4⁺ populations, consistent with an inflammation-induced epithelial repair program. Notably, SC/TA cells from both inflamed and non-inflamed IBD tissues exhibited persistent transcriptional changes that were distinct from those in healthy controls. Single-cell analysis identified transcriptionally heterogeneous SC/TA subpopulations, including a previously uncharacterized inflammation-associated cluster enriched in immune signalling pathways. Pseudotime trajectory analysis demonstrated a shift in differentiation toward deep crypt secretory (Paneth-like) cell lineages under inflammatory conditions.</p> Conclusions <p>Chronic intestinal inflammation reshapes the epithelial stem and progenitor cell compartment, promoting altered differentiation and the emergence of immune-responsive epithelial states. These findings highlight the plasticity of the human intestinal epithelium in IBD and point to new avenues for therapeutic strategies aimed at maintaining epithelial integrity during chronic inflammation.</p>

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Intestinal stem and progenitor cells exhibit distinct adaptive responses to inflammatory stress in IBD

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月21日

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  • Brinda Balasubramanian,
  • Shivam Patel,
  • Louis Gall,
  • Nicholas R. F. Hannan,
  • William Dalleywater,
  • Joerg Huelsken,
  • Carmen Pin,
  • Gordon W. Moran,
  • Paloma Ordóñez-Morán

摘要

Background

Intestinal epithelial stem cells (SCs) and their transit-amplifying (TA) progeny are critical for mucosal repair and regeneration. However, their behaviour under chronic inflammatory conditions, such as those observed in Inflammatory Bowel Disease (IBD), remains incompletely understood.

Methods

We investigated the impact of chronic inflammation on intestinal stem/progenitor cells by integrating bulk RNA sequencing from the largest IBD biopsy cohort to date with single-cell transcriptomic analysis and experimental assays using patient-derived intestinal organoids.

Results

Active inflammation was associated with a reduction in canonical LGR5⁺ intestinal stem cells and a concurrent expansion of OLFM4⁺ populations, consistent with an inflammation-induced epithelial repair program. Notably, SC/TA cells from both inflamed and non-inflamed IBD tissues exhibited persistent transcriptional changes that were distinct from those in healthy controls. Single-cell analysis identified transcriptionally heterogeneous SC/TA subpopulations, including a previously uncharacterized inflammation-associated cluster enriched in immune signalling pathways. Pseudotime trajectory analysis demonstrated a shift in differentiation toward deep crypt secretory (Paneth-like) cell lineages under inflammatory conditions.

Conclusions

Chronic intestinal inflammation reshapes the epithelial stem and progenitor cell compartment, promoting altered differentiation and the emergence of immune-responsive epithelial states. These findings highlight the plasticity of the human intestinal epithelium in IBD and point to new avenues for therapeutic strategies aimed at maintaining epithelial integrity during chronic inflammation.