Intestinal Stem Cells Retain an Epigenetic Memory of Prior Inflammation
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Background & Aims
Intestinal epithelial damage and impaired repair are hallmarks of ulcerative colitis (UC), even after inflammation resolves. Inflammatory injury in barrier tissues induces epigenetic memory in epithelial stem cells, and the tendency of UC to relapse at previously inflamed sites indicates this imprinting may occur in long-lived cells like intestinal stem cells (ISCs). We hypothesized that inflammatory exposure induces epigenetic memory in ISCs. This study aimed to uncover the long-term molecular and functional consequences of inflammatory exposure in ISCs from patients with UC.
Methods
Paired colonic organoids were derived from inflamed and uninflamed regions of the same UC patients and cultured under standardized conditions in long-term culture. Chromatin accessibility and gene expression were profiled by ATAC-seq and RNA-seq. Functional assays included organoid-forming efficiency, transepithelial resistance, and wound repair.
Results
Prior-inflamed (PI) organoids exhibited reduced clonogenicity and impaired barrier function relative to matched uninflamed (NI) organoids. Chromatin profiling identified 2,252 PI-specific accessible regions enriched at enhancer elements and marked by AP-1, and associated with genes involved in epithelial stress responses, regeneration, and inflammation. Although these regions remained accessible, ∼95% of associated genes were not upregulated in PI organoids, indicating a primed state. PI organoids showed transcriptional upregulation and accelerated healing upon inflammatory or injury re-challenge. Together, this supports a model in which inflammation-experienced ISCs are epigenetically primed for amplified responses following injury.
Conclusions
ISCs retain a chromatin-based memory of inflammation that persists in the absence of immune cues and shapes future responses to injury. While this may support epithelial adaptation to secondary insults, it may predispose tissue to relapse in patients with UC.
WHAT YOU NEED TO KNOW
BACKGROUND AND CONTEXT
Intestinal stem cells regenerate the epithelium in homeostasis and after injury, but it is unclear how prior inflammation shapes their long-term behavior.
NEW FINDINGS
Human intestinal stem cells from ulcerative colitis patients retain a stable chromatin memory of prior inflammation that primes them for enhanced gene activation and epithelial responses upon re-exposure to inflammatory signals.
LIMITATIONS
This study was performed in patient-derived organoids, which model epithelial cells, and may not fully capture in vivo tissue complexity. Mechanistic dissection will be necessary to fully define causality.
CLINICAL RESEARCH RELEVANCE
Understanding how intestinal stem cells retain and respond to past inflammation at the molecular level may explain why ulcerative colitis recurs, even after apparent healing. This insight could guide therapeutic strategies aimed at modulating epithelial repair responses to reduce disease relapse.
BASIC RESEARCH RELEVANCE
This study reveals that inflammation induces persistent chromatin changes in intestinal stem cells, uncovering a conserved mechanism of epithelial memory. These findings provide a foundation for understanding how epigenetic priming influences repair and dysfunction in chronic intestinal disease.
LAY SUMMARY
Inflammation leaves a lasting memory in intestinal stem cells that changes how they respond to future injury, which may help explain disease flares or remission in ulcerative colitis.
