Cellular and molecular gastroenterology and hepatology · 2026
Intestinal Stem Cells From Patients With Inflammatory Bowel Disease Retain an Epigenetic Memory of Inflammation.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Hamdan Feda H, Farhadipour Mona, Perez Isaiah, Kossick Kimberlee, Smith Hannah, Edwinson Adam, de Hoyos-Vega Jose M, Gonzalez Michelle, Chiang David, Klatt Emily, Rumer Kristy, Pachon Mauricio Perez, Sagstetter Mary, Friton Jessica, Kammer Erin, English Alana, Chini Lucas C S, Carnahan Jarl F, Baca Noah A, Hohenstein Jessie, Mopuri Rohini, Bhagwate Aditya, Raffals Laura E, Graham Rondell, Sun Zhifu, Grover Madhusudan, Revzin Alexander, Kattah Michael, Faubion William A, Druliner Brooke R
Аннотация
BACKGROUND & AIMS: Intestinal epithelial damage and impaired repair are hallmarks of ulcerative colitis (UC), even after inflammation resolves. Intestinal stem cells (ISCs) can retain stable epigenetic changes after inflammation, highlighting the potential for long-lived epithelial memory in the gut. Inflammatory injury in barrier tissues induces epigenetic memory in epithelial stem cells, and the tendency of UC to relapse at previously inflamed sites led us to hypothesize that ISCs from patients with inflammatory bowel disease acquire lasting memory of prior inflammation.
METHODS: To test this, we derived colonic organoids from inflamed (I) and noninflamed regions of the same patients with UC and propagated in long-term culture.
RESULTS: Chromatin profiling revealed 2252 accessible regions unique to I organoids, associated with stress response, repair, and inflammatory genes. Although these regions remained accessible, ∼95% of associated genes were not upregulated in I organoids, indicating a primed state. Upon inflammatory or injury re-challenge, I organoids exhibited heightened transcriptional responses and accelerated wound closure, despite reduced clonogenicity and impaired barrier function, indicating a retained inflammatory memory program.
CONCLUSIONS: Our findings demonstrate that human ISCs retain a chromatin-based memory of inflammation that persists in the absence of immune cues and shapes future responses to injury. Although this may support epithelial adaptation to secondary insults, it may predispose tissue to relapse in patients with UC.
METHODS: To test this, we derived colonic organoids from inflamed (I) and noninflamed regions of the same patients with UC and propagated in long-term culture.
RESULTS: Chromatin profiling revealed 2252 accessible regions unique to I organoids, associated with stress response, repair, and inflammatory genes. Although these regions remained accessible, ∼95% of associated genes were not upregulated in I organoids, indicating a primed state. Upon inflammatory or injury re-challenge, I organoids exhibited heightened transcriptional responses and accelerated wound closure, despite reduced clonogenicity and impaired barrier function, indicating a retained inflammatory memory program.
CONCLUSIONS: Our findings demonstrate that human ISCs retain a chromatin-based memory of inflammation that persists in the absence of immune cues and shapes future responses to injury. Although this may support epithelial adaptation to secondary insults, it may predispose tissue to relapse in patients with UC.