{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T23:57:58Z","timestamp":1791503878295,"version":"4.3.4"},"reference-count":76,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"809","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,7,30]]},"abstract":"<jats:p>\n                    Hirschsprung disease (HSCR) is a congenital condition characterized by the improper migration of enteric neural crest cells, leading to aganglionosis most commonly in the rectosigmoid colon. This severe and life-threatening disorder often results in the development of Hirschsprung-associated enterocolitis (HAEC), which can occur either before or after surgical resection of the affected bowel segment. Using colonic tissue from patients with HSCR alongside the well-established endothelin receptor B knockout mouse model, we investigated epithelial regeneration dynamics and stromal-epithelial cross-talk in the distal ganglionic colon, a critical site for HAEC development. In individuals with HSCR but without epithelial damage, the distal ganglionic colon displayed impaired epithelial regeneration and alteration of intestinal stem cell dynamics, characterized by the reduction of leucine-rich repeat-containing G protein\u2013coupled receptor 5 (LGR5\n                    <jats:sup>+<\/jats:sup>\n                    ) epithelial stem cells. This phenomenon was consistent in the mouse model, where impaired regenerative ability preceded HAEC when epithelial damage occurred on site. Patients with HSCR also exhibited remodeling in stromal cells in this distal ganglionic colon region, with fewer primary sources of Wingless-related integration site (Wnt) signal-releasing stromal cells and the exclusive presence of proinflammatory (matrix metalloproteinase 1\n                    <jats:sup>+<\/jats:sup>\n                    ) stromal cells. Stromal cells from the HSCR distal ganglionic colon failed to sustain the growth of colonic organoids. However, ibuprofen suppressed the proinflammatory stromal cells, leading to effective restoration of epithelial organoid growth. These observations underscore the crucial role of impaired stromal-epithelial cross-talk in HSCR and the pathogenesis of HAEC and suggest potential therapeutic targets for the prevention or treatment of the condition.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adp4679","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T17:58:26Z","timestamp":1753898306000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":11,"title":["Impairment of stromal-epithelial regenerative cross-talk in Hirschsprung disease primes for the progression to enterocolitis"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7786-6238","authenticated-orcid":true,"given":"Zhen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of General Surgery, Capital Institute of Pediatrics Affiliated Children\u2019s Hospital, Beijing 100020, China."},{"name":"Department 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