Zhen Zhang, Dorothy Lee, Lingya Liu, Yi Xiong, Carol Lee, Ji-Eun Kim, Sinobol Chusilp, Ethan Lau, Yina Tian, Mehrsa Feizi, Mashriq Alganabi, Anthea Lafreniere, Tianran Cheng, Ruijie Zhou, Lu Han, Lihua Wu, Ping Xiao, Ya Gao, Giada Benedetti, Lucy Holland, Lucinda Tullie, Giovanni Giuseppe Giobbe, Long Li, Qi Li, Atsuyuki Yamataka, Vivian S. W. Li, Paolo De Coppi, Qian Jiang, Agostino Pierro, Bo Li
{"title":"Impairment of stromal-epithelial regenerative cross-talk in Hirschsprung disease primes for the progression to enterocolitis","authors":"Zhen Zhang, Dorothy Lee, Lingya Liu, Yi Xiong, Carol Lee, Ji-Eun Kim, Sinobol Chusilp, Ethan Lau, Yina Tian, Mehrsa Feizi, Mashriq Alganabi, Anthea Lafreniere, Tianran Cheng, Ruijie Zhou, Lu Han, Lihua Wu, Ping Xiao, Ya Gao, Giada Benedetti, Lucy Holland, Lucinda Tullie, Giovanni Giuseppe Giobbe, Long Li, Qi Li, Atsuyuki Yamataka, Vivian S. W. Li, Paolo De Coppi, Qian Jiang, Agostino Pierro, Bo Li","doi":"10.1126/scitranslmed.adp4679","DOIUrl":null,"url":null,"abstract":"<div >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–coupled receptor 5 (LGR5<sup>+</sup>) 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<sup>+</sup>) 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.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adp4679","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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–coupled receptor 5 (LGR5+) 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+) 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.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.