Impairment of stromal-epithelial regenerative cross-talk in Hirschsprung disease primes for the progression to enterocolitis

IF 14.6 1区 医学 Q1 CELL BIOLOGY
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
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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.
巨结肠疾病中基质-上皮再生串扰的损害是发展为小肠结肠炎的主要原因
巨结肠病(HSCR)是一种先天性疾病,其特征是肠神经嵴细胞的不适当迁移,导致神经节病最常见于直肠乙状结肠。这种严重和危及生命的疾病通常导致先天性巨结肠相关小肠结肠炎(HAEC)的发展,可发生在手术切除受影响肠段之前或之后。利用HSCR患者的结肠组织和完善的内皮素受体B敲除小鼠模型,我们研究了远节结结肠(HAEC发展的关键部位)上皮再生动力学和基质-上皮间质串扰。在患有HSCR但没有上皮损伤的个体中,远节结结肠表现出上皮再生受损和肠道干细胞动力学改变,其特征是富含亮氨酸的含重复G蛋白偶联受体5 (LGR5 +)上皮干细胞的减少。这一现象在小鼠模型中是一致的,当原位上皮损伤发生时,再生能力受损先于HAEC。HSCR患者在远节结结肠区域的基质细胞中也表现出重塑,无翼相关整合位点(Wnt)信号释放基质细胞的主要来源较少,并且只存在促炎基质金属蛋白酶1 +基质细胞。来自HSCR远节结结肠的基质细胞不能维持结肠类器官的生长。然而,布洛芬抑制促炎基质细胞,导致上皮类器官生长的有效恢复。这些观察结果强调了间质-上皮相互作用受损在HSCR和HAEC发病机制中的关键作用,并提出了预防或治疗这种疾病的潜在治疗靶点。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
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.
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