Zhang Zhen, Lee Dorothy, Liu Lingya, Xiong Yi, Lee Carol, Kim Ji-Eun, Chusilp Sinobol, Lau Ethan, Tian Yina, Feizi Mehrsa, Alganabi Mashriq, Lafreniere Anthea, Cheng Tianran, Zhou Ruijie, Han Lu, Wu Lihua, Xiao Ping, Gao Ya, Benedetti Giada, Holland Lucy, Tullie Lucinda, Giobbe Giovanni Giuseppe, Li Long, Li Qi, Yamataka Atsuyuki, Li Vivian S W, De Coppi Paolo, Jiang Qian, Pierro Agostino, Li Bo
Department of General Surgery, Capital Institute of Pediatrics Affiliated Children's Hospital, Beijing 100020, China.
Department of Translational Medicine, Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Sci Transl Med. 2025 Jul 30;17(809):eadp4679. doi: 10.1126/scitranslmed.adp4679.
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.
先天性巨结肠（HSCR）是一种先天性疾病，其特征是肠神经嵴细胞迁移异常，最常见的是导致直肠乙状结肠无神经节症。这种严重且危及生命的疾病常导致先天性巨结肠相关小肠结肠炎（HAEC）的发生，可在受影响肠段手术切除之前或之后出现。我们使用HSCR患者的结肠组织以及成熟的内皮素受体B基因敲除小鼠模型，研究了远端神经节结肠上皮再生动力学和基质 - 上皮相互作用，该部位是HAEC发生的关键部位。在无上皮损伤的HSCR个体中，远端神经节结肠上皮再生受损，肠道干细胞动力学改变，其特征是富含亮氨酸重复序列的G蛋白偶联受体5（LGR5）上皮干细胞减少。这种现象在小鼠模型中也一致，当局部发生上皮损伤时，再生能力受损先于HAEC出现。HSCR患者在该远端神经节结肠区域的基质细胞也表现出重塑，释放无翅相关整合位点（Wnt）信号的基质细胞主要来源减少，且仅存在促炎（基质金属蛋白酶1）基质细胞。HSCR远端神经节结肠的基质细胞无法维持结肠类器官的生长。然而，布洛芬抑制了促炎基质细胞，从而有效恢复了上皮类器官的生长。这些观察结果强调了基质 - 上皮相互作用受损在HSCR和HAEC发病机制中的关键作用，并提示了预防或治疗该疾病的潜在治疗靶点。
