Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung's disease

Deshu Xu, Weiwei Liang, Chaoting Lan, Lanying Li, Weiyong Zhong, Meng Yao, Xiaoyu Zuo, Jixiao Zeng, Wei Zhong, Qiang Wu, Andrew Lew, Wenhao Zhou, Huimin Xia, Fan Bai, Yuxia Zhang, Yan Zhang
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Abstract

Objective: Enteric nervous system dysfunction is linked to digestive and neurological disorders. Hirschsprung's disease (HSCR) is characterized by the loss of enteric neuron cells (ENCs) in the distal colon. Embryonic enteric neural crest cell (ENCC) migration defects contribute to HSCR development in some infants, but postnatal factors that regulate ENC fate are undetermined. We sought to establish how postnatal changes contribute to HSCR by profiling the colonic microenvironment of HSCR infants. Design: In this study, we recruited infants with HSCR, infants with anorectal malformations but normal ENC development (CT), and an group of age-matched healthy control subjects. Laboratory findings and clinical manifestations were recorded. Single-cell and spatial transcriptome sequencing were applied to colonic tissues from a sub-cohort of CT and HSCR infants. Patient specimens, a mouse model of neonatal ischemic enterocolitis, and Sox10 knockdown mouse (Sox10WT/MUT) were used to reveal the factors that leads to ENC loss in HSCR infants. Results: We discover that intestinal ischemia promotes CLDN1+ hypertrophic nerve trunk formation and ENC death. Mechanistically, ischemia leads to defective nitric oxide (NO) signaling in ENCs, which aggravates mitochondria damage and caspase-mediated apoptosis that can be ameliorated by a NO donor drug. Conclusion: We show that ischemia contributes to postnatal ENC loss in HSCR infants and suggest that NO donor drugs may alleviate ischemia-related ENC death.
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缺血促进肥大神经干形成和赫氏胃肠病肠神经元细胞死亡
目的:肠神经系统功能障碍与消化系统和神经系统疾病有关。赫氏病(HSCR)的特征是远端结肠中肠神经元细胞(ENCs)的缺失。胚胎肠神经嵴细胞(ENCC)迁移缺陷会导致一些婴儿发生 HSCR,但调节 ENC 命运的产后因素尚未确定。我们试图通过分析 HSCR 婴儿的结肠微环境来确定产后变化是如何导致 HSCR 的。设计:在这项研究中,我们招募了患有 HSCR 的婴儿、肛门直肠畸形但 ENC 发育正常的婴儿(CT)以及一组年龄匹配的健康对照受试者。我们记录了实验室检查结果和临床表现。对 CT 和 HSCR 婴儿亚群的结肠组织进行了单细胞和空间转录组测序。利用患者标本、新生儿缺血性小肠结肠炎小鼠模型和Sox10基因敲除小鼠(Sox10WT/MUT)来揭示导致HSCR婴儿ENC缺失的因素。结果我们发现肠缺血促进了CLDN1+肥大神经干的形成和ENC的死亡。从机理上讲,缺血导致 ENC 中的一氧化氮(NO)信号传导缺陷,从而加重线粒体损伤和 Caspase 介导的细胞凋亡,而 NO 供体药物可改善这种情况:结论:我们的研究表明,缺血是导致 HSCR 婴儿出生后耳蜗坏死的原因之一,并建议使用一氧化氮供体药物来缓解缺血相关的耳蜗坏死。
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