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Mesenteric Neural Crest Cells Are the Embryological Basis of Skip Segment Hirschsprung's Disease.

Authors
  • Yu, Qi1
  • Du, Mengjie1
  • Zhang, Wen2
  • Liu, Li1
  • Gao, Zhigang3
  • Chen, Wei4
  • Gu, Yan1
  • Zhu, Kun5
  • Niu, Xueyuan1
  • Sun, Qiming6
  • Wang, Liang7
  • 1 Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China. , (China)
  • 2 Department of Pathology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China. , (China)
  • 3 Department of Pediatric General Surgery, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China. , (China)
  • 4 Institute of Translational Medicine, and Children's Hospital Affiliated and Key Laboratory of Diagnosis and Treatment of Neonatal Diseases of Zhejiang Province, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China. , (China)
  • 5 Department of Pathology, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China. , (China)
  • 6 Department of Biochemistry, Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. , (China)
  • 7 Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier
Publication Date
Jan 01, 2021
Volume
12
Issue
1
Pages
1–24
Identifiers
DOI: 10.1016/j.jcmgh.2020.12.010
PMID: 33340715
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Defective rostrocaudal colonization of the gut by vagal neural crest cells (vNCCs) results in Hirschsprung's disease (HSCR), which is characterized by aganglionosis in variable lengths of the distal bowel. Skip segment Hirschsprung's disease (SSHD), referring to a ganglionated segment within an otherwise aganglionic intestine, contradicts HSCR pathogenesis and underscores a significant gap in our understanding of the development of the enteric nervous system. Here, we aimed to identify the embryonic origin of the ganglionic segments in SSHD. Intestinal biopsy specimens from HSCR patients were prepared via the Swiss-roll technique to search for SSHD cases. NCC migration from the neural tube to the gut was spatiotemporally traced using targeted cell lineages and gene manipulation in mice. After invading the mesentery surrounding the foregut, vNCCs separated into 2 populations: mesenteric NCCs (mNCCs) proceeded to migrate along the mesentery, whereas enteric NCCs invaded the foregut to migrate along the gut. mNCCs not only produced neurons and glia within the gut mesentery, but also continuously complemented the enteric NCC pool. Two new cases of SSHD were identified from 183 HSCR patients, and Ednrb-mutant mice, but not Ret-/- mice, showed a high incidence rate of SSHD-like phenotypes. mNCCs, a subset of vNCCs that migrate into the gut via the gut mesentery to give rise to enteric neurons, could provide an embryologic explanation for SSHD. These findings lead to novel insights into the development of the enteric nervous system and the etiology of HSCR. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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