肠神经系统
生物
神经嵴
诱导多能干细胞
卡哈尔间质细胞
肌间神经丛
干细胞
细胞生物学
间充质
胃肠道
运动性
胚胎干细胞
神经科学
神经系统
解剖
免疫学
间充质干细胞
遗传学
基因
胚胎
免疫组织化学
生物化学
作者
Michael J. Workman,Maxime M. Mahé,Stephen L. Trisno,Holly M. Poling,Carey L. Watson,Nambirajan Sundaram,Che Shoa Chang,Jacqueline V. Schiesser,P. Aubert,Edouard G. Stanley,Andrew G. Elefanty,Yuichiro Miyaoka,Mohammad A. Mandegar,Bruce R. Conklin,Michel Neunlist,Samantha A. Brugmann,Michael A. Helmrath,James M. Wells
出处
期刊:Nature Medicine
[Springer Nature]
日期:2016-11-21
卷期号:23 (1): 49-59
被引量:449
摘要
The enteric nervous system (ENS) of the gastrointestinal tract controls many diverse functions, including motility and epithelial permeability. Perturbations in ENS development or function are common, yet there is no human model for studying ENS-intestinal biology and disease. We used a tissue-engineering approach with embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining human-PSC-derived neural crest cells (NCCs) and developing human intestinal organoids (HIOs). NCCs recombined with HIOs in vitro migrated into the mesenchyme, differentiated into neurons and glial cells and showed neuronal activity, as measured by rhythmic waves of calcium transients. ENS-containing HIOs grown in vivo formed neuroglial structures similar to a myenteric and submucosal plexus, had functional interstitial cells of Cajal and had an electromechanical coupling that regulated waves of propagating contraction. Finally, we used this system to investigate the cellular and molecular basis for Hirschsprung's disease caused by a mutation in the gene PHOX2B. This is, to the best of our knowledge, the first demonstration of human-PSC-derived intestinal tissue with a functional ENS and how this system can be used to study motility disorders of the human gastrointestinal tract.
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