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Nat Med. 2017 Jan;23(1):49-59. doi: 10.1038/nm.4233. Epub 2016 Nov 21.

Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system.

Author information

1
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
2
Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
3
Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
4
INSERM UMR 913, University of Nantes, CHU de Nantes-Institut des Maladies de l'Appareil Digestif, Nantes, France.
5
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
6
Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
7
Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
8
Gladstone Institutes, San Francisco, California, USA.
9
Departments of Medicine and Molecular and Cellular Pharmacology, University of California at San Francisco, San Francisco, California, USA.
10
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Abstract

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.

PMID:
27869805
PMCID:
PMC5562951
DOI:
10.1038/nm.4233
[Indexed for MEDLINE]
Free PMC Article

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