Journal
NATURE MEDICINE
Volume 23, Issue 1, Pages 49-59Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4233
Keywords
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Funding
- US National Institutes of Health [U18TR000546, U18EB021780, U01DK103117, R0IDK098350, R01DK092456]
- Athena Blackburn Research Scholar Award in Neuroenteric Diseases
- Cincinnati Digestive Disease Center Award [P30 DK0789392]
- Clinical Translational Science Award [U54 RR025216]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [U18TR000546] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [U18EB021780] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U01DK103117, K99DK110414, P30DK078392, R01DK098350, R01DK092456] Funding Source: NIH RePORTER
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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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