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Innervation of Human Intestinal Organoids

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Published on: January 17, 2025

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

Michael J Workman¹, Maxime M Mahe², Stephen Trisno¹

¹Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Nature Medicine

|November 22, 2016

Summary

Researchers developed a human intestinal organoid model with a functional enteric nervous system (ENS) using stem cells. This breakthrough allows studying gastrointestinal motility disorders and ENS-intestinal biology.

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Generation, Maintenance, and Characterization of Human Pluripotent Stem Cell-derived Intestinal and Colonic Organoids

Generation, Maintenance, and Characterization of Human Pluripotent Stem Cell-derived Intestinal and Colonic Organoids

Published on: July 9, 2021

Area of Science:

Stem cell biology
Neuroscience
Gastroenterology

Background:

The enteric nervous system (ENS) regulates crucial gastrointestinal functions like motility and permeability.
Current limitations exist in studying ENS-intestinal biology and diseases due to the lack of human models.
Perturbations in ENS development or function are linked to various gastrointestinal disorders.

Purpose of the Study:

To engineer human intestinal tissue with a functional ENS using a tissue-engineering approach.
To create a novel human model for investigating ENS-intestinal biology and diseases.
To explore the potential of this model in studying motility disorders like Hirschsprung's disease.

Main Methods:

Utilized embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal organoids (HIOs).
Combined human-PSC-derived neural crest cells (NCCs) with HIOs to recapitulate ENS development in vitro.
Grew ENS-containing HIOs in vivo to assess neuroglial structure and function.

Main Results:

Successfully recapitulated normal intestinal ENS development, with NCCs migrating, differentiating into neurons and glial cells, and exhibiting neuronal activity.
ENS-containing HIOs grown in vivo formed complex neuroglial structures resembling myenteric and submucosal plexuses.
Demonstrated functional interstitial cells of Cajal and electromechanical coupling regulating contractile waves in the engineered tissue.
Utilized the model to investigate the PHOX2B mutation's role in Hirschsprung's disease.

Conclusions:

This study presents the first human-PSC-derived intestinal tissue with a functional ENS.
The developed model provides a powerful platform for studying ENS-intestinal biology and human gastrointestinal motility disorders.
This system offers new avenues for investigating the cellular and molecular basis of diseases like Hirschsprung's disease.