Neural Crest Cell Implantation Restores Enteric Nervous System Function and Alters the Gastrointestinal Transcriptome in Human Tissue-Engineered Small Intestine

Stem Cell Reports. 2017 Sep 12;9(3):883-896. doi: 10.1016/j.stemcr.2017.07.017. Epub 2017 Aug 10.


Acquired or congenital disruption in enteric nervous system (ENS) development or function can lead to significant mechanical dysmotility. ENS restoration through cellular transplantation may provide a cure for enteric neuropathies. We have previously generated human pluripotent stem cell (hPSC)-derived tissue-engineered small intestine (TESI) from human intestinal organoids (HIOs). However, HIO-TESI fails to develop an ENS. The purpose of our study is to restore ENS components derived exclusively from hPSCs in HIO-TESI. hPSC-derived enteric neural crest cell (ENCC) supplementation of HIO-TESI establishes submucosal and myenteric ganglia, repopulates various subclasses of neurons, and restores neuroepithelial connections and neuron-dependent contractility and relaxation in ENCC-HIO-TESI. RNA sequencing identified differentially expressed genes involved in neurogenesis, gliogenesis, gastrointestinal tract development, and differentiated epithelial cell types when ENS elements are restored during in vivo development of HIO-TESI. Our findings validate an effective approach to restoring hPSC-derived ENS components in HIO-TESI and may implicate their potential for the treatment of enteric neuropathies.

Keywords: cells; enteric nervous system; enteric neural crest; human intestinal organoids; human pluripotent stem cells; tissue-engineered small intestine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Line
  • Enteric Nervous System / physiology*
  • Enteroendocrine Cells / metabolism
  • Epithelial Cells / metabolism
  • Gene Expression Profiling
  • Gene Ontology
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestine, Small / physiology*
  • Mice, Inbred NOD
  • Mice, SCID
  • Neural Crest / cytology*
  • Neural Crest / transplantation*
  • Neuroglia / metabolism
  • Organoids / metabolism
  • Pluripotent Stem Cells / metabolism
  • Sensory Receptor Cells / metabolism
  • Synapses / metabolism
  • Tissue Engineering / methods*
  • Transcriptome / genetics*