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Enteric Nervous System Regeneration with Pre-Migratory Neural Crest Stem Cells

Review of "Premigratory neural crest stem cells generate enteric neurons populating the mouse colon and regulating peristalsis in tissue‐engineered intestine" from STEM CELLS Translational Medicine by Stuart P. Atkinson

Stem cell‐based replacement therapy represents an exciting treatment option for Hirschsprung's disease [1], which results from the absence of the neural crest cell-derived enteric nervous system within the distal large intestine [2]. A recent STEM CELLS Translational Medicine study from researchers led by Yi Dong (East China Normal University, Shanghai), Wei Chen, and Jinfa Tou (Zhejiang University, Hangzhou, China) sought to explore the potential of multipotent mouse pre-migratory neural crest stem cells (pNCSCs) [3] to reconstitute the enteric nervous system after transplantation into the adult mouse intestine and establish neuron‐dependent bowel motility [4]. Excitingly, Yuan et al. now report that non-enteric NCSCs may represent an exciting alternative treatment option for enteric nervous system regeneration in patients suffering from conditions such as Hirschsprung's disease.

The authors first isolated pNCSCs from trunk-level neural tubes derived from mouse embryos employing a previously established procedure [5] and confirmed their i) identity through immunostaining for expected markers (Nestin, P75, AP2, and SOX10), ii) multipotent differentiation potential, and iii) ability to generate peripheral neurons that displayed an appropriate morphology and marker expression profile. The study then demonstrated that pNCSCs transplanted into the external muscle layer survived, migrated, and efficiently differentiated into fully functional enteric neurons that successfully integrated into the neural network of the adult mouse large intestine over a period of two months.

Their subsequent analysis evaluated mature tissue‐engineered intestinal tissue, formed through a combination of pNCSCs and human intestinal organoids implanted into the subrenal capsule of nude mice, in the hope of proving the ability of pNCSC-derived neurons to mediate peristalsis [6, 7]. Overall, pNCSCs efficiently differentiated into neurons within human intestinal organoids, while analysis of motility suggested that they integrated and then mediated neuron‐dependent peristalsis within this tissue‐engineered intestine, providing evidence for their potential to induce gut motility.

Overall, these findings suggest that pNCSCs that lack any induction by intestinal microenvironmental cues can integrate within the mouse large intestine and mediate gut motility, thereby suggesting their application in the regeneration of the enteric nervous system in patients suffering from conditions such as Hirschsprung's disease. In addition, the authors note that easier-to-isolate non-enteric adult NCSCs could share developmental origins with pNCSCs and, therefore, may represent potential candidates for novel enteric nervous system regeneration strategies.

For more on the potential of pre-migratory neural crest stem cells and novel treatment options for enteric nervous system disorders, stay tuned to the Stem Cells Portal!


  1. Burns AJ, Goldstein AM, Newgreen DF, et al., White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies. Developmental Biology 2016;417:229-251.
  2. Burns AJ and Thapar N, Neural stem cell therapies for enteric nervous system disorders. Nature Reviews Gastroenterology & Hepatology 2014;11:317-328.
  3. Baggiolini A, Varum S, Mateos José M, et al., Premigratory and Migratory Neural Crest Cells Are Multipotent In Vivo. Cell Stem Cell 2015;16:314-322.
  4. Yuan H, Hu H, Chen R, et al., Premigratory neural crest stem cells generate enteric neurons populating the mouse colon and regulating peristalsis in tissue-engineered intestine. STEM CELLS Translational Medicine 2021;10:922-938.
  5. Etchevers H, Primary culture of chick, mouse or human neural crest cells. Nature Protocols 2011;6:1568-1577.
  6. Workman MJ, Mahe MM, Trisno S, et al., Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nature Medicine 2017;23:49-59.
  7. Schlieve CR, Fowler KL, Thornton M, et al., Neural Crest Cell Implantation Restores Enteric Nervous System Function and Alters the Gastrointestinal Transcriptome in Human Tissue-Engineered Small Intestine. Stem Cell Reports 2017;9:883-896.