Transplantation of enteric nervous system stem cells rescues nitric oxide synthase deficient mouse colon

• Published in: Nature communications Vol. 8; no. 1; p. 15937
• Main Authors: McCann, Conor J., Cooper, Julie E., Natarajan, Dipa, Jevans, Benjamin, Burnett, Laura E., Burns, Alan J., Thapar, Nikhil
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-07-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 101/1; 13/100; 13/106; 14/19; 14/34; 14/35; 64/60; 692/308/2171; Animals; Colon; Colon - enzymology; Colon - physiopathology; Disorders; Enteric nervous system; Enteric Nervous System - cytology; Enteric Nervous System - enzymology; Female; Gastric motility; Gastrointestinal Motility; Gastrointestinal tract; Humanities and Social Sciences; Humans; Interstitial cells; Interstitial cells of Cajal; Intestinal Pseudo-Obstruction - enzymology; Intestinal Pseudo-Obstruction - genetics; Intestinal Pseudo-Obstruction - physiopathology; Intestinal Pseudo-Obstruction - surgery; Male; Mice; Mice, Inbred C57BL; Motility; multidisciplinary; Nervous system; Neural stem cells; Neural Stem Cells - transplantation; Neurons; Neurons - transplantation; Neuropathy; Nitric oxide; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - genetics; Nitric-oxide synthase; Recovery of function; Restoration; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Therapy; Transit; Transplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15937

Enteric nervous system neuropathy causes a wide range of severe gut motility disorders. Cell replacement of lost neurons using enteric neural stem cells (ENSC) is a possible therapy for these life-limiting disorders. Here we show rescue of gut motility after ENSC transplantation in a mouse model of human enteric neuropathy, the neuronal nitric oxide synthase (
nNOS
−/−
) deficient mouse model, which displays slow transit in the colon. We further show that transplantation of ENSC into the colon rescues impaired colonic motility with formation of extensive networks of transplanted cells, including the development of nNOS
+
neurons and subsequent restoration of nitrergic responses. Moreover, post-transplantation non-cell-autonomous mechanisms restore the numbers of interstitial cells of Cajal that are reduced in the
nNOS
−/−
colon. These results provide the first direct evidence that ENSC transplantation can modulate the enteric neuromuscular syncytium to restore function, at the organ level, in a dysmotile gastrointestinal disease model.
Isolated human and mouse enteric nervous system stem cells (ENSCs) are capable of integrating and promoting innervation of the mouse colon. Here the authors show that transplantation of mouse ENSCs into a mouse model of human enteric neuropathy restores colon motility.