Abstract
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.
Highlights
Enteric nervous system neuropathy causes a wide range of severe gut motility disorders
We report that transplantation of a population of selected enteric neural crest-derived cells has a clear and positive functional impact, rescuing motility in a pathophysiological mouse model that recapitulates the phenotype of several clinically relevant human disorders
We demonstrate that this rescue is achieved through both cell-autonomous restoration of nitrergic responses that were absent, and non-cell-autonomous rescue of interstitial cells of Cajal (ICC) numbers, which were found to be deficient in the neuronal nitric oxide synthase (nNOS) À / À colon
Summary
Enteric nervous system neuropathy causes a wide range of severe gut motility disorders. We show rescue of gut motility after ENSC transplantation in a mouse model of human enteric neuropathy, the neuronal nitric oxide synthase (nNOS À / À ) deficient mouse model, which displays slow transit in the colon. Post-transplantation non-cell-autonomous mechanisms restore the numbers of interstitial cells of Cajal that are reduced in the nNOS À / À 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. Recent studies have demonstrated the successful integration of murine and human ENSC within aganglionic colon both in vivo[16,19] and ex vivo[20,21]; the severity of the gut phenotype and poor survival of homozygote mice has limited their in vivo use for investigating the potential functional rescue, at the organ level, of ENSC-based therapies. We propose that ENSC can modulate the neuromuscular syncytium via both cell-autonomous and non-cell-autonomous mechanisms to restore function, at the organ level, and rescue motility
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