White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies

Burns, Alan J.; Goldstein, Allan M.; Newgreen, Donald F.; Stamp, Lincon A.; Schäfer, Karl Herbert; Metzger, Marco; Hotta, Ryo; Young, Heather M.; Andrews, Peter W.; Thapar, Nikhil; Belkind‐Gerson, Jaime; Bondurand, Nadège; Bornstein, Joel C.; Chan, Wood Yee; Cheah, Kathryn S.E.; Gershon, Michael D.; Heuckeroth, Robert O.; Hofstra, Robert M.W.; Just, Lothar; Kapur, Raj P.; King, Sebastian K.; McCann, Conor J.; Nagy, Nándor; Ngan, Elly Sau-Wai; Obermayr, Florian; Pachnis, Vassilis; Pasricha, Pankaj J.; Sham, Mai Har; Tam, Paul Kwong Hang; Berghe, Pieter Vanden

doi:10.1016/j.ydbio.2016.04.001

Cited by 120 publications

(135 citation statements)

References 242 publications

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“…Our studies may explain why impaired motility (including constipation) is observed in HSCR patients after transitional zone pull-through (TZPT) (where part of the hypoganglionated gut remains after surgery) [43]. Additionally, our observations argue that the promise of successful treatment of long-segment HSCR by stem cell transplantation [44–47], would require colonization of aganglionic gut segments along their full length. Further work using such zebrafish models has the potential to establish links between states of ganglionosis and their capacity to mediate peristalsis and other ENS regulated processes, and determine, for example, the minimal neurofunctional unit required to restore organized motility.…”

Section: Discussionmentioning

confidence: 93%

A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity

et al. 2016

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Hirschsprung disease (HSCR) is characterized by absence of enteric neurons from the distal colon and severe intestinal dysmotility. To understand the pathophysiology and genetics of HSCR we developed a unique zebrafish model that allows combined genetic, developmental and in vivo physiological studies. We show that ret mutant zebrafish exhibit cellular, physiological and genetic features of HSCR, including absence of intestinal neurons, reduced peristalsis, and varying phenotype expressivity in the heterozygous state. We perform live imaging experiments using a UAS-GAL4 binary genetic system to drive fluorescent protein expression in ENS progenitors. We demonstrate that ENS progenitors migrate at reduced speed in ret heterozygous embryos, without changes in proliferation or survival, establishing this as a principal pathogenic mechanism for distal aganglionosis. We show, using live imaging of actual intestinal movements, that intestinal motility is severely compromised in ret mutants, and partially impaired in ret heterozygous larvae, and establish a clear correlation between neuron position and organised intestinal motility. We exploited the partially penetrant ret heterozygous phenotype as a sensitised background to test the influence of a candidate modifier gene. We generated mapk10 loss-of-function mutants, which show reduced numbers of enteric neurons. Significantly, we show that introduction of mapk10 mutations into ret heterozygotes enhanced the ENS deficit, supporting MAPK10 as a HSCR susceptibility locus. Our studies demonstrate that ret heterozygous zebrafish is a sensitized model, with many significant advantages over existing murine models, to explore the pathophysiology and complex genetics of HSCR.

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Section: Discussionmentioning

confidence: 93%

A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity

et al. 2016

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“…Given the missing heritability in Hirschprung disease, our results are also a suggestion to look for ErbB3 variants. Another possible clinical relevance is to neuropathic cases of chronic intestinal pseudoobstruction (43).…”

Section: Discussionmentioning

confidence: 99%

Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest

Espinosa-Medina

Jevans

Boismoreau

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Most of the enteric nervous system derives from the "vagal" neural crest, lying at the level of somites 1-7, which invades the digestive tract rostro-caudally from the foregut to the hindgut. Little is known about the initial phase of this colonization, which brings enteric precursors into the foregut. Here we show that the "vagal crest" subsumes two populations of enteric precursors with contrasted origins, initial modes of migration, and destinations. Crest cells adjacent to somites 1 and 2 produce Schwann cell precursors that colonize the vagus nerve, which in turn guides them into the esophagus and stomach. Crest cells adjacent to somites 3-7 belong to the crest streams contributing to sympathetic chains: they migrate ventrally, seed the sympathetic chains, and colonize the entire digestive tract thence. Accordingly, enteric ganglia, like sympathetic ones, are atrophic when deprived of signaling through the tyrosine kinase receptor ErbB3, while half of the esophageal ganglia require, like parasympathetic ones, the nerve-associated form of the ErbB3 ligand, Neuregulin-1. These dependencies might bear relevance to Hirschsprung disease, with which alleles of Neuregulin-1 are associated.enteric nervous system | neural crest | chicken | mouse | Neuregulin1

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“…49 The existence of enteric neural stem cells in the postnatal or adult gut was once considered heretical but is now well documented, at least in animal models. 50 Most of the basic research has focused on myenteric ganglia and murine models. According to a recently published study, enteric neurons undergo postnatal homeostatic apoptosis and replacement by stem cells, 51 although this finding is controversial.…”

Section: Pathogenesis Of Ind Bmentioning

confidence: 99%

Intestinal Neuronal Dysplasia Type B: An Updated Review of a Problematic Diagnosis

Kapur

Reyes‐Múgica

2018

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Intestinal neuronal dysplasia type B (IND B) is a controversial histopathologic phenotype that has been associated with intestinal dysmotility, either as an isolated condition or in conjunction with established pathologic disorders (eg, Hirschsprung disease). Many factors contribute to the debate over the existence and/or clinical significance of IND B, including a large body of published data based on inconsistent diagnostic criteria and methods, which have fostered many unwarranted conclusions that lack sufficient scientific basis.Objective.-To critically analyze existing published data regarding IND B to provide supporting evidence-based diagnostic practice and to stimulate necessary and scientifically sound research.Data Sources.-This update focuses on published literature related to the pathology of IND B because without a reliable pathologic diagnosis, studies of epidemiology, pathogenesis, natural history, management, and outcome are all suspect. Problems with existing data are identified explicitly with suggestions as to how future investigations should be designed and evaluated to better understand this entity.Conclusions.-Inconsistencies in diagnostic criteria and methods used to define IND B justifiably encumber the universal acceptance of IND B as a neuropathologic etiology for intestinal dysmotility. IND B will remain a controversial diagnosis until rigorous, well-controlled scientific studies are conducted to establish reproducible and reliable diagnostic criteria that reliably translate from one laboratory to another.

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White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies

Cited by 120 publications

References 242 publications

A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity

A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity

Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest

Intestinal Neuronal Dysplasia Type B: An Updated Review of a Problematic Diagnosis

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