Surgical Intervention to Rescue Hirschsprung Disease in a Rat Model

Stamp, Lincon A.; Obermayr, Florian; Pontell, Louise; Young, Heather M.; Xie, Dan; Croaker, David; Song, Zan-Min; Furness, John B.

doi:10.5056/jnm15079

Cited by 13 publications

(19 citation statements)

References 37 publications

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“…Other factors from the surrounding epithelium like Shh and Ih also have effects on the ENS since their ablation severely reduces ENCC numbers (35,36). Further, in rat models of HSCR, some regions of the distal colon are constricted with thick muscle and deep epithelial folds while other regions have thin external muscle with a stretched mucosa (37). This observation is assumed to be an effect of reduced enteric neuron density on the surrounding tissues, but could arise from the effects of mesenchymal defects on the ENS.…”

Section: Non-autonomous Effects Of the Ens And The Mesenchymementioning

confidence: 99%

The gastrointestinal development ‘parts list’: transcript profiling of embryonic gut development in wildtype andRet-deficient mice

Chatterjee

Nandakumar

Auer

et al. 2019

Preprint

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The development of the gut from endodermal tissue to an organ with multiple distinct structures and functions occurs over a prolonged time during embryonic days E10.5-E14.5 in the mouse. During this process, one major event is innervation of the gut by enteric neural crest cells (ENCC) to establish the enteric nervous system (ENS). To understand the molecular processes underpinning gut and ENS development, we generated RNA-seq profiles from wildtype mouse guts at E10.5, E12.5 and E14.5 from both sexes. We also generated these profiles from homozygous Ret null embryos, a model for Hirschsprung disease (HSCR), in whom the ENS is absent. These data reveal four major features: (1) between E10.5 to E14.5 the developmental genetic programs change from expression of major transcription factors (TF) and its modifiers to genes controlling tissue (epithelium, muscle, endothelium) specialization; (2) the major effect of Ret is not only on ENCC differentiation to enteric neurons but also on the enteric mesenchyme and epithelium; (3) a muscle genetic program exerts significant effects on ENS development, and (4) sex differences in gut development profiles are minor. The genetic programs identified, and their changes across development, suggests that both cell autonomous and non-autonomous factors, and interactions between the different developing gut tissues, are important for normal ENS development and its disorders. Significance statementThe mammalian gut is a complex set of tissues formed during development by orchestrating the timing of expression of many genes. Here we uncover the identity of these genes, their pathways and how they change during gut organogenesis. We used RNA-seq profiling in the wildtype mouse gut in both sexes during development (E10.5 -E14.5), as well as in a Ret null mouse, a model of Hirschsprung disease (HSCR). These studies have allowed us to expand the universe of genes and developmental processes that contribute to enteric neuronal innervation and to its dysregulation in disease.

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Section: Non-autonomous Effects Of the Ens And The Mesenchymementioning

confidence: 99%

The gastrointestinal development ‘parts list’: transcript profiling of embryonic gut development in wildtype andRet-deficient mice

Chatterjee

Nandakumar

Auer

et al. 2019

Preprint

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“…We therefore recommend against reparative cell emplacement and surgery trials in neonatal mice, despite the appropriate mutants. Larger animal models, starting with rats (Stamp et al, 2015), will overcome this problem because intestinal stoma creation is possible and is tolerated for extended periods.…”

Section: What Are the Most Appropriate Models For Experimentation mentioning

confidence: 99%

“…The first is a shift to the rat: much of the experience gained with the mouse will be applicable to this genetically convenient model, with the additional advantage that anticipated surgical approaches – colostomy, transfer of cells to the distal colon, and later bowel anastomosis – required for human HSCR postnatally are possible in the EdnrB rat HSCR model (Stamp et al, 2015). The second is to approach the potential scaling difficulty.…”

Section: What Are the Most Appropriate Models For Experimentation mentioning

confidence: 99%

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

Burns

Goldstein

Newgreen

et al. 2016

Developmental Biology

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123

128

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Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts’ views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.

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“…Tissue for hematoxylin and eosin and Masson's trichrome staining was processed as described previously. 23 Tissue from three randomly chosen sections of ileum and distal colon were graded by a blinded observer (J.B.F.) using a Â40 objective lens and 8-point graded scales (Table 1).…”

Section: Ihc Analysis and Histopathologymentioning

confidence: 99%

A Novel Mutation in Nucleoporin 35 Causes Murine Degenerative Colonic Smooth Muscle Myopathy

Parish

Stamp

Lorenzo

et al. 2016

The American Journal of Pathology

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Chronic intestinal pseudo-obstruction (CIPO) is a rare but life-threatening disease characterized by severe intestinal dysmotility. Histopathologic studies in CIPO patients have identified several different mechanisms that appear to be involved in the dysmotility, including defects in neurons, smooth muscle, or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA recognition motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited a reduced lifespan. Histopathologic examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the subtype of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO. (Am J Pathol 2016 http://dx

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Surgical Intervention to Rescue Hirschsprung Disease in a Rat Model

Cited by 13 publications

References 37 publications

The gastrointestinal development ‘parts list’: transcript profiling of embryonic gut development in wildtype andRet-deficient mice

The gastrointestinal development ‘parts list’: transcript profiling of embryonic gut development in wildtype andRet-deficient mice

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

A Novel Mutation in Nucleoporin 35 Causes Murine Degenerative Colonic Smooth Muscle Myopathy

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