Vascular and neural stem cells in the gut: do they need each other?

Schrenk, Sandra; Schuster, Anne; Klotz, Markus; Schleser, Franziska; Lake, Jonathan I.; Heuckeroth, Robert O.; Kim, Yoo-Jin; Laschke, Matthias W.; Menger, Michael D.; Schäfer, Karl‐Herbert

doi:10.1007/s00418-014-1288-9

Cited by 13 publications

(15 citation statements)

References 44 publications

(44 reference statements)

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“…A similar relationship is seen in zebrafish [144]. While the role of endothelial cells in ENCC migration is debated [36,160–162], disrupting enteric capillary development in mouse and avian embryos arrests ENCC colonization and leads to distal aganglionosis [144,163], suggesting that endothelial cells serve as a substrate to guide ENCC migration. The mechanism for this interaction involves the ECM receptor, β1 integrin, since ENCCs are able to migrate in vitro on cultured endothelial cells, but do not in the presence of β1 integrin blockade [144].…”

Section: Molecular and Cellular Control Of Ens Developmentmentioning

confidence: 80%

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Nagy

Goldstein

2017

Seminars in Cell & Developmental Biology

178

134

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The enteric nervous system (ENS) is comprised of a network of neurons and glial cells that are responsible for coordinating many aspects of gastrointestinal (GI) function. These cells arise from the neural crest, migrate to the gut, and then continue their journey to colonize the entire length of the GI tract. Our understanding of the molecular and cellular events that regulate these processes has advanced significantly over the past several decades, in large part facilitated by the use of rodents, avians, and zebrafish as model systems to dissect the signals and pathways involved. These studies have highlighted the highly dynamic nature of ENS development and the importance of carefully balancing migration, proliferation, and differentiation of enteric neural crest-derived cells (ENCCs). Proliferation, in particular, is critically important as it drives cell density and speed of migration, both of which are important for ensuring complete colonization of the gut. However, proliferation must be tempered by differentiation among cells that have reached their final destination and are ready to send axonal extensions, connect to effector cells, and begin to produce neurotransmitters or other signals. Abnormalities in the normal processes guiding ENCC development can lead to failure of ENS formation, as occurs in Hirschsprung disease, in which the distal intestine remains aganglionic. This review summarizes our current understanding of the factors involved in early development of the ENS and discusses areas in need of further investigation.

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Section: Molecular and Cellular Control Of Ens Developmentmentioning

confidence: 80%

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Nagy

Goldstein

2017

Seminars in Cell & Developmental Biology

178

134

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“…This appearance could therefore be linked to tissue hypoxia due to vascular defects, which was suggested in our previous studies in spinal cord in severe SMA mice [ 27 ]. Close interactions between the enteric nervous and vascular systems are indicated in vitro in cell culture assay of vascular cells and ENS-derived cells, in vivo in tyrosine kinase receptor RET knockout enteric ganglia deficiency mice and in human Hirschsprung’s disease [ 39 ]. Interestingly, contradictory data exists from mouse models and patients with enteric ganglia deficiency: with a reduction of blood vessel density in the RET knockout mouse model, but more blood vessels detected in the enteric aganglionic zone of patients with Hirschsprung’s disease [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Close interactions between the enteric nervous and vascular systems are indicated in vitro in cell culture assay of vascular cells and ENS-derived cells, in vivo in tyrosine kinase receptor RET knockout enteric ganglia deficiency mice and in human Hirschsprung’s disease [ 39 ]. Interestingly, contradictory data exists from mouse models and patients with enteric ganglia deficiency: with a reduction of blood vessel density in the RET knockout mouse model, but more blood vessels detected in the enteric aganglionic zone of patients with Hirschsprung’s disease [ 39 ]. We report similar inconsistencies in vascular density and enteric neuron numbers between SMA mice and patients.…”

Section: Discussionmentioning

confidence: 99%

Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

et al. 2016

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Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.

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“…Typically migratory ENC cells occupy the myenteric layer early, prior to visible structural or molecular correlations including smooth muscle differentiation ( Newgreen & Hartley, 1995 ). A spatial association of the early ENS with the pre-existing intestinal vascular layer has been suggested but this is controversial ( Delalande et al , 2014 ; Hackett-Jones et al , 2011 ; Hatch & Mukouyama, 2015 ; Nagy et al , 2009 ; Schrenk et al , 2015 ; Young et al , 2004 ). The sub-mucosal ENS cells originate later from this outer layer by centripetal migration (except in the avian hindgut), a process involving the response of DCC-expressing ENC cells to netrin produced by the endoderm ( Jiang et al , 2003 ).…”

Section: Introductionmentioning

confidence: 99%

Why are enteric ganglia so small? Role of differential adhesion of enteric neurons and enteric neural crest cells.

et al. 2015

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The avian enteric nervous system (ENS) consists of a vast number of unusually small ganglia compared to other peripheral ganglia. Each ENS ganglion at mid-gestation has a core of neurons and a shell of mesenchymal precursor/glia-like enteric neural crest (ENC) cells. To study ENS cell ganglionation we isolated midgut ENS cells by HNK-1 fluorescence-activated cell sorting (FACS) from E5 and E8 quail embryos, and from E9 chick embryos. We performed cell-cell aggregation assays which revealed a developmentally regulated functional increase in ENS cell adhesive function, requiring both Ca 2+ -dependent and independent adhesion. This was consistent with N-cadherin and NCAM labelling. Neurons sorted to the core of aggregates, surrounded by outer ENC cells, showing that neurons had higher adhesion than ENC cells. The outer surface of aggregates became relatively non-adhesive, correlating with low levels of NCAM and N-cadherin on this surface of the outer non-neuronal ENC cells. Aggregation assays showed that ENS cells FACS selected for NCAM-high and enriched for enteric neurons formed larger and more coherent aggregates than unsorted ENS cells. In contrast, ENS cells of the NCAM-low FACS fraction formed small, disorganised aggregates. This suggests a novel mechanism for control of ENS ganglion morphogenesis where i) differential adhesion of ENS neurons and ENC cells controls the core/shell ganglionic structure and ii) the ratio of neurons to ENC cells dictates the equilibrium ganglion size by generation of an outer non-adhesive surface.

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Vascular and neural stem cells in the gut: do they need each other?

Cited by 13 publications

References 44 publications

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

Why are enteric ganglia so small? Role of differential adhesion of enteric neurons and enteric neural crest cells.

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