Migration and differentiation of transplanted enteric neural crest-derived cells in murine model of Hirschsprung’s disease

Nishikawa, Ryuhei; Hotta, Ryo; Shimojima, Naoki; Shibata, Shinsuke; Nagoshi, Narihito; Nakamura, Masaya; Matsuzaki, Yuji; Okano, Hirotaka James; Kuroda, Takeshi; Morikawa, Yasuhide

doi:10.1007/s10616-014-9754-8

Cited by 16 publications

(11 citation statements)

References 43 publications

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“…In order to visualize the aganglionic segment in live animals using this model, we applied BAC treatment to a transgenic line in which the ENS is labeled with green fluorescent protein (GFP) (P0-Cre/GFP mouse) [ 12 – 15 ]. Here we established a chemically-induced aganglionosis mouse model with a fluorescence-labeled enteric neural network.…”

Section: Introductionmentioning

confidence: 99%

Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model

et al. 2016

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Gastrointestinal motility disorders, severe variants in particular, remain a therapeutic challenge in pediatric surgery. Absence of enteric ganglion cells that originate from neural crest cells is a major cause of dysmotility. However, the limitations of currently available animal models of dysmotility continue to impede the development of new therapeutics. Indeed, the short lifespan and/or poor penetrance of existing genetic models of dysmotility prohibit the functional evaluation of promising approaches, such as stem cell replacement strategy. Here, we induced an aganglionosis model using topical benzalkonium chloride in a P0-Cre/GFP transgenic mouse in which the neural crest lineage is labeled by green fluorescence. Pathological abnormalities and functional changes in the gastrointestinal tract were evaluated 2–8 weeks after chemical injury. Laparotomy combined with fluorescence microscopy allowed direct visualization of the enteric neural network in vivo. Immunohistochemical evaluation further confirmed the irreversible disappearance of ganglion cells, glial cells, and interstitial cell of Cajal. Remaining stool weight and bead expulsion time in particular supported the pathophysiological relevance of this chemically-induced model of aganglionosis. Interestingly, we show that chemical ablation of enteric ganglion cells is associated with a long lifespan. By combining genetic labeling of neural crest derivatives and chemical ablation of enteric ganglion cells, we developed a newly customized model of aganglionosis. Our results indicate that this aganglionosis model exhibits decreased gastrointestinal motility and shows sufficient survival for functional evaluation. This model may prove useful for the development of future therapies against motility disorders.

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Section: Introductionmentioning

confidence: 99%

Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model

et al. 2016

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“…Currently, the treatment of HD is to resect the aganglionic, transitional zone, and part of the dilated bowel, but there are still several postoperative lifethreatening complications, such as enterocolitis, anastomotic fistula, relapse, etc [4,5]. With the development of transplantation in the central nervous system (CNS), transplanted gut neural crest stem cells (GNCSCs) to reconstruct the ENS may be a potential replacement therapy for HD [6][7][8]. The precise migration mechanism of NCCs is not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Detection of autophagy in Hirschsprung’s disease

Huang¹,

Ge²,

Li³

et al. 2015

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Hirschsprung's disease (HD) is a common congenital gastrointestinal malformation, characterized by the lack of ganglion cells from the distal rectum to the proximal bowel, but the pathogenesis is not well understood. This paper evaluates the effects of autophagy in HD. Using electron microscopy, the autophagosomes were detected in three segments: narrow segment (NS), transitional segment (TS), and dilated segment (DS). Typical autophagosome structures are found in the Auerbach plexus of both NS and TS. Real-time PCR results showed that Beclin1 (NS vs. TS, P<0.01) and LC3 (NS vs. TS, P<0.05) mRNA were the highest in the NS, but p75 (NS vs. TS, P<0.01) was the highest in the DS. Correlation analysis results showed a positive correlation between Beclin1 and LC3 mRNA levels (R=0.736, P=0.000), whereas inverse correlations were found between p75 and Beclin1/LC3 mRNA levels (p75 vs. Beclin1: R=-0.714, P=0.000; p75 vs. LC3: R=-0.619, P=0.000). Immunohistochemistry analyses indicated a consistent result with mRNA levels, by increased Beclin1-positive and LC3-positive neurons, but reduced p75-positive neurons in the Auerbach plexus of TS compared with DS. These findings indicated that autophagy exists in the bowel of patients with HD. On the basis of the detection of the highest expression of the autophagy genes in NS, autophagy may additionally cause the lack of neurons.

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“…6,12,13 Following transplantation, the engrafted ENCCs can also engraft, migrate, and differentiate in the aganglionic colon both ex vivo and in vivo. [4][5][6][8][9][10][11]13,14 The muscle contractile ability of the colon can be improved after the transplantation of the ENCCs. 10,13 6 Additional efforts have also been made to further enhance the proliferation and differentiation of the ENCCs by supplement of glial cell line derived neurotrophic factor (GDNF) and serotonin type 4 (5-HT 4 ) receptor agonist.…”

Section: Endogenous Enteric Neural Crest Cellsmentioning

confidence: 99%

Update on the Role of Stem Cells in the Treatment of Hirschsprung Disease

2018

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Stem cells possess the ability of self-renewal and the potency to differentiate into multiple cell lineages. Somatic stem cells are present in adult tissues, but they usually exhibit limited differentiation capacity and life span. On the other hand, somatic cells from adult tissues can be reprogrammed into induced pluripotent stem cells (iPSCs) that retain a full differentiation capacity with unlimited self-renewal ability. Autologous origin of iPSCs makes them an ideal source of cells for regenerative medicine to replenish the missing or damaged cells in the patients. iPSCs nowadays have also been widely used to build human disease models to study pathological mechanisms of the diseases. Hirschsprung disease (HSCR) is a congenital disorder caused by defects in the development of enteric neural crest stem cells. The failures of the ENCCs to proliferate, differentiate, and/or migrate lead to the absence of enteric neurons in the distal colon, resulting in colonic motility dysfunction. The lack of effective treatment for HSCR urges continuous efforts to develop new therapies for this congenital disorder. In this review, we will discuss the potential applications of somatic stem cells and iPSCs for the cell-based therapy of HSCR. We will also highlight the recent advances in stem cell research for the establishment of human HSCR models for the development of novel therapies.

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Migration and differentiation of transplanted enteric neural crest-derived cells in murine model of Hirschsprung’s disease

Cited by 16 publications

References 43 publications

Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model

Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model

Detection of autophagy in Hirschsprung’s disease

Update on the Role of Stem Cells in the Treatment of Hirschsprung Disease

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