Altered distribution of interstitial cells of Cajal in Hirschsprung’s disease. Arch Pathol Lab Med

Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland.
Archives of pathology & laboratory medicine (Impact Factor: 2.84). 09/2002; 126(8):928-33. DOI: 10.1043/0003-9985(2002)126<0928:ADOICO>2.0.CO;2
Source: PubMed


Constipation or recurrent intestinal dysmotility problems are common after definitive surgical treatment in Hirschsprung disease (HD). c-Kit-positive interstitial cells of Cajal (ICCs) play a key role in the motility function and development of the gastrointestinal tract. Interstitial cells of Cajal that carry the tyrosine kinase receptor (c-Kit) develop as either myenteric ICCs or muscular ICCs under the influence of the kit ligand, which can be provided by neuronal and nonneuronal cells, for example, smooth muscle cells.
To investigate the distribution of myenteric and muscular ICCs in different parts of the colon in HD.
Resected bowel specimens from 8 patients with rectosigmoid HD were investigated using combined staining with c-Kit enzyme and fluorescence immunohistochemistry and acetylcholinesterase and nicotinamide adenine dinucleotide phosphate (NADPH) histochemistry in whole-mount preparations and conventional frozen sections.
In the normal bowel, ICCs formed a dense network surrounding the myenteric plexus and at the innermost part of the circular muscle. Myenteric ICCs were absent or sparse in the aganglionic bowel and sparse in the transitional zone. The expression of myenteric ICCs in the ganglionic bowel in HD was reduced compared to that in the normal bowel, and they formed only sparse networks. Muscular ICCs were found in the aganglionic bowel, transitional zone, and normoganglionic bowel of HD in a reduced density compared to the normal bowel.
This study demonstrates altered distribution of ICCs in the entire resected bowel of HD patients. This finding suggests that persistent dysmotility problems after pull-through operation in HD may be due to altered distribution and impaired function of ICCs.

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Available from: Udo Rolle, Sep 25, 2014
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    • "The development of antibodies to c-kit has allowed for routine identification of ICCs in pathology specimens [41]. Distribution of ICC has been found to be abnormal in several diseases in which intestinal peristalsis is impaired, such as Hirschsprung disease, hypoganglionosis, neuronal intestinal dysplasia, and infantile pyloric stenosis [38] [41]. It has been shown by Vargun et al. [23] that in the absence of ICC, spontaneous depolarization and repolarization of smooth muscle cells fail to occur, and the regular pattern of peristaltic waves disappears. "
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    • "We suggest that there is another critical point in HSCR guts, the ICC network that requires repair. The number of ICC has been found to be remarkably reduced in the narrow segment of the HSCR colon, which is pathologic [15]–[18]. "
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    ABSTRACT: Interstitial cells of Cajal (ICC) are critical to gastrointestinal motility. The phenotypes of ICC progenitors have been observed in the mouse gut, but whether they exist in the human colon and what abnormal changes in their quantity and ultrastructure are present in Hirschsprung's disease (HSCR) colon remains uncertain. In this study, we collected the surgical resection of colons, both proximal and narrow segments, from HSCR patients and normal controls. First, we identified the progenitor of ICC in normal adult colon using immunofluorescent localization techniques with laser confocal microscopy. Next, the progenitors were sorted to observe their morphology. We further applied flow cytometry to examine the content of ICC progenitors in these fresh samples. The ultrastructural changes in the narrow and proximal parts of the HSCR colon were observed using transmission electron microscopy (TEM) and were compared with the normal adult colon. The presumed early progenitor (c-Kit(low)CD34(+)Igf1r(+)) and committed progenitor (c-Kit(+)CD34(+)Igf1r(+)) of ICC exist in adult normal colon as well as in the narrow and proximal parts of the HSCR colon. However, the proportions of mature, early and committed progenitors of ICC were dramatically reduced in the narrow segment of the HSCR colon. The proportions of mature and committed progenitors of ICC in the proximal segment of the HSCR colon were lower than in the adult normal colon. Ultrastructurally, ICC, enteric nerves, and smooth muscle in the narrow segment of the HSCR colon showed severe injury, including swollen vacuola or ted mitochondria, disappearance of mitochondrial cristae, dilated rough endoplasmic reticulum, vesiculation and degranulation, and disappearance of the caveolae on the ICC membrane surface. The contents of ICC and its progenitors in the narrow part of the HSCR colon were significantly decreased than those of adult colon, which may be associated with HSCR pathogenesis.
    PLoS ONE 01/2014; 9(1):e86100. DOI:10.1371/journal.pone.0086100 · 3.23 Impact Factor
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    • "In this disease, the enteric nervous system is absent (aganglionosis) in a portion of the GI tract (mostly distal colon) and slow wave activity is absent in the affected area.[136] There is a lot of debate regarding the role of ICC in Hirschsprung's disease; some studies have demonstrated a decreased density of ICC in the aganglionic area,[137] while others have shown absent or sparse ICC in both the aganglionated and ganglionated portions of the resected bowels.[138] However, other studies have shown no differences in the colonic distribution of ICC between Hirschsprung's disease patients and controls.[139] "
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    ABSTRACT: Gastrointestinal (GI) motility function and its regulation is a complex process involving collaboration and communication of multiple cell types such as enteric neurons, interstitial cells of Cajal (ICC), and smooth muscle cells. Recent advances in GI research made a better understanding of ICC function and their role in the GI tract, and studies based on different types of techniques have shown that ICC, as an integral part of the GI neuromuscular apparatus, transduce inputs from enteric motor neurons, generate intrinsic electrical rhythmicity in phasic smooth muscles, and have a mechanical sensation ability. Absence or improper function of these cells has been linked to some GI tract disorders. This paper provides a general overview of ICC; their discovery, subtypes, function, locations in the GI tract, and some disorders associated with their loss or disease, and highlights some controversial issues with regard to the importance of ICC in the GI tract.
    Saudi Journal of Gastroenterology 03/2013; 19(1):3-15. DOI:10.4103/1319-3767.105909 · 1.12 Impact Factor
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