Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon

Universität Mannheim, Mannheim, Baden-Württemberg, Germany
Gastroenterology (Impact Factor: 16.72). 11/2002; 123(5):1459-67. DOI: 10.1053/gast.2002.36600
Source: PubMed


A variety of gastrointestinal motility disorders have been attributed to alterations of interstitial cells of Cajal and malformations of the enteric nervous system. This study evaluates both the distribution of interstitial cells of Cajal and the pathohistology of the enteric nervous system in 2 severe human colorectal motility disorders.
Colonic specimens obtained from patients with slow-transit constipation (n = 11), patients with megacolon (n = 6), and a control group (n = 13, nonobstructing neoplasia) were stained with antibodies against c-kit (marker for interstitial cells of Cajal) and protein gene product 9.5 (neuronal marker). The morphometric analysis of interstitial cells of Cajal included the separate registration of the number and process length within the different regions of the muscularis propria. The structural architecture of the enteric nervous system was assessed on microdissected whole-mount preparations.
In patients with slow-transit constipation, the number of interstitial cells of Cajal was significantly decreased in all layers except the outer longitudinal muscle layer. The myenteric plexus showed a reduced ganglionic density and size (moderate hypoganglionosis) compared with the control group. Patients with megacolon were characterized by a substantial decrease in both the number and the process length of interstitial cells of Cajal. The myenteric plexus exhibited either complete aganglionosis or severe hypoganglionosis.
The enteric nervous system and interstitial cells of Cajal are altered concomitantly in slow-transit constipation and megacolon and may play a crucial role in the pathophysiology of colorectal motility disorders.

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    • "This framework can be further enhanced by incorporating the virtual network generation algorithms, such that the simulations are not limited to the small spatial scale of the experimental data. The augmented framework can then be used as a virtual platform to investigate ICC structure-function relationships in, for example, gastroparesis and slow-transit constipation where multiple cellular pathologies and competing theories co-exist [5] [10]. Another potential application of the virtual network generation algorithms is to generate large-scale networks to inform multiscale models [31] [32], which, for instance, can be used to investigate the mechanisms of conduction slowing and dysrhythmias recently observed in a high-resolution electrical mapping study of gastroparetic patients with ICC depletion [6]. "
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    ABSTRACT: Interstitial cells of Cajal (ICC) play a central role in coordinating normal gastrointestinal (GI) motility. Depletion of ICC numbers and network integrity contributes to major functional GI motility disorders. However, the mechanisms relating ICC structure to GI function and dysfunction remains unclear, partly because there is a lack of large-scale ICC network imaging data across a spectrum of depletion levels to guide models. Experimental imaging of these large-scale networks remains challenging because of technical constraints, and hence we propose the generation of realistic virtual ICC networks in silico using the Single Normal Equation Simulation (SNESIM) algorithm. ICC network imaging data obtained from wild-type (normal) and 5-HT2B serotonin receptor knockout (depleted ICC) mice were used to inform the algorithm, and the virtual networks generated were assessed using ICC network structural metrics and biophysically-based computational modeling. When the virtual networks were compared to the original networks, there was less than 10% error for four out of five structural metrics and all four functional measures. The SNESIM algorithm was then modified to enable the generation of ICC networks across a spectrum of depletion levels, and as proof-of-concept, virtual networks were successfully generated with a range of structural and functional properties. The SNESIM and modified SNESIM algorithms therefore offer an alternative strategy for obtaining large-scale ICC network imaging data across a spectrum of depletion levels. These models can be applied to accurately inform the physiological consequences of ICC depletion.
    No preview · Article · Mar 2015 · IEEE transactions on bio-medical engineering
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    • "The ICC volume in the W/W v mice did not recover after mast cell reconstitution or the blockade of COX-2 and iNOS because of the genetic mutation in these mice. Clinical studies using immunohistochemical, morphological and ultrastructural approaches found that ICC were depleted and their networks disrupted in several human gut motility disorders , including diabetes mellitus (He et al., 2001; Nakahara et al., 2002; Iwasaki et al., 2006; Miller et al., 2008; Pasricha et al., 2008), slow transit constipation (He et al., 2000; Lyford et al., 2002), Hirschprung's disease (Vanderwinden et al., 1996), gastroparesis (Zarate et al., 2003), chronic constipation (Yu et al., 2002), and megacolon (Wedel et al., 2002). The depletion of ICC volume and impairment of ICC networks were proposed as the underlying causes of disordered motility function. "
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    ABSTRACT: The initial hypothesis suggested that the interstitial cells of Cajal (ICC) played an essential role in mediating enteric neuronal input to smooth muscle cells. Much information for this hypothesis came from studies in W/W(v) mice lacking ICC. However, mast cells, which play critical roles in regulating inflammation in their microenvironment, are also absent in W/W(v) mice. We tested the hypothesis that the depletion of mast cells in W/W(v) mice generates inflammation in fundus muscularis externa (ME) that impairs smooth muscle reactivity to Ach, independent of the depletion of ICC. We performed experiments on the fundus ME from wild type (WT) and W/W(v) mice before and after reconstitution of mast cells by bone marrow transplant. We found that mast cell deficiency in W/W(v) mice significantly increased COX-2 and iNOS expression and decreased smooth muscle reactivity to Ach. Mast cell reconstitution or concurrent blockade of COX-2 and iNOS restored smooth muscle contractility without affecting the suppression of c-kit in W/W(v) mice. The expression of nNOS and ChAT were suppressed in W/W(v) mice; mast cell reconstitution did not restore them. We conclude that innate inflammation induced by mast cell deficiency in W/W(v) mice impairs smooth muscle contractility independent of ICC deficiency. The impairment of smooth muscle contractility and the suppression of the enzymes regulating the synthesis of Ach and NO in W/W(v) mice need to be considered in evaluating the role of ICC in regulating smooth muscle and enteric neuronal function in W/W(v) mice.
    Full-text · Article · Feb 2014 · Frontiers in Physiology
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    • "Since interstitial cell of Cajal was postulated as a pacemaker cell in the gut in the early 1990s, many have attempted to study the possible pathophysiological roles of this cell [12]. ICC alteration was reported in many gastrointestinal conditions such as achalasia [14], gastroparesis [18], gastric outlet obstruction (hypertrophied pyloric stenosis) [15], chronic intestinal pseudo-obstruction [16], megacolon [17], and slow-transit constipation [17,22]. However, it has long been a debate whether alteration of the ICC is a cause, or a secondary effect of the disorders [12,13]. "
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    ABSTRACT: The network of interstitial cells of Cajal (ICC) is altered in obstructive bowel disorders (OBD). However, whether alteration in ICC network is a cause or consequence of OBD remains unknown. This study tested the hypothesis that mechanical dilation in obstruction disrupts the ICC network and that ICC do not mediate mechanotranscription of COX-2 and impairment of smooth muscle contractility in obstruction. Medical-grade silicon bands were wrapped around the distal colon to induce partial obstruction in wild-type and ICC deficient (W/W(v)) mice. In wild-type mice, colon obstruction led to time-dependent alterations of the ICC network in the proximal colon segment. Although unaffected on days 1 and 3, the ICC density decreased markedly and the network was disrupted on day 7 of obstruction. COX-2 expression increased, and circular muscle contractility decreased significantly in the segment proximal to obstruction. In W/W(v) control mice, COX-2 mRNA level was 4.0 (±1.1)-fold higher (n=4) and circular muscle contractility was lower than in wild-type control mice. Obstruction further increased COX-2 mRNA level in W/W(v) mice to 7.2 (±1.0)-fold vs. W/W(v) controls [28.8 (±4.1)-fold vs. wild-type controls] on day 3. Obstruction further suppressed smooth muscle contractility in W/W(v) mice. However, daily administration of COX-2 inhibitor NS-398 significantly improved muscle contractility in both W/W(v) sham and obstruction mice. Lumen dilation disrupts the ICC network. ICC deficiency has limited effect on stretch-induced expression of COX-2 and suppression of smooth muscle contractility in obstruction. Rather, stretch-induced COX-2 plays a critical role in motility dysfunction in partial colon obstruction.
    Preview · Article · Sep 2013 · PLoS ONE
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