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Deficiency of c-KIT+ cells in patients with a myopathic form of chronic idiopathic intestinal pseudo-obstruction
Abstract
Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a syndrome characterized by a failure of intestinal movement, but the cause of dysmotility remains unknown. Because interstitial cells of Cajal (ICCs) are believed to initiate basic contractile activity of the gastrointestinal tract, there is a possibility that changes in ICCs are involved in the development of CIIP. ICCs express c-kit in mice, and it has been reported that the c-kit+ cells, the location and shape of which resemble those in mice, are detected in the human gastrointestinal muscular layer using immunohistochemistry. In the present study, we counted the number of c-kit+ cells in the affected intestine of two patients with myopathic form of CIIP and compared this number with the number of c-kit+ cells in the normal intestine.
The c-kit+ cells in the external muscle layer were detected by immunohistochemistry, and the number of them was counted under the microscope. Mast cells, which are known to express c-kit, were detected by staining with Alcian blue, and the number of them was also counted.
Immunohistochemistry revealed that the distribution pattern of c-kit+ cells resembles that of ICCs in the external muscle layer of normal control subjects. The numbers of c-kit+ cells apart from mast cells in two patients with myopathic form of CIIP decreased to about 3% of those in normal subjects.
The failure of intestinal movement in patients with CIIP, at least in a subpopulation, might be related to a deficiency of c-kit+ cells, probably ICCs.
... Transmembrane protein 16A (TMEM16A) was the first CaCC protein to be identified and was once thought to be a candidate intestinal epithelial CaCC (Ousingsawat et al., 2009); however, some researchers believe that a non-TMEM16A CaCC exists in the intestinal epithelium (Namkung et al., 2011). On the other hand, there is increasing evidence that TMEM16A plays an important role in the regulation of intestinal motility (Sanders et al., 2012), which is based on the following results: (a) the interstitial cells of Cajal (ICC) highly express TMEM16A (Isozaki et al., 1997;He et al., 2001); (b) the major function of the ICC is to participate in intestinal electric slow-wave generation and transmission and the regulation of intestinal smooth muscle contractions (Sanders and Ward, 2006); (c) pharmacological inhibition of TMEM16A function blocks the slow wave (Hwang et al., 2009); and (d) knockout of the TMEM16A gene leads to the disappearance of the slow wave in intestinal smooth muscle (Hwang et al., 2009). ...
... The ICC participate in electrical activity transmission as a pacemaker for rhythmic electrical activity and constitute a bridge between nerves and smooth muscle (Sanders and Ward, 2006). Dysfunctions in the ICC lead to a variety of gastrointestinal motility disorders (Isozaki et al., 1997;He et al., 2001;Bettolli et al., 2008). Recent studies have found that TMEM16A (also known as Dog1) is highly expressed in different sources of ICC and that the intestinal ICC network in TMEM16A gene knockout mice develops normally; however, the slow-wave activity of small intestinal smooth muscle disappears (Isozaki et al., 1997;He et al., 2001;Hwang et al., 2009). ...
... Dysfunctions in the ICC lead to a variety of gastrointestinal motility disorders (Isozaki et al., 1997;He et al., 2001;Bettolli et al., 2008). Recent studies have found that TMEM16A (also known as Dog1) is highly expressed in different sources of ICC and that the intestinal ICC network in TMEM16A gene knockout mice develops normally; however, the slow-wave activity of small intestinal smooth muscle disappears (Isozaki et al., 1997;He et al., 2001;Hwang et al., 2009). Klein et al. provide precise evidence that intestinal ICC not only modulate intestinal smooth muscle contractions by producing rhythmic slow-wave potential but also play an important role in the signal transduction between intestinal neurons and gastrointestinal smooth muscle (Klein et al., 2013). ...
Secretory diarrhea, which primarily originates through intestinal pathogens and viruses, is a health burden in many regions worldwide. Enterocyte Cl⁻ channels, as the final step in enterotoxin-induced fluid secretion, constitute an attractive class of targets for diarrhea therapy. Chloride channel inhibitors have become a new class of candidates for antisecretion and anti-intestinal motility agents. In the present study, we identified plumbagin as a transmembrane protein 16A (TMEM16A) inhibitor in a cell-based fluorescence-quenching assay, and the IC50 value was ∼12.46 µM. Short-circuit current measurements showed that plumbagin reversibly inhibited the Eact-induced Cl⁻ current on the apical side of TMEM16A-transfected Fischer rat thyroid (FRT) cells with no significant effect on cytoplasmic Ca²⁺ signaling. Notably, plumbagin also inhibited the activity of intestinal epithelial calcium-activated chloride channel (CaCC) and cystic fibrosis transmembrane conductance regulator (CFTR) in both HT-29 cells and mouse colons, but had no effects on the activity of the Na⁺-K⁺ ATPase or K⁺ channels. In in vivo experiments, the administration of plumbagin reduced both Escherichia coli heat-stable enterotoxin (STa)- and cholera toxin (CT)-induced intestinal fluid secretion. In neonatal mouse models of CT- and rotavirus infection-induced diarrhea, 0.4 µg plumbagin inhibited secretory diarrhea by >40% and 50%, respectively, without affecting intestinal epithelial integrity or the rotaviral infection. In addition, plumbagin exerted inhibitory effects on the vasoactive intestinal peptide (VIP)-, prostaglandin E2 (PGE2)-, and 5-hydroxytryptamine (5-HT)-stimulated Cl⁻ currents. In the evaluations of intestinal motility, plumbagin significantly delayed intestinal motility and inhibited intestinal smooth muscle contractility without an evident impact on contractive frequency. Collectively, our results indicate that plumbagin inhibits both Ca²⁺- and cAMP-activated Cl⁻ channels, accounting for the mechanisms of plumbagin inhibition of chloride secretion and intestinal motility. Thus, plumbagin can be a lead compound in the treatment of CT-induced, Traveler’s, and rotaviral diarrhea, as well as other types of secretory diarrhea that result from excessive intestinal fluid secretion and increased intestinal peristalsis.
... ICCs play an important role in regulating generation of slow waves in the GI tract, and loss of ICCs or disruption of ICC networks has been associated with abnormal GI function [35][36][37]. Therefore, we performed immunostaining using an antibody against cKit to assess whether the ICC network was affected by deletion of IP 3 R1. ...
... Slow waves drive phasic contractions that are the basic contractions of segmentation and gastric peristalsis. Loss of ICCs or disruption of ICC networks has been associated with abnormal GI function [35][36][37]. We did not find obvious changes in the distribution of ICCs in pcR1KO colons, suggesting that IP 3 R1 is not required for the development and formation of ICC networks, which is consistent with what have been found in IP 3 R1 global knockout mice [22]. ...
Background
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of intracellular Ca²⁺ release channels located on the membrane of endoplasmic reticulum, which have been shown to play critical roles in various cellular and physiological functions. However, their function in regulating gastrointestinal (GI) tract motility in vivo remains unknown. Here, we investigated the physiological function of IP3R1 in the GI tract using genetically engineered mouse models.
Methods
Pdgfrb-Cre mice were bred with homozygous Itpr1 floxed (Itpr1f/f) mice to generate conditional IP3R1 knockout (pcR1KO) mice. Cell lineage tracing was used to determine where Pdgfrb-Cre-mediated gene deletion occurred in the GI tract. Isometric tension recording was used to measure the effects of IP3R1 deletion on muscle contraction.
Results
In the mouse GI tract, Itpr1 gene deletion by Pdgfrb-Cre occurred in smooth muscle cells, enteric neurons, and interstitial cells of Cajal. pcR1KO mice developed impaired GI motility, with prolonged whole-gut transit time and abdominal distention. pcR1KO mice also exhibited lethality as early as 8 weeks of age and 50% of pcR1KO mice were dead by 40 weeks after birth. The frequency of spontaneous contractions in colonic circular muscles was dramatically decreased and the amplitude of spontaneous contractions was increased in pcR1KO mice. Deletion of IP3R1 in the GI tract also reduced the contractile response to the muscarinic agonist, carbachol, as well as to electrical field stimulation. However, KCl-induced contraction and expression of smooth muscle-specific contractile genes were not significantly altered in pcR1KO mice.
Conclusions
Here, we provided a novel mouse model for impaired GI motility and demonstrated that IP3R1 plays a critical role in regulating physiological function of GI tract in vivo.
... Within the pathophysiological realm, dysfunction of ICC has been implicated in a myriad of motility conditions, including achalasia, 85,86 gastroparesis, 71,87-89 intestinal pseudo-obstruction [90][91][92][93] and slow-transit constipation. [94][95][96] Lower numbers of ICC have been found in gastroparesis, 71 slow-transit constipation, 94,95 and intestinal pseudo-obstruction. ...
... [94][95][96] Lower numbers of ICC have been found in gastroparesis, 71 slow-transit constipation, 94,95 and intestinal pseudo-obstruction. 91 In achalasia, increased number of organelles (smooth endoplasmic reticulum and mitochondria) has been found in ICC located in the lower esophageal sphincter, possibly contributing to overactive contraction. 76 Gastroparesis also involves abnormal initiation and conduction of ICC pacemaker activity. ...
Anticholinergic drugs are well-known to cause adverse effects, such as constipation, but their effects on baseline contractile activity in the gut driven by slow waves is not well established. In a video-based gastrointestinal motility monitoring (GIMM) system, a mouse's small intestine was placed in Krebs solution and recorded using a high definition camera. Untreated controls were recorded for each specimen, then treated with a therapeutic concentration of the drug, and finally, treated with a supratherapeutic dose of the drug. Next, the video clips showing gastrointestinal motility were processed, giving us the segmentation motions of the intestine, which were then converted via Fast Fourier Transform (FFT) into their respective frequency spectrums. These contraction quantifications were analysed from the video recordings under standardised conditions to evaluate the effect of drugs. Six experimental trials were included with benztropine and promethazine treatments. Only the supratherapeutic dose of benztropine was shown to significantly decrease the amplitude of contractions; at therapeutic doses of both drugs, neither frequency nor amplitude was significantly affected. We have demonstrated that intestinal slow waves can be analysed based on the colonic frequency or amplitude at a supratherapeutic dose of the anticholinergic medications. More research is required on the effects of anticholinergic drugs on these slow waves to ascertain the true role of ICC in neurological control of gastrointestinal motility.
... Because of the critical involvement of the ICC-MP in motor pattern generation of the intestine, it is imperative that a thorough understanding of its network properties is needed and that we need to understand the influence of perturbations of the ICC-MP network on pacemaker activity and motor patterns. Loss of ICC has been convincingly demonstrated to be linked to gastroparesis (Faussone-Pellegrini et al., 2012;Grover et al., 2012;Pasricha, 2015), chronic constipation (Lyford et al., 2002;Kashyap et al., 2011;Knowles and Farrugia, 2011) and intestinal pseudo-obstruction (Isozaki et al., 1997;Kenny et al., 1998). Abnormal intestinal motility has consistently been associated with reduced ICC (Becheanu et al., 2008;Miller et al., 2008;Rumessen et al., 2010;Lammers et al., 2011;Rumessen et al., 2011). ...
... Of course, within the uncoupled section there is no propulsion and content passage may be impaired if the section is large enough. A consistent finding in motility dysfunction is the reduction in ICC (Isozaki et al., 1997;Kenny et al., 1998;Lyford et al., 2002;Kashyap et al., 2011;Knowles and Farrugia, 2011;Lammers et al., 2011). Here we show that network properties protect the pacemaking for consequences of incidental loss. ...
New Findings
What is the central question of this study?
What are the effects of interstitial cells of Cajal (ICC) network perturbations on intestinal pacemaker activity and motor patterns?
What is the main finding and its importance?
Two‐dimensional modelling of the ICC pacemaker activity according to a phase model of weakly coupled oscillators showed that network properties (coupling strength between oscillators, frequency gradient and frequency noise) strongly influence pacemaker network activity and subsequent motor patterns. The model explains motor patterns observed in physiological conditions and provides predictions and testable hypotheses for effects of ICC loss and frequency modulation on the motor patterns.
Interstitial cells of Cajal (ICC) are the pacemaker cells of gut motility and are associated with motility disorders. Interstitial cells of Cajal form a network, but the contributions of its network properties to gut physiology and dysfunction are poorly understood. We modelled an ICC network as a two‐dimensional network of weakly coupled oscillators with a frequency gradient and showed changes over time in video and graphical formats. Model parameters were obtained from slow‐wave‐driven contraction patterns in the mouse intestine and pacemaker slow‐wave activities from the cat intestine. Marked changes in propagating oscillation patterns (including changes from propagation to non‐propagating) were observed by changing network parameters (coupling strength between oscillators, the frequency gradient and frequency noise), which affected synchronization, propagation velocity and occurrence of dislocations (termination of an oscillation). Complete uncoupling of a circumferential ring of oscillators caused the proximal and distal section to desynchronize, but complete synchronization was maintained with only a single oscillator connecting the sections with high enough coupling. The network of oscillators could withstand loss; even with 40% of oscillators lost randomly within the network, significant synchronization and anterograde propagation remained. A local increase in pacemaker frequency diminished anterograde propagation; the effects were strongly dependent on location, frequency gradient and coupling strength. In summary, the model puts forth the hypothesis that fundamental changes in oscillation patterns (ICC slow‐wave activity or circular muscle contractions) can occur through physiological modulation of network properties. Strong evidence is provided to accept the ICC network as a system of coupled oscillators.
... One of the most prominent roles of ICC is the pacemaking of GI motor patterns, achieved by actively initiating and propagating electrical oscillations that excite and cause contractions in the GI musculature [2], [3]. ICC loss and injury is now a major research focus as it is recognized as a hallmark of several GI functional motility disorders [4], notably gastroparesis [5], [6], intestinal pseudo-obstruction [7], [8], and slow-transit constipation [9], [10]. ...
... The imaging of ex vivo ICC networks is technically challenging, and the obtained data are still generally limited to small fields-of-view in the order of a few hundred micrometers to millimeters [11]. Also, most studies on ICC loss compare normal networks against depleted networks at some set depletion severity, such as that induced by a gene knockout (KO) [3], [12] or disease [6], [7], and there is no systematic method to experimentally control the depletion severity so that networks at an intermediate depletion level can be imaged and investigated. A comprehensive imaging dataset encompassing large-scale ICC networks across a spectrum of depletion levels would be of substantial benefit in investigating the pathophysiology of ICC loss. ...
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.
... This was accompanied by a complete loss of CD34 þ fibroblasts, indicating the possibility that ICC stem cells were also affected. Knowles (212) found ICC abnormalities in 15% of patients with intestinal pseudo-obstruction, whereas in two patients studied, ICC numbers were reduced to 3% of normal (213). In another study, 45% of patients showed a marked decrease in ICC (214). ...
Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.
... ICC loss has been associated with slow transit constipation, chronic idiopathic intestinal obstruction, diabetes, and other human dyskinesia. [43][44][45][46] The mitochondrial pathway is considered to be the most important pathway of apoptosis. In a pathological state, the permeability of the mitochondria increases, and cytokines are released, promoting apoptosis. ...
Objective
This study observes the morphological changes in the enteric nervous system (ENS) – interstitial cells of Cajal (ICC) – smooth muscle cells (SMC) network in sphincter of Oddi dysfunction (SOD) in hypercholesterolemic rabbits following treatment with Shaoyao Gancao decoction (SGD), as well as the apoptosis of the ICC.
Methods
In this study, 48 healthy adult New Zealand rabbits are randomly divided into three groups (n = 16 in each group): the control, the model, and the SGD treatment groups. The hypercholesterolemic rabbit model is established. Hematoxylin and eosin staining, transmission electron microscopy, immunofluorescence, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, immunohistochemistry, Western blot analysis, and reverse transcription-polymerase chain reaction are used to detect the morphological changes in the ENS–ICC–SMC network, the expression of apoptosis-related proteins in the ICC, and to observe the curative effect of SGD after treatment.
Results
Compared with the control group, the morphology and the ultrastructure of the SO are destroyed in the model group. In addition, the protein gene product 9.5 (PGP9.5), nitric oxide (NO), the SMCs, and the ICC all significantly decreased while substance P (SP) significantly increased. Compared with the model group, the SO morphology and ultrastructure are repaired in the SGD group. In addition, the PGP9.5, NO, the SMCs, and the ICC significantly increased while SP decreased. In addition, SGD may activate the stem cell factor (SCF)/c-Kit signaling pathway to treat SO dysfunction by up-regulating the expression of c-Kit and SCF. Similarly, this pathway restores SO by up-regulating the expression of Bcl2 and inhibiting cleaved caspase-3, Bax, and the tumor necrosis factor.
Conclusion
Shaoyao Gancao decoction can promote the recovery of sphincter of Oddi dysfunction in hypercholesterolemic rabbits by protecting the ENS–ICC–SMC network.
... These studies suggest that at least a certain group of ICCs does not require intact enteric neurons for their development or maintenance. [31][32][33] Altered distributions of ICCs have been described in several disorders of human intestinal motility, including hypertrophic pyloric stenosis, 34 HD, [35][36][37] intestinal pseudoobstruction, [38][39][40] slow-transit constipation, 41 and ulcerative colitis. 42 Vanderwinden et al 35 described scarce ICCs with disrupted network in the aganglionic bowel, whereas the distribution of ICCs in the ganglionic bowel of HD was similar to that observed in the controls. ...
Context.—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.
Objective.—To investigate the distribution of myenteric and muscular ICCs in different parts of the colon in HD.
Methods.—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.
Results.—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.
Conclusion.—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.
... Decrease or total loss of the numbers of c-kit+ cells (Isozaki et al., 1997;Jain, Moussa, Tandon, Culpepper-Morgan, & Proctor, 2003). Abnormal distribution of the ICCs have also been observed (Feldstein, Miller, El-Youssef, et al., 2003;Yamataka et al., 1998). ...
The interstitial cells of Cajal (ICC) form interconnected networks throughout the gastrointestinal (GI) tract. ICC act as the pacemaker cells that initiate the rhythmic bioelectrical slow waves and intermediary between the GI musculature and nerves, both of which are critical to GI motility. Disruptions to the number of ICC and the integrity of ICC networks have been identified as a key pathophysiological mechanism in a number of clinically challenging GI disorders. The current analyses of ICC generally rely on either functional recordings taken directly from excised tissue or morphological analysis based on images of labeled ICC, where the structural‐functional relationship is investigated in an associative manner rather than mechanistically. On the other hand, computational physiology has played a significant role in facilitating our understanding of a number of physiological systems in both health and disease, and investigations in the GI field are beginning to incorporate several mathematical models of the ICC. The main aim of this review is to present the major modeling advances in GI electrophysiology, in order to introduce a multi‐scale framework for mathematically quantifying the functional consequences of ICC degradation at both cellular and tissue scales. The outcomes will inform future investigators utilizing modeling techniques in their studies.
This article is categorized under:
• Metabolic Diseases > Computational Models
... (4) They appear to be involved in mechanotransduction [46,47]. Abnormalities within the number of ICC or the integrity of the ICC networks can lead to PIPO in infants and children [48][49][50][51]. Fig. 1 Phases I-III are depicted in the tracing. ...
Purpose of Review
The purpose of this review is to discuss current knowledge on pediatric intestinal pseudo-obstruction. We will also review new mutations that have been identified through advancement in genetic testing, allowing for a better understanding of the underlying mechanisms of intestinal dysmotility and potential etiologies.
Recent Findings
With the advancements in genetic testing, new mutations have been identified in the diagnosis of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a disorder leading to pediatric pseudo-obstruction. MYLK, LMOD1, MYL9, and MYH11 encode for various proteins within smooth muscle cells; abnormalities within these proteins lead to abnormal intestinal smooth muscle contractions.
Summary
Chronic intestinal pseudo-obstruction (CIPO) is defined by symptoms of bowel obstruction in the absence of a lumen-occluding lesion. CIPO is a heterogeneous group of disorders caused by abnormalities in the enteric neurons, intestinal smooth muscle, and/or the interstitial cells of Cajal (ICC). Symptoms can be non-specific and etiologies include both primary and secondary causes of CIPO that contribute to the delay in recognizing this condition and making the correct diagnosis. Chronic intestinal pseudo-obstruction has been recognized in both adults and children with fundamental differences in the etiology, symptom onset, clinical features and natural history of this disorder. For this reason, it has been considered a separate entity referred to as pediatric intestinal pseudo-obstruction (PIPO).
... Quantitative and qualitative abnormalities of ICC/ ICC networks are implicated in CIPO. c-kit+ ICC were reported absent in the intestine of two patients with the myopathic form of CIPO [51], in the small and large intestine of six cases of idiopathic CIPO [48], and in the distal ileum and colon of a pediatric case of intestinal pseudoobstruction [49]. Abnormal distribution of ICC/ ICC networks was reported in the small intestine and colon of pediatric and adult patients with intestinal pseudoobstruction [52][53][54]. ...
Background
MNGIE is a rare and fatal disease in which absence of the enzyme thymidine phosphorylase induces systemic accumulation of thymidine and deoxyuridine and secondary mitochondrial DNA alterations. Gastrointestinal (GI) symptoms are frequently reported in MNGIE patients, however, they are not resolved with the current treatment interventions.
Recently, our understanding of the GI pathology has increased, which rationalizes the pursuit of more targeted therapeutic strategies. In particular, interstitial cells of Cajal (ICC) play key roles in GI physiology and are involved in the pathogenesis of the GI dysmotility. However, understanding of the triggers of ICC deficits in MNGIE is lacking. Herein, we review the current knowledge about the pathology of GI dysmotility in MNGIE, discuss potential mechanisms in relation to ICC loss/dysfunction, remark on the limited contribution of the current treatments, and propose intervention strategies to overcome ICC deficits. Finally, we address the advances and new research avenues offered by organoids and tissue engineering technologies, and propose schemes to implement to further our understanding of the GI pathology and utility in regenerative and personalized medicine in MNGIE.
Conclusion
Interstitial cells of Cajal play key roles in the physiology of the gastrointestinal motility. Evaluation of their status in the GI dysmotility related to MNGIE would be valuable for diagnosis of MNGIE. Understanding the underlying pathological and molecular mechanisms affecting ICC is an asset for the development of targeted prevention and treatment strategies for the GI dysmotility related to MNGIE.
... ICC-IM and ICC-DMP are densely innervated by excitatory motor neurons [14] and inhibitory motor neurons [15,16]. Disruption or loss of ICC has been implicated in a host of GI motility disorders, including achalasia [17,18], slow transit constipation [19,20], intestinal pseudo-obstruction [21,22], Crohn's disease [23], inflammation [24,25], and diabetic gastroparesis [26][27][28][29], as well as altered gut motility associated with aging. The mechanisms underlying ICC maintenance and turnover in vivo remain controversial, however, it is well recognized that ICC display a high degree of plasticity and regenerative capacity ( Figure 1). ...
Effective digestion requires propagation of food along the entire length of the gastrointestinal tract. This process involves coordinated waves of peristalsis produced by enteric neural cell types, including different categories of interstitial cells of Cajal (ICC). Impaired food transport along the gastrointestinal tract, either too fast or too slow, causes a range of gut motility disorders that affect millions of people worldwide. Notably, loss of ICC has been shown to affect gut motility. Patients that suffer from gut motility disorders regularly experience diarrhoea and/or constipation, insomnia, anxiety, attention lapses, irritability, dizziness, and headaches that greatly affect both physical and mental health. Limited treatment options are available for these patients, due to the scarcity of human gut tissue for research and transplantation. Recent advances in stem cell technology suggest that large amounts of rudimentary, yet functional, human gut tissue can be generated in vitro for research applications. Intriguingly, these stem cell-derived gut organoids appear to contain functional ICC, although their frequency and functional properties are yet to be fully characterised. By reviewing methods of gut organoid generation, together with what is known of the molecular and functional characteristics of ICC, this article highlights short- and long-term goals that need to be overcome in order to develop ICC-based therapies for gut motility disorders.
... Kajalzellen sind zwischen den beiden Muskelschichten des Gastrointestinaltrakts lokalisiert und an der Regulation der Darmperistaltik beteiligt. Ihre Entwicklung und Differenzierung wird durch die RTK c-Kit reguliert (Isozaki 1995;Isozaki 1997). GIST sind nicht nur durch die starke Expression von c-Kit charakterisiert, sondern auch durch eine Mutation in c-Kit, die in etwa 88 % als Tumor-Ursache gilt (Hirota 1998). ...
Gastrointestinale Stromatumore (GIST) sind typischerweise auf eine aktivierende Mutation in der Rezeptortyrosinkinase c Kit zurückzuführen. Eine Behandlung mit dem Tyrosinkinase-Inhibitor Imatinib führt bei der großen Mehrheit der Patienten zunächst zu einer Tumorregression. Nach durchschnittlich zwei Jahren entwickeln viele Patienten eine Resistenz gegen Imatinib, die sehr häufig mit einer sekundären Mutation in c Kit einhergeht. Als Zweitlinientherapie stehen weitere Tyrosinkinase-Inhibitoren zur Verfügung, die jedoch bislang nur mäßige Wirkung zeigen. Erschwerend kommt hinzu, dass die Wirksamkeit der Inhibitoren stark vom c Kit Genotyp abhängt. Das Verständnis der Protein-Interaktionsnetzwerke der c Kit Mutanten und des c Kit Wildtyps ist in diesem Zusammenhang essentiell. Zielsetzung dieser Arbeit war es, das Protein-Interaktionsnetzwerk von c Kit Wildtyp und ausgewählten GIST-assoziierten c Kit Mutanten genauer zu untersuchen. Dabei sollten bekannte Medikamenten-Zielmoleküle, wie z.B. Hsp90, genauer charakterisiert und neue potentielle Zielmoleküle gefunden werden. Die Identifizierung der Interaktionspartner erfolgte mit einer im Rahmen dieser Arbeit für c Kit Wildtyp etablierten expressions-entkoppelten Tandem-Affinitätsreinigung (u TAP). Als Modell für den stimulierten Zustand der Rezeptortyrosinkinase wurde in vitro phosphoryliertes c Kit Wildtyp Köderprotein im u-TAP Assay eingesetzt. Das Interaktionsnetzwerk von c Kit Wildtyp wurde in An- und Abwesenheit von Imatinib und des Hsp90 Inhibitors 17AAG untersucht. Beide Wirkstoffe hatten nahezu keinen Einfluss auf das Protein-Interaktionsnetzwerk von c Kit Wildtyp. Interaktionsanalysen der GIST-assoziierten c Kit Mutanten wiesen eine Bindung von Hsp90 und dessen Cochaperon Cdc37 nach, die beim Wildtyp nicht auftrat. Cdc37 gilt bereits als potentielles Medikamenten-Zielmolekül für verschiedene onkogene Proteine. Die Interaktion von Cdc37 mit c-Kit Mutanten wurde im Rahmen dieser Arbeit erstmals identifiziert und verifiziert. Darüber hinaus konnte eine vom Genotyp abhängige Affinität von c Kit zu Hsp90 und Cdc37 gemessen werden. Aufgrund der bekannten stabilisierenden Funktion von Hsp90 und Cdc37 erlaubt die Affinität Rückschlüsse auf die Stabilität einer Mutante und deren Sensitivität gegenüber Hsp90 Inhibitoren. c Kit Wildtyp degradierte in Anwesenheit von 17AAG deutlich weniger als die mit Hsp90 und Cdc37 interagierenden c Kit Mutanten. Die 17AAG-Sensitivität korrelierte für die meisten c Kit Mutanten mit der Affinität zu Hsp90 und Cdc37. Diese Genotyp-spezifische Sensitivität von c Kit gegenüber 17AAG könnte als Grundlage für eine individuelle GIST-Therapie dienen. Zusätzlich kann Cdc37 als potentieller neuer Angriffspunkt zur Behandlung von GIST betrachtet werden.
... Un changement à leur niveau peut être le déclencheur de nombreux désordres intestinaux. Ces cellules sont ainsi associées à plusieurs pathologies dont la maladie de Hirschprung [373][374], la sténose pylorique hypertrophique de l'enfant [375][376], la pseudo-obstruction intestinale chronique myopathique [377][378]. D'après le registre PROGIST publié en février 2010, 95,3% des tumeurs mésenchymateuses gastrointestinales sont positives pour le marqueur cKit [380]. ...
Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. As its pathophysiology is still poorly understood, it is difficult to treat. Several parameters have been described as involved in the initiation of atrial fibrillation, but the precise mechanisms of initiation of atrial fibrillation are not understood. In this study, histological, biochemical, genetic and transcriptomic approaches have been performed in order to identify the substrates involved in the initiation of human atrial fibrillation. Thus, it has been demonstrated presence of interstitial cells Cajal-like in myocardial sleeves of pulmonary veins that may be the cause of ectopic foci, a possible early embryonic origin through lack of expression of the pitx2 gene in atrial fibrillation patients, overexpression of the autonomic nervous system to both adrenergic and cholinergic pathways, a change in the flow of potassium current IKs through intervention of KCNE regulatory proteins and cytoskeletal muscle protein. In addition, a complication of atrial fibrillation is the occurrence of stroke. It has been shown at left atrial level an overexpression of Von Willebrand factor in patients with atrial fibrillation and an increase of serological VEGF in paroxysmal subtype of atrial fibrillation. These new data allow completing the knowledge on atrial fibrillation and subsequently considering the possibility of new therapeutic strategies that could be more effective.
... Electrical slow wave are not observed in mice lacking ICC networks which demonstrate the absent or delayed intestinal motility [5,6]. ICC are also found to be diminished or lost in human disease with associated alterations in gastric and small intestinal motility, such as diabetic gastroparesis [7], intestinal pseudo-obstruction [8,9], and congenital absence of the enteric nervous system etc. [10] Rhubarb (Da Huang) is one of the oldest and bestknown Chinese herbal medicines, first recorded in the Classic of the Materia Medica [11], Shen Nong Ben Cao Jing of the Han dynasty, and is classified as a top medicinal plant [12]. ...
... Un changement à leur niveau peut être le déclencheur de nombreux désordres intestinaux. Ces cellules sont ainsi associées à plusieurs pathologies dont la maladie de Hirschprung [373][374], la sténose pylorique hypertrophique de l'enfant [375][376], la pseudo-obstruction intestinale chronique myopathique [377][378]. D'après le registre PROGIST publié en février 2010, 95,3% des tumeurs mésenchymateuses gastrointestinales sont positives pour le marqueur cKit [380]. ...
... It is unquestionable that ICCs are necessary for the creation of slow electrical waves, which condition slow peristalsis in smooth muscles. The absence of slow activity of smooth muscles limits or completely inhibits its peristalsis [29][30][31]. ...
Interstitial cells of Cajal (ICCs) were discovered in the gastrointestinal tract over 100 years ago and since then numerous digestive tract pathologies involving ICCs have been described. Many researchers explored ICCs presence and function in the upper urinary tract. Currently, we know that ICCs have potential plasticity, their own spontaneous activity and that they are responsible for Ca2+ waves generation and neuromuscular transmission. ICCs are also involved in the conjugation, propagation and modulation of peristaltic waves in the upper urinary tract. Despite everything we know about ICCs, their role in the pathogenesis of the upper urinary tract abnormalities remains still unclear and results of published studies are confusing. The authors' intention was to review the scientific literature regarding ICCs and to summarise the current knowledge about their nature in the upper urinary tract.
... Many studies have reported that loss of interstitial cells of Cajal (ICC), or injury to ICC networks can play an improtant role in various chronic GI motility disorders, including the aforementioned conditions. [6][7][8][9][10] ICC are known to control spontaneous contraction in GI smooth muscle through the generation of slow waves. [11][12][13] ICC also mediate inhibitory neurotransmission in such areas as the lower esophageal sphincter and the pylorus. ...
Bone marrow derived Kit-positive cells colonize the gut but fail to restore pacemaker function in intestines lacking interstitial cells of Cajal. McCann CJ, Hwang SJ, Hennig GW, Ward SM, Sanders KM.
... Loss of interstitial cells of Cajal (ICC) or disruption of ICC networks have been implicated in a variety of GI motility disorders including achalasia, 1 slow transit constipation, 2 intestinal pseudoobstruction, 3 Crohn's disease, 4 inflammation 5 and diabetic gastroparesis. 6,7 Although ICC defects have been associated with these disorders, there have been few studies to determine whether ICC can be made to repopulate gastrointestinal (GI) muscles with the goal of recovering normal motor activity. ...
Background/Aims
Several motility disorders are associated with disruption of interstitial cells of Cajal (ICC), which provide important functions, such as pacemaker activity, mediation of neural inputs and responses to stretch in the gastrointestinal (GI) tract. Restoration of ICC networks may be therapeutic for GI motor disorders. Recent reports have suggested that Kit+ cells can be restored to the GI tract via bone marrow (BM) transplantation. We tested whether BM derived cells can lead to generation of functional activity in intestines naturally lacking ICC.
Methods
BM cells from Kit+/copGFP mice, in which ICC are labeled with a green fluorescent protein, were transplanted into W/WV intestines, lacking ICC. After 12 weeks the presence of ICC was analyzed by immunohistochemistry and functional analysis of electrical behavior and contractile properties.
Results
After 12 weeks copGFP+ BM derived cells were found within the myenteric region of intestines from W/WV mice, typically populated by ICC. Kit+ cells failed to develop interconnections typical of ICC in the myenteric plexus. The presence of Kit+ cells was verified with Western analysis. BM cells failed to populate the region of the deep muscular plexus where normal ICC density, associated with the deep muscular plexus, is found in W/WV mice. Engraftment of Kit+-BM cells resulted in the development of unitary potentials in transplanted muscles, but slow wave activity failed to develop. Motility analysis showed that intestinal movements in transplanted animals were abnormal and similar to untransplanted W/WV intestines.
Conclusions
BM derived Kit+ cells colonized the gut after BM transplantation, however these cells failed to develop the morphology and function of mature ICC.
Several functional gastrointestinal disorders (FGIDs) have been associated with the degradation or remodeling of the network of interstitial cells of Cajal (ICC). Introducing fractal analysis to the field of gastroenterology as a promising data analytics approach to extract key structural characteristics that may provide insightful features for machine learning applications in disease diagnostics. Fractal geometry has advantages over several physically based parameters (or classical metrics) for analysis of intricate and complex microstructures that could be applied to ICC networks.
In this study, three fractal structural parameters: Fractal Dimension, Lacunarity, and Succolarity were employed to characterize scale-invariant complexity, heterogeneity, and anisotropy; respectively of three types of gastric ICC network structures from a flat-mount transgenic mouse stomach.
The Fractal Dimension of ICC in the longitudinal muscle layer was found to be significantly lower than ICC in the myenteric plexus and circumferential muscle in the proximal, and distal antrum, respectively (both p < 0.0001). Conversely, the Lacunarity parameters for ICC-LM and ICC-CM were found to be significantly higher than ICC-MP in the proximal and in the distal antrum, respectively (both p < 0.0001). The Succolarity measures of ICC-LM network in the aboral direction were found to be consistently higher in the proximal than in the distal antrum (p < 0.05).
The fractal parameters presented here could go beyond the limitation of classical metrics to provide better understanding of the structural-functional relationship between ICC networks and the conduction of gastric bioelectrical slow waves.
Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.
Coordinated movements of the gastrointestinal tract are regulated by multiple control systems including the enteric nervous system, extrinsic neurons, epithelial cells, interstitial cells of Cajal (ICC), platelet-derived growth factor receptor α (PDGFRα)-expressing cells, and myogenic mechanisms. Studies using laboratory animals have shown that enteric neurons develop early, but the first gastrointestinal motility patterns are myogenic, and not neurally mediated. Nevertheless, contractile activity mediated by neurons is prominent by birth, and required for propulsion of content as is evident from the bowel obstruction proximal to the aganglionic region in infants with Hirschsprung disease and in animal models of this disease. ICC development requires signaling via the tyrosine kinase receptor, Kit. Studies in preterm and term humans have shown that esophageal peristalsis and sphincter function mature during the late fetal and early postnatal stages. Maturation continues to advance beyond birth with improvement in the characteristics of sensory-motor aspects of reflexes, coordination and integration with other organ systems. However, little is known about the maturation and adaptation of motility in the small and large bowel of human infants.
Functional and motility gastrointestinal disorders are the most common complaints to the pediatric gastroenterologist. Disorders affecting the small intestine carry a significant morbidity and mortality due to the severe limitation of therapeutic interventions available and the complications associated with such interventions. Congenital colorectal disorders are rare but also carry significant morbidity and poor quality of life plus the social stigma associated with its complications. In this review, we summarize the clinical presentation, diagnostic evaluations, and the therapeutic interventions available for the most common and severe gastrointestinal functional and motility disorders of the small bowel, colon, and anorectum.
Purpose of review:
Small bowel dysmotility is a broad heterogeneous term that encompasses a wide range of gastrointestinal disorders resulting from abnormal gut motility. Chronic intestinal pseudo-obstruction (CIPO) is a severe, rare, and complex small bowel motility disorder at the extreme end of this spectrum. It is characterized by failure of the intestinal tract to propel contents, which results in signs and symptoms of bowel obstruction albeit in the absence of any obstructive lesion(s). In this article, we discuss up-to-date diagnostic techniques, management options, and histopathological findings in CIPO.
Recent findings:
We will emphasize the latest diagnostic methodologies and therapeutic options as well as enteric histopathologic abnormalities in patients with CIPO. CIPO continues to be a clinical challenge. Several novel pharmacological agents hold promise including gastrointestinal hormone agonists and prokinetics. Furthermore, histopathologic findings may help guide therapy and provide further prognostic significance. At present, nutritional support, symptom management, and avoidance of long-term complications are the mainstay of treatment in CIPO.
Objective:
Gastrointestinal dysmotility in critically ill patients is important as enteral nutrition is crucial. However, normal gut motility is impaired under conditions of critical illness subsequent to severe insult. Interstitial cells of Cajal (ICC) form an extensive network associated with the myenteric plexus in the enteric nervous system. There are few reports about ICC distribution in critically ill patients. The aim of this study was to evaluate ICC in critically ill patients.
Methods:
Postmortem colon harvest was obtained from critically ill patients. Control specimens were obtained from patients without bowel movement problems who underwent hemicolectomy. The tissues were stained with c-Kit for ICC. The number of ICC was identified by counting from 10 high-power fields (HPFs).
Results:
Specimens from six patients were analyzed and compared with those from six control patients. All patients had abnormalities of crypt architecture and inflammatory cell infiltrations. Mucosal thickness tended to be lower in the critically ill patients than in the controls (147 ± 47 versus 231 ± 127 μm; P = 0.15). Muscle layer thickness tended to be higher in the critically ill patients than in the controls (494 ± 163 versus 394 ± 258 μm; P = 0.44). ICC in the critically ill patients were almost depleted in the colon compared with those in the controls. Significantly fewer ICC were present in the critically ill patients than in the controls (0.45 versus 7.25 cells/HPF; P < 0.05).
Conclusions:
Critical illness is associated with diminished numbers of ICC in the colon. This finding could have implications for dysmotility in critically ill patients.
Targeted treatment has become a major modality in cancer management. Such cancer drugs are generally designed to treat tumors with certain genetic/genomic makeups. Mutational testing prior to prescribing targeted therapy is crucial in identifying who can receive clinical benefit from specific cancer drugs. Over the last two decades, gastrointestinal stromal tumors (GISTs) have evolved from histogenetically obscure to being identified as distinct gastrointestinal mesenchymal tumors with well-defined clinical and molecular characteristics, for which multiple lines of targeted therapies are available. Although the National Comprehensive Cancer Network (NCCN) strongly recommends mutational testing for optimal management of GIST, many GIST patients still have neither a mutation test performed or any mutation-guided cancer management. Here, we review the mutation landscape of GIST, mutational testing methods, and the recent development of new therapies targeting GIST with specific mutations. .
Our understanding of the physiological roles played by interstitial cells of Cajal (ICC) in relation to gastrointestinal (GI) motility is still rudimentary. Nevertheless, studies into the pathophysiology of ICC are emerging at a rapid pace. Caution should be exercised, however, in assuming correlations between changes in Kit immunoreactivity, findings of ultrastructural abnormalities in ICC, and the pathophysiology and symptoms of the patients. Recent studies have revealed reduced numbers or the absence of ICC in small intestine and colon that do not exhibit normal peristaltic activity. Furthermore, important evidence is emerging that motor abnormalities in newborns may be associated with delayed maturation of the ICC network. These preliminary clinical studies provide plausible hypotheses toward the pathophysiology of certain motor disorders and strongly encourage basic scientific studies directed toward discovering the intrinsic properties of ICC as well as obtaining a deeper understanding of the physiological roles played by these cells.
Dysmotility of the small intestine and colon has a wide range of clinical manifestations, regardless of the underlying cause of the disorder. This chapter focuses on the small intestine, motility disorders of the colon that are manifested predominantly as constipation and megacolon. It also discusses the roles of endothelins and of gene mutation M918T in the maldevelopment of the enteric nervous system (ENS) and their role in Hirschsprung disease. Malnutrition develops in patients with severe dysmotility of the small intestine as the result of an inadequate intake of food and vomiting. In patients with severe dysmotility of the small intestine, chronic intestinal pseudoobstruction may develop. The chapter presents a case study which illustrates: (1) postnatal maturation of interstitial cells of Cajal (ICCs), (2) the importance of the conservative management of children with neonatal megacolon or pseudo obstruction, and (3) the importance of ICCs to the overall peristaltic function of the colon.
Regulation of colonic motility depends upon the integrity of enteric inhibitory neurotransmission mediated by nitric oxide (NO), purine neurotransmitters, and neuropeptides. Intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor α-positive (PDGFRα(+)) cells are involved in generating responses to NO and purine neurotransmitters, respectively. Previous studies have suggested a decreased nitrergic and increased purinergic neurotransmission in Kit(W)/Kit(W-v) (W/W(v) ) mice that display lesions in ICC-IM along the gastrointestinal tract. However, contributions of NO to these phenotypes have not been evaluated. We utilized small-chamber superfusion assays and HPLC to measure the spontaneous and electrical field stimulation (EFS)-evoked release of nicotinamide adenine dinucleotide (NAD(+))/ADP-ribose, uridine adenosine tetraphosphate (Up4A), adenosine 5'-triphosphate (ATP) and metabolites from the tunica muscularis of human, monkey and murine colons and circular muscle of monkey colon, and we tested drugs that modulate NO levels or blocked NO receptors. NO inhibited EFS-evoked release of purines in the colon via presynaptic neuromodulation. Colons from W/W(v) , Nos1(-/-) and Prkg1(-/-) mice displayed augmented neural release of purines that was likely due to altered nitrergic neuromodulation. Colons from W/W(v) mice demonstrated decreased nitrergic and increased purinergic relaxations in response to nerve stimulation. W/W(v) mouse colons demonstrated reduced Nos1 expression and reduced NO release. Our results suggest that enhanced purinergic neurotransmission may compensate for the loss of nitrergic neurotransmission in muscles with partial loss of ICC. The interactions between nitrergic and purinergic neurotransmission in the colon provides novel insight into the role of neurotransmitters and effector cells in the neural regulation of gastrointestinal motility.
Coordinated movements of the gastrointestinal tract are regulated by multiple control systems including intrinsic and extrinsic neurons, interstitial cells of Cajal (ICC), platelet-derived growth factor receptor α (PDGFRα)-expressing cells, and myogenic mechanisms. Studies using laboratory animals have shown that although enteric neurons develop early, the first gastrointestinal motility patterns are myogenic and not neurally mediated. However, neurally mediated contractile activity is prominent by birth and is essential for propulsive activity as shown by the bowel obstruction that occurs proximal to the aganglionic region in infants with Hirschsprung disease and in animal models of Hirschsprung disease. The development of ICC requires signaling via the tyrosine kinase receptor, Kit. Genetic alterations of Kit, and reduced ICC density, have recently been linked to a severe case of idiopathic constipation and megacolon in a child. Studies in preterm and term humans have shown that esophageal peristalsis and sphincter function mature during the late fetal and early postnatal stages. Little is known about the development of motility in the small and large bowel of human infants.
Interstitial cells of mesenchymal origin form gap junctions with smooth muscle cells in visceral smooth muscles and provide important regulatory functions. In gastrointestinal (GI) muscles, there are two distinct classes of interstitial cells, c-Kit+ interstitial cells of Cajal and PDGFRα+ cells, that regulate motility patterns. Loss of these cells may contribute to symptoms in GI motility. disorders.
AIM: To investigate the impact of long-term chronic water immersion-restraint stress on the number of interstitial cells of Cajal (ICC) in the gastric antrum of rats and to explore the relationship between ICC and gastric motility changes caused by chronic stress. METHODS: Forty-eight male Sprague-Dawley rats were randomly and equally divided into six groups: three experiment groups and three matched control groups. The three experimental groups underwent water immersion-restraint stress for one hour daily for 3, 7 and 14 d, respectively, while the three control groups were allowed free access to food and water. On days 4, 8 and 29, the rats in both groups were sacrificed. Gastric tissue samples were collected from areas at the lesser curvature of the membranous stomach and the lesser curvature of the glandular stomach as well as areas near the upper one third of the great curvature of the glandular stomach and the pylorus of the glandular stomach. Paraffin-embedded sections were then made. The number of ICC was counted after immunohistochemical staining for c-Kit. RESULTS: Intermuscular (ICC-MY) and intramuscular ICC (ICC-IM) were predominant types of ICC in normal rats, whereas submucosal ICC (ICC-SM) and ICC in the deep muscular plexus (ICC-DMP) were minor ones. The number of ICC were statistically different between the experiment and control groups on days 7 and 28 after stress: the number of ICC increased on day 7 but decreased on day 28 in the experiment groups. After stress, significant changes were found in the number of ICC-MY and ICC-IM, but not in that of ICC-SM and ICC-DMP. CONCLUSION: Long-term chronic water immersion-restraint stress alters the number of ICC in the gastric antrum of rats.
OBJECTIVE: Interstitial cells of Cajal are critical for the generation of electrical slow waves that regulate the phasic contractile activity of the tunica muscularis of the GI tract. Under certain pathophysiological conditions loss of interstitial cells of Cajal may play a role in the generation of certain motility disorders. The aim of the present study was to determine if there is an abnormality in the density or distribution of interstitial cells of Cajal from patients with Crohn's disease. METHODS: Small intestines from control subjects and patients with Crohn's disease were examined using immunohistochemistry and antibodies against the Kit receptor, which is expressed in interstitial cells of Cajal within the tunica muscularis of the GI tract. The density and distribution of interstitial cells of Cajal were assessed in the longitudinal and circular muscle layers and in the myenteric and deep muscular plexus regions of Crohn's and control tissues. RESULTS: Tissues from Crohn's disease patients showed an almost complete abolition of interstitial cells of Cajal within the longitudinal and circular muscle layers and a significant reduction in numbers at the level of the myenteric and deep muscular plexuses. CONCLUSIONS: In tissues from Crohn's disease patients, the density of interstitial cells of Cajal was reduced throughout the tunica muscularis in comparison to control small intestines. The disturbance of intestinal motility that occurs in patients with Crohn's disease may be a consequence of the loss of or defects in specific populations of interstitial cells of Cajal within the tunica muscularis.
The phrase intestinal dysmotility refers to a broad range of clinical conditions characterized by impaired peristalsis. In children, common symptoms of intestinal dysmotility include constipation, encopresis, diarrhea, vomiting, and abdominal pain. Less frequently, severe chronic constipation, failure to thrive, abdominal distension, enterocolitis, or other obstructive symptoms are present. The majority of patients with a history of dysmotility suffer from functional disorders that have no established organic etiology and are diagnosed using symptom-based criteria (Stordal et al. 2001; Loening-Baucke 2006). However, for pediatric patients, particularly those with severe symptoms, anatomic pathology is often sought and occasionally found to explain their clinical problems. In some, the cause is an acute or intermittent obstructive condition (e.g., atresia, volvulus, intussusception, etc.) associated with obvious gross pathology, subjects that are covered in Chap. 1. Conditions dominated by diarrhea, which are principally inflammatory or infectious, are also discussed elsewhere in this text (see Chaps. 4 and 6). The pathological correlates of the remaining infants and children, who exhibit severe chronic constipation or pseudo-obstruction, are the focus of this chapter.
The phrase intestinal dysmotility refers to a broad range of clinical conditions that are characterized by impaired peristalsis. In children, common symptoms of intestinal dysmotility include constipation, encoporesis, diarrhea, vomiting, and abdominal pain. Less frequently, severe chronic constipation, failure-to-thrive, abdominal distension, enterocolitis, or other obstructive symptoms are present. The majority of patients with a history of dysmotility suffer from functional disorders which have no established organic etiology and are diagnosed using symptom-based criteria.1,2 However, for pediatric patients, particularly those with severe symptoms, anatomic pathology is often sought and occasionally found to explain their clinical problems. In some cases, the cause will be an acute or intermittent obstructive condition (e.g., atresia, volvulus, intussusception, and so on) associated with obvious gross pathology, subjects that are covered in Chapter 1. Conditions dominated by diarrhea, which are principally inflammatory or infectious disorders, are also discussed elsewhere in this text (see Chapter 5). The pathological correlates of the remaining infants and children who exhibit severe chronic constipation or pseudo-obstruction are the focus of this chapter.
Autoimmune impairment and destruction of the enteric nervous plexus are thought to play a central role in the pathogenesis of paraneoplastic motility disorders. We present a case of a small-cell lung carcinoma-related paraneoplastic motility disorder associated with abnormal interstitial cells of Cajal networks. Antibodies against c-Kit and protein gene product 9.5 were used to selectively stain interstitial cells of Cajal and the enteric nervous plexus, respectively. A 68-yr-old man presented with anorexia, early satiety, nausea, and weight loss. Investigations revealed gastroparesis, delayed small intestinal transit, and mediastinal lymphadenopathy. The patient was seropositive for type 1 antineuronal nuclear autoantibody and P/Q-type calcium channel antibody. Biopsy of mediastinal lymph nodes revealed metastatic small-cell carcinoma cells that were immunoreactive for c-Kit. Immunohistochemical staining of a full-thickness small intestinal biopsy revealed a relatively intact myenteric plexus but a sparse and disorganized interstitial cells of Cajal network. The histopathology of this case suggests that interstitial cells of Cajal may be a target in the pathogenesis of paraneoplastic motility disorders.
Interstitial cells of Cajal (ICC) are fundamental regulators of GI motility. Here, we report the manometrical abnormalities and abnormalities of ICC distribution and ultrastructure encountered in a 30-yr-old patient with megaduodenum and pseudo-obstruction. Full thickness biopsies taken during laparoscopic placement of a jejunostomy showed vacuolated myocytes and fibrosis predominantly in the outer third of the circular muscle layer of the duodenum, suggestive for visceral myopathy. The distribution of ICC was also strikingly abnormal: by light microscopy, ICC surrounding the myenteric plexus were lacking in the megaduodenum, whereas ICC were normally present in the duodenal circular muscle and in the jejunum. By electron microscopy, very few ICC were identified around the duodenal myenteric plexus. These findings suggest that abnormalities in ICC may contribute to the disturbed motility in some myopathic forms of intestinal pseudo-obstruction.
In der kontroversen Diskussion um die unklare Ätiologie der Appendizits wird oft eine Motilitätsstörungen angeführt. Die Interstitial cells of Cajal sind bedeutend für die Motilität und die Entstehung der Peristaltik im menschlichen Kolon. Bei einigen Motilitätsstörungen des Darmes wurde eine Rarifizierung dieser Zellen beobachtet. Die ICC wuden noch nie in der Appendix vermiformis beschrieben.In dieser Arbeit wurden erstmals die ICC in der Appendix mittels einer immunhistochemischen Färbung durch einen maus-monoklonalen Antikörper ( NCL- cKit) nachgewiesen sowie analysiert. Es konnten keine Subgruppen IC-SMP und IC-MP in der Appendix nachgewiesen werden. Die IC-LM zeigten sich reduziert im Vergleich zum Kolon. Die IC-CM konnten zahlreich und regelmäßig dargestellt werden. Eine unterschiedliche Verteilung bzw. Dichte der ICC in der normalen Appendix, der akut und chronisch entzündeten Appendizits konnte nicht nachgewiesen werden.Schlussfolgernd und in Übereinstimmung mit den Beobachtungen anderer Autoren besitzt die Appendix eine reduzierte Motilität und eine physiologische Koprosthase, die aber allein nicht zu einer Entzündung führt. Erst unter dem Einfluss der aus der Literatur bekannten Kofaktoren wird die Koprosthase verstärkt. Erst dies führt zu einer Alteration der Schleimhaut und zur Appendizitis.
The diagnosis of enteric neuromuscular disorders has come a long way since the first description of an enteric neuropathic disorder by the Danish physician Harald Hirschsprung in 1886. Advances in specialized enteric histopathological staining techniques have made it possible to identify subtle neuropathies and myopathies that cause intestinal motility disorders, from the common and now better understood and relatively easily diagnosed Hirschsprung's disease to the less common and more severe and not well-characterized chronic idiopathic intestinal pseudoobstruction, which continues to present a diagnostic challenge to the gastroenterologist and histopathologist alike. This article will discuss the common gastrointestinal motility disorders and some of the specialized histological stains, such as the relatively common enzyme stain, acetylcholinesterase, used to diagnose Hirschsprung's disease; advanced tinctorial stains, such as Masson trichrome, which may aid in diagnosis of enteric myopathies causing pseudoobstruction; and immunohistochemical stains such as C-Kit or PG 9.5, which may aid in the diagnosis of enteric neuropathies causing pseudoobstruction.
Gastrointestinal motility is an area of research that has gained renewed interest in recent years. However, it is evident that there still remains much to be learnt and discovered. The chapters in this volume entitled “New Advances in Gastrointestinal Motility Research” result from a meeting which took place at The University of Auckland, New Zealand in October/November 2011 and provide a summary of discussions. Both the meeting and this book were brainchilds of Professor Andrew Pullan. However, Professor Andrew Pullan tragically passed away between the inception and completion of this series. This book not simply dedicated to him and his family but is a reflection of his ideas and work. The 12 remaining chapters of this volume are arranged into 4 broad sections: covering gastrointestinal cellular activity and tissue structure; techniques for measuring, analyzing and visualizing high-resolution extra-cellular recordings; methods for modulating gastric electrical activity as well as sensing the resultant activity using non-invasive bio-electro-magnetic fields; and finally methods for assessing manometric and videographic motility patterns and the application of these data for predicting the flow and mixing behavior of luminal contents by using computational fluid dynamic techniques. As a result, this volume aims to provide both an overview of existing research techniques over a range of research areas as well as to highlight future directions and challenges for the community as a whole.
Coordinated movements of the gastrointestinal tract are regulated by multiple mechanisms including intrinsic and extrinsic neurons, interstitial cells of Cajal (ICC), and myogenic mechanisms. Studies using laboratory animals have shown that although enteric neurons develop early, the first gastrointestinal motility patterns are myogenic, and not neurally mediated. However, neurally mediated contractile activity is prominent by birth, and is essential for propulsive activity as shown by the bowel obstruction that occurs proximal to the aganglionic region in infants with Hirschsprung’s disease. The development of ICC requires signaling via the tyrosine kinase receptor, Kit. Genetic alterations of Kit, and reduced ICC density, have recently been linked to a severe case of idiopathic constipation and megacolon in a child. Studies in preterm and term humans have shown that esophageal peristalsis and sphincter function mature during the late fetal and early postnatal stages. Little is known about the development of motility in the small and large bowel of human infants.
Interstitial cells of Cajal (ICC) are mesoderm-derived mesenchymal cells found in the smooth muscle layers of the gastrointestinal tract. They contribute to the normal function of the gut by generating rhythmic electrical activity, as intermediaries in neuromuscular signalling, altering the membrane potential of adjacent smooth muscle and responding to mechanical stretch. Depletion of ICC is associated with several gastrointestinal motility disorders including diabetic gastroparesis, slow transit constipation and intestinal pseudo-obstruction. This chapter reviews the information that can be obtained from measuring and characterizing networks of interstitial cells of Cajal in health and disease, the applications of that information in computer modelling and about how mathematical modelling might inform further efforts to characterize and/or reverse ICC network depletion. We describe the appropriate techniques for tissue collection and handling when investigating effects on ICC networks. Methods for identifying, accurately quantifying and mapping ICC are presented together with new analyses that can identify changes to the geometry as well as the density of the ICC networks. Finally we discuss the information that is obtained on the relationship between ICC network changes and alterations to gastrointestinal function and show how computer modelling of virtual ICC networks could be used to predict those relationships.
Background
Interstitial cells of Cajal (ICC) are required for normal intestinal motility. ICC are found throughout the human colon and are decreased in the sigmoid colon of patients with slow transit constipation.
Aims
The aims of this study were to determine the normal distribution of ICC within the human colon and to determine if ICC are decreased throughout the colon in slow transit constipation.
Patients
The caecum, ascending, transverse, and sigmoid colons from six patients with slow transit constipation and colonic tissue from patients with resected colon cancer were used for this study.
Methods
ICC cells were identified with a polyclonal antibody to c-Kit, serial 0.5 μm sections were obtained by confocal microscopy, and three dimensional software was employed to reconstruct the entire thickness of the colonic muscularis propria and submucosa.
Results
ICC were located within both the longitudinal and circular muscle layers. Two networks of ICC were identified, one in the myenteric plexus region and another, less defined network, in the submucosal border. Caecum, ascending colon, transverse colon, and sigmoid colon displayed similar ICC volumes. ICC volume was significantly lower in the slow transit constipation patients across all colonic regions.
Conclusions
The data suggest that ICC distribution is relatively uniform throughout the human colon and that decreased ICC volume is pan-colonic in idiopathic slow transit constipation.
This pathologically accelerated transit is often well accepted by patients since it is associated with partial relief of other digestive symptoms, but it contributes to determine intestinal malabsorption and deteriorate nutritional conditions. Indeed, many patients are afflicted by inability to maintain a normal body weight, despite dietary manipulations, both because of the deranged digestive functions and because food ingestion often exacerbates digestive symptoms and consequently patients tend to avoid a normal oral nutrition.
We review current methods for the spatiotemporal (ST) mapping of phasic and tonic contractile activity in the various components of the intestinal tract. Basic mapping techniques extract the movement of gut organ boundaries from a sequence of images and condense this information into 2D maps. More complex techniques determine the extent to which locations on the gut organ are lengthening or shortening in a particular direction and also present this data in a 2D map. The latter either track the position of applied markers or use cross-correlation of consecutive images to quantify the movement of serosal patterns. In situations where the above techniques have difficulties, intensity mapping can be useful for identifying motility patterns but is less quantitative. Finally, we discuss ancillary methods for deriving further information from ST maps and practical considerations for applying the mapping techniques.
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