Interstitial cells of Cajal mediate mechanosensitive responses in the stomach

Changes in motor activity are a basic response to filling of smooth muscle organs. Responses to gastric filling, for example, are thought to be regulated by neural reflexes. Here, we demonstrate a previously uncharacterized aspect of stretch-dependent responses in visceral smooth muscles that is mediated by mechanosensitive interstitial cells of Cajal. Length ramps were applied to the murine antral muscles while recording intracellular electrical activity and isometric force. Stretching muscles by an average of 27 +/- 1% of resting length resulted in 5 mN of force. Increasing length caused membrane depolarization and increased slow-wave frequency. The responses were dependent on the rate of stretch. Stretch-dependent responses were not inhibited by neuronal antagonists or nifedipine. Increases in slow-wave frequency, but not membrane depolarization, were inhibited by reducing external Ca(2+) (100 microM) and by Ni(2+) (250 microM). Responses to stretch were inhibited by indomethacin (1 microM) and were absent in cyclooxygenase II-deficient mice, suggesting that cyclooxygenase II-derived eicosanoids may mediate these responses. Dual microelectrode impalements of muscle cells within the corpus and antrum showed that stretch-induced changes in slow-wave frequency uncoupled proximal-to-distal propagation of slow waves. This uncoupling could interfere with gastric peristalsis and impede gastric emptying. Stretch of antral muscles of W/W(V) mice, which lack intramuscular interstitial cells of Cajal, did not affect membrane depolarization or slow-wave frequency. These data demonstrate a previously uncharacterized nonneural stretch reflex in gastric muscles and provide physiological evidence demonstrating a mechanosensitive role for interstitial cells of Cajal in smooth muscle tissues.     

Interstitial cells of Cajal are involved in the afferent limb of the rectoanal inhibitory reflex

BACKGROUND AND AIMS: Interstitial cells of Cajal (ICC) have been shown to be involved in nitrergic neurotransmission of the lower oesophageal sphincter and pylorus. Here we studied the role of ICC and nitric oxide (NO) in the inhibitory neurotransmission of the murine internal anal sphincter (IAS). METHODS: The rectoanal inhibitory reflex, rectal compliance, and relaxation of the isolated IAS to electrical stimulation were measured in controls, KIT (W)/KIT (Wv) mice, and neuronal NO synthase (nNOS) deficient mice. In addition, we evaluated the effect of blockade of nNOS using N-nitro-L-arginine methyl ester. Distribution of nNOS positive neurones and ICC in the IAS was assessed immunohistochemically. RESULTS: KIT positive ICC were present in a dense network in the IAS of controls but not in KIT (W)/KIT(Wv) mice. Relaxation of IAS muscle strips induced by electrical stimulation was diminished in nNOS-/- mice but not in KIT (W)/KIT (Wv) mice. Blockade of NOS reduced the relaxation of IAS muscle strips in both mice. Relaxation of the IAS to rectal distension was significantly diminished in KIT (W)/KIT (Wv) mice and nNOS deficient mice. In concert, in vivo blockade of NOS attenuated the relaxation of the IAS in controls. No significant difference in compliance was found. CONCLUSION: The inhibitory innervation of the IAS and the rectoanal inhibitory reflex are mediated by NO and the rectoanal inhibitory reflex requires an intact network of ICC in the IAS. Thus both loss of nitrergic innervation and deficiency of ICC lead to impaired anal relaxation and may play an important role in rectal evacuation disorders.     

小鼠胆囊Cajal间质细胞的初步研究

目的研究小鼠胆囊Cajal间质细胞的形态、分布与超微结构。方法取CDl小鼠胆囊，亚甲蓝染色、免疫荧光激光扫描共聚焦显微镜以及透射电镜技术观察胆囊Cajal间质细胞的形态、分布与超微结构。结果在胆囊组织可见清晰的呈深蓝色网状结构的Cajal间质细胞。胆囊Cajal间质细胞多呈纺锤形，胞体饱满，细胞两极有细长突起或多极突起，呈点和（或）丝状分布于胆囊全层。具有典型超微结构的胆囊Caja[间质细胞与平滑肌细胞、神经细胞相毗邻。结论CDI小鼠胆囊全层存在网络状分布的呈纺锤形的Cajal间质细胞，这可能与胆囊慢波产生有关并有可能作为神经系统控制胆囊平滑肌细胞运动的中介。     

Cajal间质细胞与胆道系统

Cajal间质细胞(ICC)是一类分布于胃肠道及少部分胃肠外器官,具有胃肠起搏及信号转导等功能的细胞.已有较多报道证实其与一系列胃肠动力性疾病如假性肠梗阻、先天性巨结肠、糖尿病胃轻瘫等疾病的发生密切相关.近年来还发现,ICC在胆道系统的胆囊、胆囊管、Oddi括约肌等多处存在,并参与Oddi括约肌自主节律性运动的调控等活...     

Interstitial cells of Cajal, the Maestro in health and disease

Interstitial cells of Cajal (ICC) are important players in the symphony of gut motility. They have a very signif icant physiological role orchestrating the normal peristaltic activity of the digestive system. They are the pacemaker cells in gastrointestinal (GI) muscles. Absence, reduction in number or altered integrity of the ICC network may have a dramatic effect on GI system motility. More understanding of ICC physiology will foster advances in physiology of gut motility which will help in a future break...     

消化道Cajal间质细胞介导肠神经传递的研究进展

消化道Cajal间质细胞(ICC)与胃肠运动功能关系密切。ICC根据形态和功能主要分成三种类型。ICC超微结构与肠神经联系紧密,形态学和功能学研究证实ICC介导肠神经的胃肠道作用。     

ICC与胃肠道炎症免疫

胃肠道Cajal间质细胞(ICC)与各种原因所致的胃肠道炎症,胃肠动力紊乱密切相关.ICC在胃肠道发生炎症时,他的结构,数量,功能均有不同程度的改变.同时胃肠道炎性病变的免疫机制也越来越受到人们的重视.本文就胃肠道炎症的免疫过程中ICC发生的变化作一综述.     

Interstitial cells of Cajal are present in human extrahepatic bile ducts

Background and Aims: Interstitial cells of Cajal (ICC) are distributed with smooth muscle throughout the gastrointestinal tract and are involved in regulating motility. ICC were recently discovered in the wall of the human gallbladder. This study sought to determine whether ICC are present in human bile ducts. Methods: Biliary tract samples were obtained from several sources: surgical specimens (n = 16, 11 women, mean age 61 years); archival post‐mortem specimen (n = 1, 86 years, man); and cadavers (n = 2, 68 and 80 years, men). Paraffin‐embedded sections (3 µm) from the gallbladder (fundus, body and neck) and both extrahepatic and intrahepatic bile ducts were investigated. A double immunofluorescence protocol using polyclonal and monoclonal c‐kit antibodies and mast cell tryptase was used to distinguish c‐kit‐positive cells with typical ICC morphology from c‐kit‐positive mast cells. Small bowel samples were used as positive controls. ICC in the gallbladder were confirmed by ultrastructural study. Results: c‐kit‐positive cells with characteristic ICC morphology were identified in the subepithelial and muscular layers of the gallbladder and extrahepatic bile ducts. They were most prominent within the muscle layer of the extrahepatic bile ducts where they were organized into loosely arranged laminae running parallel to circular smooth muscle fibers. ICC were not found in intrahepatic bile ducts. Conclusion: This study demonstrates for the first time that ICC are present in human extrahepatic bile ducts where they are more densely aggregated than in the gallbladder. This cellular network is likely to be involved in biliary tract motility and its related disorders.     

Interstitial cells of Cajal in the gut-A gastroenterologist’s point of view

Alterations of normal function of interstitial cells of Cajal （ICC） are reported in many intestinal disorders. Diagnosis of their involvement is rare （infrequent）, but necessary to propose a specifi c treatment. This article reviews the place of ICC in the pathogenesis of achalasia, gastroesophageal reflux disease, infantile hypertrophic pyloric stenosis, chronic intestinal pseudoobstruction and slow transit constipation. Moreover we discuss the role of the Cajal cells in the development of stromal tumors of the gastrointestinal tract.     

Interstitial cells of Cajal in the human fetal small bowel as shown by c-kit immunohistochemistry

Background—Interstitialcells of Cajal (ICCs) express the tyrosine kinase receptor c-kit, whichis required for their development and spontaneous pacemaker activity inthe bowel. From murine models it has been proposed that ICCs do notdevelop until after birth, but more recent findings indicate that c-kitis expressed early in the embryonic period. The temporal development ofICCs in the human gut remains unknown.
Aim—To investigateICCs in the human fetal small bowel using c-kit immunohistochemistry.
Subjects—Small bowelspecimens were obtained at post mortem examination of 16 fetuses andnine neonates, eight of whom were premature, born at gestational agesof 13 to 41 weeks, without gastrointestinal disorders.
Methods—Immunohistochemicalanalysis was performed on material fixed in formalin and embedded inparaffin. The specimens were exposed to antibodies raised against c-kit(an ICC marker) and neurone specific enolase (a general neuronalmarker). The ABC complex method was used to visualise binding ofantibodies to the corresponding antigens.
Results—c-kitimmunoreactive cells were visualised from 13 weeks of gestation. Theimmunoreactivity was mainly localised in association with the myentericplexus. From about 17-18 weeks of gestation, the ICCs formed a layeralong the myenteric plexus, whereas this layer appeared to be disruptedat 13-16 weeks of gestation.
Conclusions—ICCs arec-kit immunoreactive at least from a gestational age of 13 weeks inthe human fetal small intestine. From 17-18 weeks of gestation untilbirth, they form a continuous layer around the myenteric ganglia.

Keywords:interstitial cells of Cajal; c-kit; myentericplexus; human; fetal; development

     

Cajal间质细胞与慢传输型便秘

Cajal间质细胞是胃肠道神经系统(ENS)的一种非神经但又与神经密切相关的特殊间质细胞。近年的研究表明Cajal间质细胞(ICC)可能是肠道慢波的起搏者，并参与了NANC神经肌肉信息传递过程，有潜在的控制胃肠道动力的作用，而且与人类胃肠道运动性疾病以及胃肠道肿瘤的发病机制有关。慢传输型便秘(STC)就是胃肠运动性疾病中的一种，它是以结肠动     

Alterations in the Density of Interstitial Cells of Cajal in Achalasia

The aim of this study was to assess the quantity of interstitial cells of Cajal (ICC) in the lower esophageal sphincter (LES) in achalasia. LES muscle was obtained from 11 achalasia and nine esophageal cancer (control) patients during surgery. Immunohistochemistry was performed and average cell counts per high-power field (HPF) were obtained. Overall, more ICC were observed in achalasia (median = 14.0 cells/HPF; range = 0–22.6 cells/HPF) as compared with controls (median = 6.2 cells/HPF; range = 1.6–10.8 cells/HPF) (P = 0.047). There were two subsets of findings within the achalasia group: 8/11(73%) had an increased quantity of ICC (median = 17.1 cells/HPF; range = 11.6–22.6; P = 0.015) as compared with controls, whereas the remaining 3/11(27%) had a paucity of ICC (median = 0 cells/HPF; range = 0–2; P = 0.02). ICC levels were positively correlated with age of the patient (P = 0.043). Our study demonstrates that subsets of abnormal ICC levels are observed in idiopathic achalasia of the esophagus.     

The Importance of Interstitial Cells of Cajal in the Gastrointestinal Tract

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.     

Interstitial cells of Cajal: a novel hypothesis for the pathophysiology of irritable bowel syndrome

Irritable bowl syndrome (IBS) affects a large proportion of the world's population, and accounts for a considerable number of visits to gastroenterologists and general practitioners. Despite its high prevalence, the precise mechanism of IBS has not been identified to date. The interstitial cells of Cajal (ICC) participate in the production of slow waves and the regulation of their propagation through the gastrointestinal system; thus, they are important components of gastrointestinal motility. The present review proposes that ICC play a central role in the pathophysiology of IBS. This hypothesis is based on many links between ICC and currently proposed mechanisms of IBS pathophysiology. It appears that ICC may be involved in almost all of the previously explained pathogenic mechanisms of IBS. If proven, this hypothesis may provide a key to solving the IBS mystery.     

培养的小鼠小肠和胃Cajal间质细胞起搏电流的特性

目的:探讨培养的小鼠小肠和胃Cajal间质细胞(ICC)起搏电流的特性.方法:用二型胶原酶分离ICC并在含有干细胞因子的培养液中培养,72 h后通过免疫组织化学方法进行鉴定.利用传统全细胞模式膜片钳技术记录胃窦和小肠ICC的起搏电流.把电极内液的钙螯合剂EGTA浓度由0.1 mmol/L增加到10 mmol/L,使游离钙浓度降低,观察细胞内低钙对起搏电流的影响.结果:培养72 h后的ICC在光镜下表现出自胞体发出2-4条长突起,并与邻近ICC突起相互连接成网络状;激光共聚焦显微镜下观察到ICC表面酪氨酸激酶受体c-kit表达呈阳性;膜电位钳制在-60 mV的条件下,ICC上可以记录到自发而节律性内向电流,即起搏电流.在胃和小肠ICC之间以及单个ICC和ICC网络之间,电流幅度、频率有差异.在传统的全细胞膜片钳模式下,通过增加电极内液中EGTA浓度使细胞内游离钙降低时,可以激活ICC的内向电流;在细胞外给予钙调蛋白抑制剂W-7时,可以激活ICC内向电流的同时明显增加起搏电流的幅度.结论:小鼠胃和小肠ICC产生的起搏电流频率与小鼠胃和小肠自律运动的频率非常接近;网络ICC产生的起搏电流比单个ICC稳定、幅度高、频率快;ICC内游离钙浓度的降低是产生起搏电流的重要因素;钙调蛋白在ICC内参与起搏电流的抑制性调节.