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      Roles of interstitial cells of Cajal in regulating gastrointestinal motility: in vitro versus in vivo studies

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          Abstract

          The aim of this article is to provide a better understanding of the roles of interstitial cells of Cajal (ICC) in regulating gastrointestinal motility by reviewing in vitro and in vivo physiological motility studies. Based on the in vitro studies, ICC are proposed to have the following functions: to generate slow waves, to mediate neurotransmission between the enteric nerves and the gastrointestinal muscles and to act as mechanoreceptors. However, there is limited evidence available for these hypotheses from the in vivo motility studies. In this review, we first introduce the major subtypes of ICC and their established functions. Three Kit mutant mouse and rodent models are presented and the loss of ICC subtypes in these mutants is reviewed. The physiological motility findings from various in vitroand in vivo experiments are discussed to give a critical review on the roles of ICC in generating slow waves, regulating gastrointestinal motility, mediating neural transmission and serving as mechanoreceptors. It is concluded that the role of ICC as pacemakers may be well established, but other cells may also be involved in the generation of slow waves; the theory that ICC are mediators of neurotransmission is challenged by the majority of the in vivo motility studies; the hypothesis that ICC are mechanoreceptors has not found supportive evidence from the in vivo studies yet. More studies are needed to explain discrepancies in motility findings between the in vitro and in vivo experiments.

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          Most cited references110

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          A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract.

          Electrical rhythmicity in gastrointestinal muscles has been studied for a century, but the pacemakers driving this phenomenon have been elusive. Anatomic studies suggest that interstitial cells of Cajal (ICC) may be pacemakers and conductors of electrical activity. ICC may also mediate neurotransmission from enteric neurons. Functional evaluations of ICC include the following. (1) Electrophysiology experiments on dissected muscle strips show that slow waves originate from specific sites. These pacemaker areas are populated by networks of ICC that make gap junctions with smooth muscle cells. Removal of pacemaker regions interferes with slow wave generation and propagation. (2) Chemicals that label ICC histochemically can damage ICC and abolish rhythmicity. (3) isolated ICC are spontaneously active, and several voltage-dependent ion channels, including a low-threshold Ca2+ conductance, are expressed. (4) ICC are innervated by enteric neurons, and they respond to neurotransmitters. ICC may produce nitric oxide and amplify inhibitory neurotransmission. (5) Some classes of ICC fall to develop in animals with mutations in c-kit or stem cell factor, the ligand for c-Kit receptors. Without ICC, electrical slow waves are absent. Many questions remain about the function of ICC, but modern technologies should now facilitate rapid progress toward determining the role of these cells in normal physiology and pathological conditions.
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            Requirement of c-kit for development of intestinal pacemaker system.

            A discovery that the protooncogene encoding the receptor tyrosine kinase, c-kit, is allelic with the Dominant white spotting (W) locus establishes that c-kit plays a functional role in the development of three cell lineages, melanocyte, germ cell, and hematopoietic cell which are defective in W mutant mice. Recent analyses of c-kit expression in various tissues of mouse, however, have demonstrated that c-kit is expressed in more diverse tissues which are phenotypically normal in W mutant mice. Thus, whether or not c-kit expressed outside the three known cell lineages plays a functional role is one of the important questions needing answering in order to fully elucidate the role of c-kit in the development of the mouse. Here, we report that some of the cells in smooth muscle layers of developing intestine express c-kit. Blockade of its function for a few days postnatally by an antagonistic anti-c-kit monoclonal antibody (mAb) results in a severe anomaly of gut movement, which in BALB/c mice produces a lethal paralytic ileus. Physiological analysis indicates that the mechanisms required for the autonomic pacing of contraction in an isolated gut segment are defective in the anti-c-kit mAb-treated mice, W/Wv mice and even W/+ mice. These findings suggest that c-kit plays a crucial role in the development of a component of the pacemaker system that is required for the generation of autonomic gut motility.
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              Interstitial cells of Cajal generate a rhythmic pacemaker current.

              Networks of interstitial cells of Cajal embedded in the musculature of the gastrointestinal tract are involved in the generation of electrical pacemaker activity for gastrointestinal motility. This pacemaker activity manifests itself as rhythmic slow waves in membrane potential, and controls the frequency and propagation characteristics of gut contractile activity. Mice that lack a functional Kit receptor fail to develop the network of interstitial cells of Cajal associated with Auerbach's plexus in the mouse small intestine and do not generate slow wave activity. These cells could provide an essential component of slow wave activity (for example, a biochemical trigger that would be transferred to smooth muscle cells), or provide an actual pacemaker current that could initiate slow waves. Here we provide direct evidence that a single cell, identified as an interstitial cell of Cajal by light microscopy, electron microscopy and expression of Kit mRNA, generates spontaneous contractions and a rhythmic inward current that is insensitive to L-type calcium channel blockers. Identification of the pacemaker of gut motility will aid in the elucidation of the pathophysiology of intestinal motor disorders, and provide a target cell for pharmacological treatment.
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                Author and article information

                Contributors
                Role: Guest Editor
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                jcmm
                Journal of Cellular and Molecular Medicine
                Blackwell Publishing Ltd (Oxford, UK )
                1582-1838
                1582-4934
                August 2008
                18 April 2008
                : 12
                : 4
                : 1118-1129
                Affiliations
                Division of Gastroenterology, Department of Medicine, University of Texas Medical Branch Galveston, TX, USA
                Author notes
                *Correspondence to: Jiande CHEN, Ph.D., GI Research, Route 0632, 1108 The Strand, Room 221, University of Texas Medical Branch, Galveston, TX 77555-0632, USA. Tel.: 409-747-3071; Fax: 409-747-3084 E-Mail: jianchen@ 123456utmb.edu
                Article
                10.1111/j.1582-4934.2008.00352.x
                3865654
                18429936
                79a2f37e-46d2-42a1-8bf8-4b2ab182afab
                © 2008 The Authors Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 01 April 2008
                : 14 April 2008
                Categories
                Reviews

                Molecular medicine
                icc,gastrointestinal motility,electrogastrography,neurotransmission,slow waves,emptying

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