Physiology, Injury, and Recovery of Interstitial Cells of Cajal: Basic and Clinical Science

Abstract

In the last 15 years, our understanding of the cellular basis of gastrointestinal function has been altered irreversibly by the discovery that normal gastrointestinal (GI) motility requires interstitial cells of Cajal (ICC). Research in this relatively short time period has modified our original concept that the core unit that controls motility is made up of nerves and smooth muscle, to one that now includes ICC. This concept has now expanded to beyond the GI tract, suggesting that it may be a fundamental property of the regulation of smooth muscle function that requires rhythmic contraction. ICC are distributed throughout the GI tract, have important functions in the control of GI motility, and are often abnormal in diseased states. Recently, significant steps forward have been made in our understanding of the physiology of ICC as well as mechanisms of injury and recovery. These advances are the focus of this review. Unique motor patterns are intrinsic to every organ of the GI tract, which suit their functions related to mixing, absorption, and anally directed movement. The ICC are an integral part of the control of these motor activities. The distribution of ICC throughout the musculature is associated with nerve structures. Myenteric pacemaker ICC surround the myenteric or Auerbach's plexus and intramuscular ICC are associated with nerve varicosities throughout the muscle layers (Figure 1, Figure 2). Other subpopulations of ICC are associated with nonganglionated plexuses of nerve varicosities at the inner borders of the circular muscle layers in the intestine and colon (Figure 1, Figure 2). The best understood function is that of pacemaker activity in the stomach and small intestine where the ICC generate a periodic depolarization at a characteristic frequency in each of these organs that is called the slow wave or pacemaker activity. This involves rhythmic oscillations of intracellular calcium and activation of membrane ion channels that causes depolarization. Ion channels viewed as important in the generation of pacemaker activity include nonselective cation channels,1Koh S.D. Sanders K.M. Ward S.M. Spontaneous electrical rhythmicity in cultured interstitial cells of Cajal from the murine small intestine.J Physiol. 1998; 513: 203-213Google Scholar calcium-activated chloride channels,2Huizinga J.D. Zhu Y. Ye J. et al.High-conductance chloride channels generate pacemaker currents in interstitial cells of Cajal.Gastroenterology. 2002; 123: 1627-1636Google Scholar, 3d'Antonio C. Wang B. McKay C. et al.Substance P activates a non-selective cation channel in murine pacemaker ICC.Neurogastroenterol Motil. 2009; 21 (985–e79)Google Scholar, 4Gomez-Pinilla P.J. Gibbons S.J. Bardsley M.R. et al.Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G1370-G1381Google Scholar and sodium channels.5Strege P.R. Ou Y. Sha L. et al.Sodium current in human intestinal interstitial cells of Cajal.Am J Physiol Gastrointest Liver Physiol. 2003; 285: G1111-G1121Crossref Scopus (128) Google ScholarFigure 2ICC are associated with the enteric nervous system. A, A dense network of myenteric pacemaker ICC surrounds the myenteric plexus ganglia in the small intestine. B, ICC of the deep muscular plexus in the small intestine are bipolar and aligned with smooth muscle cells. Many ICC are fully aligned with enteric nerves (shown here are nitrergic nerves). The confocal scanning thickness was 4 μm. C-kit staining of ICC (green); the neural plexus is stained with nNOS antibody (red).View Large Image Figure ViewerDownload Hi-res image Download (PPT) ICC are not unique to the gut; they are present in other rhythmically active structures, such as the portal vein6Harhun M.I. Gordienko D.V. Povstyan O.V. et al.Function of interstitial cells of Cajal in the rabbit portal vein.Circ Res. 2004; 95: 619-626Google Scholar and the bladder.7Lang R.J. Tonta M.A. Zoltkowski B.Z. et al.Pyeloureteric peristalsis: role of atypical smooth muscle cells and interstitial cells of Cajal-like cells as pacemakers.J Physiol. 2006; 576: 695-705Google Scholar This phenomenon, however, leads to a discussion on properties of cells that are essential to give them the identity of ICC.8Huizinga J.D. Faussone-Pellegrini M.S. About the presence of interstitial cells of Cajal outside the musculature of the gastrointestinal tract.J Cell Mol Med. 2005; 9: 468-473Google Scholar Genetic abnormalities to the Kit receptor that lead to loss of ICC in the gut, may not equally influence ICC in other organs.9McCloskey K.D. Anderson U.A. Davidson R.A. et al.Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild-type and W/Wv mice.Br J Pharmacol. 2009; 156: 273-283Google Scholar The rhythmic depolarization generated by pacemaker ICC propagates into the circular and longitudinal muscle layers, resulting in periods of low and high excitability of the smooth muscle cells at the pacemaker frequency. Under unstimulated conditions, that is, much of the nocturnal period, this generally does not result in muscle contraction. However, under stimulated conditions, such as a meal, distention, and/or neural excitation, smooth muscle cells generate action potentials during the depolarized portion of the slow wave. Thus, the resulting characteristic motor patterns have the unique frequency of the ICC pacemaker system. The pacemaker frequency decreases aborally, slow waves occur simultaneously along the circumference and spread in aboral direction; hence, excitation results in a ring of circular muscle contraction that propagates anally.10Huizinga J.D. Lammers W.J. Gut peristalsis is governed by a multitude of cooperating mechanisms.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G1-G8Google Scholar In the antrum, this results in powerful peristalsis that also serves to mix and grind the stomach contents. In the small intestine, this results in peristaltic activity propagating over variable distances. Pacemaker activity also results in rhythmic, pendular movements of the longitudinal muscle layer11Lammers W.J. Spatial and temporal coupling between slow waves and pendular contractions.Am J Physiol Gastrointest Liver Physiol. 2005; 289: G898-G903Google Scholar that maximizes mixing of content, optimizing digestion and absorption. Our current understanding of the role of ICC in peristalsis requires a distinction between peristalsis and the peristaltic reflex.10Huizinga J.D. Lammers W.J. Gut peristalsis is governed by a multitude of cooperating mechanisms.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G1-G8Google Scholar The peristaltic reflex is a specific motor pattern that is evoked by a bolus and involves excitation oral to and inhibition anal to the bolus, programmed by the enteric nervous system.12Bayliss W.M. Starling E.H. The movements and innervation of the small intestine.J Physiol. 1899; 24: 99-143Google Scholar, 13Costa M. Brookes S.H. Architecture of enteric neural circuits involved in intestinal motility.Eur Rev Med Pharmacol Sci. 2008; 12: 3-19Google Scholar There is a remarkable variety of motor activities, including peristalsis, that are controlled to varying degrees by the central and the enteric nervous system, the ICC, and hormonal and myogenic mechanisms. Expression of various motor patterns is generally not the consequence of independent actions of different control systems but rather, depending on specific stimuli, varying domination of one or more of the control activities. This intermingling of control systems is probably the main reason why the exact role of ICC in GI motor disorders has been controversial, perhaps unnecessarily so. It is the perspective of the authors that the question should not be whether a particular cell type is 100% responsible for a particular function; rather, it should be how different cell types integrate their functions to coordinate GI function. Demonstration of the importance of the ICC pacemaker system can be found in the motor activity of the gastropyloroduodenal junction, where one finds a continuous musculature, but a discontinuity of the ICC pacemaker network.14Wang X.Y. Lammers W.J. Bercik P. et al.Lack of pyloric interstitial cells of Cajal explains distinct peristaltic motor patterns in stomach and small intestine.Am J Physiol Gastrointest Liver Physiol. 2005; 289: G539-G549Google Scholar Consequently, the stomach and duodenum have their own, independent, peristaltic activities and the pylorus can act independently and be controlled by the enteric nervous system to perform sphincter function. In the stomach, strong evidence exists that the intramuscular ICC provide secondary pacemaker activity and Purkinje fiber-like conduction pathways.15Hirst G.D. Garcia-Londono A.P. Edwards F.R. Propagation of slow waves in the guinea-pig gastric antrum.J Physiol. 2006; 571: 165-177Google Scholar In the colon, ICC situated at the submucosal border of the circular muscle are carrying out pacemaker function as shown in the canine and human colon.16Rae M.G. Fleming N. McGregor D.B. et al.Control of motility patterns in the human colonic circular muscle layer by pacemaker activity.J Physiol. 1998; 510: 309-320Google Scholar A dominant characteristic of ICC is their extensive innervation (Figure 2). Although smooth muscle cells are innervated primarily through nonsynaptic neurotransmission, many ICC have synapse-like contact with varicosities of the intrinsic nervous system. These synapse-like contacts include proteins involved in neurovesicle docking to presynaptic membranes in nerve fibers in close apposition to ICC and the expression of postsynaptic density proteins by ICC.17Beckett E.A. Takeda Y. Yanase H. et al.Synaptic specializations exist between enteric motor nerves and interstitial cells of Cajal in the murine stomach.J Comp Neurol. 2005; 493: 193-206Google Scholar There is substantial evidence for the notion that enteric motor neurons innervate ICC and regulate the slow wave frequency18Kim T.W. Koh S.D. Ordog T. et al.Muscarinic regulation of pacemaker frequency in murine gastric interstitial cells of Cajal.J Physiol. 2003; 546: 415-425Google Scholar and ICC excitability,19Huizinga J.D. Golden C.M. Zhu Y. et al.Ion channels in interstitial cells of Cajal as targets for neurotransmitter action.Neurogastroenterol Motil. 2004; 16: 106-111Google Scholar, 20Zhu Y. Huizinga J.D. Nitric oxide decreases the excitability of interstitial cells of Cajal through activation of the BK channel.J Cell Mol Med. 2008; 12: 1718-1727Google Scholar and thus indirectly affect smooth muscle function. In the esophagus and fundus, it has been demonstrated conclusively that ICC are associated with vagal afferent nerve endings.21Powley T.L. Wang X.Y. Fox E.A. et al.Ultrastructural evidence for communication between intramuscular vagal mechanoreceptors and interstitial cells of Cajal in the rat fundus.Neurogastroenterol Motil. 2008; 20: 69-79Google Scholar The synaptic innervation of ICC brought forth the suggestion that ICC are a primary target of nerves and possibly a preferred pathway for inhibitory and excitatory neural innervation of smooth muscle cells,22Ward S.M. Interstitial cells of Cajal in enteric neurotransmission.Gut. 2000; 47: iv40-iv43Google Scholar but this remains controversial. Purinergic and peptidergic innervations seem to follow diffusion of neurotransmitters directly to receptors on smooth muscle cells. For nitrergic and cholinergic innervation, however, evidence for an intermediary function of ICC comes from apparent lack of smooth muscle responses to enteric nerve stimulation in the fundus, lower esophageal and pyloric sphincters and colon of mice with hypomorphic mutations in Kit protein (W/Wv) or Kit ligand (Sl/Sld mice) where ICC networks are disrupted,23Ward S.M. Beckett E.A. Wang X. et al.Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons.J Neurosci. 2000; 20: 1393-1403Google Scholar, 24Burns A.J. Lomax A.E. Torihashi S. et al.Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach.Proc Natl Acad Sci U S A. 1996; 93: 12008-12013Google Scholar and from the small intestines of mice where ICC networks had been depleted by injections of neutralizing anti-Kit antibodies.25Beckett E.A. Ro S. Bayguinov Y. et al.Kit signaling is essential for development and maintenance of interstitial cells of Cajal and electrical rhythmicity in the embryonic gastrointestinal tract.Dev Dyn. 2007; 236: 60-72Google Scholar However, lack of nitrergic innervation in the absence of intramuscular ICC has not been found consistently by other investigators in the fundus or lower esophageal, pyloric and internal anal sphincters, or the whole stomach of W/Wv mice and in Ws/Ws rat fundus.26Sivarao D.V. Mashimo H.L. Thatte H.S. et al.Lower esophageal sphincter is achalasic in nNOS(−/−) and hypotensive in W/W(v) mutant mice.Gastroenterology. 2001; 121: 34-42Google Scholar, 27Farre R. Wang X.Y. Vidal E. et al.Interstitial cells of Cajal and neuromuscular transmission in the rat lower oesophageal sphincter.Neurogastroenterol Motil. 2007; 19: 484-496Google Scholar, 28Huizinga J.D. Liu L.W. Fitzpatrick A. et al.Deficiency of intramuscular ICC increases fundic muscle excitability but does not impede nitrergic innervation.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G589-G594Google Scholar, 29De Lorijn F. De Jonge W.J. Wedel T. et al.Interstitial cells of Cajal are involved in the afferent limb of the rectoanal inhibitory reflex.Gut. 2005; 54: 1107-1113Google Scholar Direct and indirect innervation of smooth muscle may exist side by side. In summary, smooth muscle activity is not the consequence of a single cascade of events, but rather parallel streams of influences. The primary ones are the following: (1) intrinsic activity of smooth muscle cells (secondary pacemaker activity, action potential generation, direct responses to depolarizing stimuli and distention); (2) nonsynaptic neurotransmission from excitatory and inhibitory motor neurons; and (3) primary pacemaker activity from ICC that can be modified by synaptic innervation of the ICC. ICC are situated ideally to monitor the contractile state of the musculature and transmit this to the extrinsic and/or intrinsic nervous system; hence, they function as mechanoreceptors by virtue of their distribution throughout the musculature and their multiple processes that contact many smooth muscle cells. There is good evidence for interactions between vagal afferent nerves and ICC in the esophagus and fundus.21Powley T.L. Wang X.Y. Fox E.A. et al.Ultrastructural evidence for communication between intramuscular vagal mechanoreceptors and interstitial cells of Cajal in the rat fundus.Neurogastroenterol Motil. 2008; 20: 69-79Google Scholar Although the functional consequences remain to be elucidated, loss of ICC-IM is associated with loss of vagal afferent nerve endings, thereby suggesting a survival dependency.30Fox E.A. Phillips R.J. Martinson F.A. et al.C-Kit mutant mice have a selective loss of vagal intramuscular mechanoreceptors in the forestomach.Anat Embryol (Berl). 2001; 204: 11-26Google Scholar One of the more advanced hypotheses is that mechanical distortion of human ICC activates a sodium channel that depolarizes the ICC and increases pacemaker frequency.5Strege P.R. Ou Y. Sha L. et al.Sodium current in human intestinal interstitial cells of Cajal.Am J Physiol Gastrointest Liver Physiol. 2003; 285: G1111-G1121Crossref Scopus (128) Google Scholar Mutations in this sodium channel macromolecular complex may lead to GI symptoms31Locke 3rd, G.R. Ackerman M.J. Zinsmeister A.R. et al.Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy.Am J Gastroenterol. 2006; 101: 1299-1304Google Scholar and may be associated with irritable bowel syndrome32Saito Y.A. Strege P.R. Tester D.J. et al.Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G211-G218Google Scholar and intestinal pseudo-obstruction.33Mazzone A. Strege P.R. Tester D.J. et al.A mutation in telethonin alters Nav1.5 function.J Biol Chem. 2008; 283: 16537-16544Google Scholar A very interesting hypothesis that has not yet been adequately explored is that mechanical interaction between ICC and smooth muscle cells involves dynamic creation of peg and socket junctions.34Thuneberg L. Peters S. Toward a concept of stretch-coupling in smooth muscle I. Anatomy of intestinal segmentation and sleeve contractions.Anat Rec. 2001; 262: 110-124Google Scholar Acknowledgment of the importance of ICC for the integrity of the motor function of the GI tract prompted interest in the fate of ICC in gut motor disorders. Damage to ICC and/or reduction of its population has been described in almost every GI motility disorder from the esophagus to the rectum. There is already a significant body of evidence for the involvement of ICC in the pathophysiology of gastroparesis and constipation, but ICC abnormalities are also present in acquired conditions such as achalasia, Chagas disease, intestinal pseudo-obstruction, and the inflammatory bowel disorders as well as congenital diseases such as Hirschsprung's and congenital hypertrophic pyloric stenosis (CHPS). All these conditions exhibit abnormalities of motor activity leading to impaired regional transit and symptoms. ICC loss or disruption is associated often with concomitant neuronal and smooth muscle changes, suggesting a close interdependence between these cell types. It is still unclear for most of these motility disorders if the disruption in ICC networks is primary or secondary and it will be important to resolve this question. Mechanisms underlying abnormalities in the populations of ICC are currently incompletely understood but various factors are likely to influence the fate of ICC: (1) a variable degree of regional obstruction and subsequent proximal dilation, (2) injury to the nervous system, (3) the immune system, and (4) ICC plasticity. Studies in animal models show that ICC viability and function are compromised in dilated bowel segments proximal to an area of partial obstruction. The degree of disruption of the ICC network is a function of the distance from the obstruction and it is reversible after the obstruction is removed35Chang I.Y. Glasgow N.J. Takayama I. et al.Loss of interstitial cells of Cajal and development of electrical dysfunction in murine small bowel obstruction.J Physiol. 2001; 536: 555-568Google Scholar (Table 1), highlighting a remarkable degree of plasticity. This could explain the recovery of the pyloric ICC-IM population in patients with CHPS after pyloromyotomy, a procedure that resolves the mechanical and functional obstruction to gastric emptying associated with this condition. It could also explain the frequently observed lack of correlation between the degree of ICC loss and the duration of the disease. The timing and type of treatments varies between patients, influencing the degree of intraluminal distension. This intrinsic ICC plasticity is important because it opens a window for recovery of the ICC phenotype and function if the underlying insult is addressed, although it remains unclear whether human ICC are as susceptible to distension as they are in smaller species.Table 1Animal Models Affecting ICCAnimalTypeNameAlterationStatus of ICCFunctional changes observedMouseModels that primarily target the ICC populationW/WvMutation of the proto-oncogene c-kit reduces tyrosine kinase activityLoss of ICC-IM in stomach and sphincters24Burns A.J. Lomax A.E. Torihashi S. et al.Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach.Proc Natl Acad Sci U S A. 1996; 93: 12008-12013Google Scholar; loss of pacemaker ICC in the intestine78Ward S.M. Burns A.J. Torihashi S. et al.Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine.J Physiol. 1994; 480: 91-97Google Scholar, 79Huizinga J.D. Thuneberg L. Kluppel M. et al.W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity.Nature. 1995; 373: 347-349Google Scholar; reduced ICC in the colonIncreased gastric compliance24Burns A.J. Lomax A.E. Torihashi S. et al.Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach.Proc Natl Acad Sci U S A. 1996; 93: 12008-12013Google Scholar; altered24Burns A.J. Lomax A.E. Torihashi S. et al.Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach.Proc Natl Acad Sci U S A. 1996; 93: 12008-12013Google Scholar or no change28Huizinga J.D. Liu L.W. Fitzpatrick A. et al.Deficiency of intramuscular ICC increases fundic muscle excitability but does not impede nitrergic innervation.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G589-G594Google Scholar in neurotransmission; increased fundic muscle excitability; abnormal intestinal motility owing to loss of pacemaker activitySld/SldMutation of the Steel locus produces an abnormal, ineffective membrane bound SCF, the ligand for KitLoss of ICC-IM in stomach and sphincters66Beckett E.A. Horiguchi K. Khoyi M. et al.Loss of enteric motor neurotransmission in the gastric fundus of Sl/Sl(d) mice.J Physiol. 2002; 543: 871-887Google Scholar; loss of pacemaker ICC in the intestine67Ward S.M. Burns A.J. Torihashi S. et al.Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants.Am J Physiol. 1995; 269: C1577-C1585Google ScholarAltered fundus neurotransmission,66Beckett E.A. Horiguchi K. Khoyi M. et al.Loss of enteric motor neurotransmission in the gastric fundus of Sl/Sl(d) mice.J Physiol. 2002; 543: 871-887Google Scholar abnormal intestinal motility owing to loss of pacemaker activityWZsGreen/+Insertion of green fluorescent protein sequence, ZsGreen, into the first exon of the c-kit geneExpresses a fluorescent tag in KIT-expressing cells68Wouters M. Smans K. Vanderwinden J.M. WZsGreen/+: a new green fluorescent protein knock-in mouse model for the study of KIT-expressing cells in gut and cerebellum.Physiol Genomics. 2005; 22: 412-421Google ScholarAllows morphologic identification of Kit-expressing cellsPharmacological blockage of tyrosine kinase activityIn vivo blockage of Kit receptor by ip injection of antibodiesSevere disruption of ICC populations53Maeda H. Yamagata A. Nishikawa S. et al.Requirement of c-kit for development of intestinal pacemaker system.Development. 1992; 116: 369-375Google Scholar, 69Torihashi S. Ward S.M. Nishikawa S. et al.c-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract.Cell Tissue Res. 1995; 280: 97-111Google ScholarIntestinal ileus with loss of pacemaker activity and ineffective neurotransmissionMurine partial bowel obstructionMechanical obstruction achieved by placing a clip on the small intestineDisruption of ICC networks proximal to the obstruction site; recovery after clip removal35Chang I.Y. Glasgow N.J. Takayama I. et al.Loss of interstitial cells of Cajal and development of electrical dysfunction in murine small bowel obstruction.J Physiol. 2001; 536: 555-568Google ScholarLoss of electrical slow waves and responses to enteric nerve stimulation proximal to obstruction site; recovery after clip removalDiabetes mellitus models exhibiting ICC alterationsDb/dbModel of human type 2 diabetes mellitusReduced ICC population in antrum, small intestine, and colon70Yamamoto T. Watabe K. Nakahara M. et al.Disturbed gastrointestinal motility and decreased interstitial cells of Cajal in diabetic db/db mice.J Gastroenterol Hepatol. 2008; 23: 660-667Google ScholarGastroparesis, intestinal dysmotility, decreased whole gut transitNOD/LtJModel of human type 1 diabetes mellitusReduction of gastric myenteric ICC and ICC–IM; loss of close connection with nerve terminals; reduced SCF production71Ordog T. Takayama I. Cheung W.K. et al.Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis.Diabetes. 2000; 49: 1731-1739Google ScholarGastroparesis with impairment in pacemaker activity and altered neurotransmissionModels of enteric agangliosisLs/lsHomozygous for the lethal spotted (ls) allele display a loss of function mutation in the endothelin-3 gene; model of short Hirschsprung's diseaseAganglionosis in the terminal regions of the large intestine; distribution and density of ICC populations seems unaltered72Ward S.M. Gershon M.D. Keef K. et al.Interstitial cells of Cajal and electrical activity in ganglionic and aganglionic colons of mice.Am J Physiol Gastrointest Liver Physiol. 2002; 283: G445-G456Google ScholarLoss of spontaneous electrical activity and postjunctional neuronal responses; unlikely to depend on changes in ICCGDNF−/− miceGlial cell line-derived neurotrophic factor knockout mice; model for long segment Hirschsprung's diseaseAganglionosis along most of the GI tract; distribution and density of ICC populations seems unaltered73Ward S.M. Ordog T. Bayguinov J.R. et al.Development of interstitial cells of Cajal and pacemaking in mice lacking enteric nerves.Gastroenterology. 1999; 117: 584-594Google ScholarNormal pacemaker activityRatModel that primarily targets the ICC populationWs/WsDeletion at the tyrosine kinase domain of Kit due to a mutation in the proto-oncogene c-kitLoss of ICC-IM in the esophagus27Farre R. Wang X.Y. Vidal E. et al.Interstitial cells of Cajal and neuromuscular transmission in the rat lower oesophageal sphincter.Neurogastroenterol Motil. 2007; 19: 484-496Google Scholar; reduction or loss of ICC populations in the stomach and colon74Mitsui R. Komuro T. Distribution and ultrastructure of interstitial cells of Cajal in the gastric antrum of wild-type and Ws/Ws rats.Anat Embryol (Berl). 2003; 206: 453-460Google Scholar; loss of pacemaker ICC in the small intestine75Takeda M. Takayama I. Terada N. et al.Immunoelectron-microscopic study of Kit-expressing cells in the jejunum of wildtype and Ws/Ws rats.Cell Tissue Res. 2001; 304: 21-30Google ScholarNeurotransmission relatively preserved, increased spontaneous contractile activity in esophagus27Farre R. Wang X.Y. Vidal E. et al.Interstitial cells of Cajal and neuromuscular transmission in the rat lower oesophageal sphincter.Neurogastroenterol Motil. 2007; 19: 484-496Google Scholar and colon; altered colonic pacemaker activity76Alberti E. Mikkelsen H.B. Wang X.Y. et al.Pacemaker activity and inhibitory neurotransmission in the colon of Ws/Ws mutant rats.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1499-G1510Google ScholarDiabetes mellitus model exhibiting ICC alterationsSTZ-DMStreptozotocin-induced diabetes mellitus in Wistar rat; model of human type 1 diabetes mellitusReduced antral and colonic ICC-IM and ICC-SMP77Forrest A. Huizinga J.D. Wang X.Y. et al.Increase in stretch-induced rhythmic motor activity in the diabetic rat colon is associated with loss of ICC of the submuscular plexus.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G315-G326Google ScholarGastroparesis; increased amplitude of stretch-induced colonic contractionsModels of enteric agangliosisETB receptor null ratEndothelin receptor null rat possess an autosomal recessive gene (sl) that leads to aganglionosis; model for long segment Hirschsprung's diseaseSevere disruption of pacemaker ICC network41Suzuki T. Won K.J. Horiguchi K. et al.Muscularis inflammation and the loss of interstitial cells of Cajal in the endothelin ETB receptor null rat.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G638-G646Google ScholarIrregular spontaneous phasic contractile activityNOTE. Pacemaker ICC refers to ICC located in the myenteric plexus; ip refers to intraperitoneal. Only a limited number of references are included because of space limitations. Open table in a new tab NOTE. Pacemaker ICC refers to ICC located in the myenteric plexus; ip refers to intraperitoneal. Only a limited number of references are included because of space limitations. ICC seem to develop independent from the enteric nervous system and an apparently normal ICC network was observed in a newborn without an enteric nervous system,36Huizinga J.D. Berezin I. Sircar K. et al.Development of interstitial cells of Cajal in a full-term infant without an enteric nervous system.Gastroenterology. 2001; 120: 561-567Google Scholar as well as in mouse models. Nevertheless, one should not conclude that there is no interaction between nerves and ICC related to survival as demonstrated for intramuscular ICC in the stomach and afferent vagal nerves.30Fox E.A. Phillips R.J. Martinson F.A. et al.C-Kit mutant mice have a selective loss of vagal intramuscular mechanoreceptors in the forestomach.Anat Embryol (Berl). 2001; 204: 11-26Google Scholar It is currently unknown whether ICC and nerves, in diseased states, simultaneously are injured by the same mechanism or if injury to ICC can be secondary to the loss of neural structures. Interestingly, nitric oxide synthase (NOS)-containing nerves have membrane-bound stem cell factor, but it is unclear if ICC have access to neuronally produced stem cell factor.37Young H.M. Torihashi S. Ciampoli D. et al.Identification of neurons that express stem cell factor in the mouse small intestine.Gastroenterology. 1998; 115: 898-908Google Scholar Neuronal NOS (nNOS)-derived NO promotes ICC proliferation in vitro and nNOS knockout mice have altered ICC networks.38Choi K.M. Gibbons S.J. Roeder J.L. et al.Regulation of interstitial cells of Cajal in the mo