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BRESR-100704; No. of pages: 16; 4C:

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v

Review

Updating old ideas and recent advances regarding the Interstitial Cells of Cajal
P. Garcia-Lopez 1 , V. Garcia-Marin⁎,1 , R. Martínez-Murillo, M. Freire
Cajal Institute, CSIC, Avda Doctor Arce 37, 28002 – Madrid, Spain

A R T I C LE I N FO Article history: Accepted 1 June 2009

AB S T R A C T Since their discovery by Cajal in 1889, the Interstitial Cells of Cajal (ICC) have generated much controversy in the scientific community. Indeed, the nervous, muscle or fibroblastic nature of the ICC has remained under debate for more than a century, as has their possible physiological function. Cajal and his colleagues considered them to be neurons, while

Keywords: Cajal Interstitial Cells of Cajal

contemporary histologists like Kölliker and Dogiel categorized these cells as fibroblasts. More recently, the role of ICC in the origin of slow-wave peristaltism has been elucidated, and several studies have shown that they participate in neurotransmission (intercalation theory). The fact that ICC assemble in the circular muscular layer and that they originate from cells which emerge from the ventral neural tube (VENT cells), a source of neurons, glia and ICC precursors other than the neural crest, suggests a neural origin for this particular subset of ICC. The discovery that ICC express the Kit protein, a type III tyrosine kinase receptor encoded by the proto-oncogene c-kit, has helped better understand their physiological role and implication in pathological conditions. Gleevec, a novel molecule designed to inhibit the mutant activated version of c-Kit receptors, is the drug of choice to treat the so-called gastrointestinal stromal tumours (GIST), the most common nonepithelial neoplasm of the gastrointestinal tract. Here we review Cajal's original contributions with the aid of unique images taken from Cajal's histological slides (preserved at the Cajal Museum, Cajal Institute, CSIC). In addition, we present a historical review of the concepts associated with this particular cell type, emphasizing current data that has advanced our understanding of the role these intriguing cells fulfil. © 2009 Elsevier B.V. All rights reserved.

Contents
1. 2. Introduction: the controversial origin of ICC . Location and morphology of ICC . . . . . . . 2.1. Intravillous and periglandular plexi. . 2.2. Auerbach plexus . . . . . . . . . . . . 2.3. Deep muscular plexus . . . . . . . . . 2.4. Intramuscular plexus . . . . . . . . . 2.5. Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 0 0 0 0 0 0

⁎ Corresponding author. Fax: +34 91 585 47 54. E-mail address: vgmarin@cajal.csic.es (V. Garcia-Marin). 1 Both authors contributed equally to this article. 0165-0173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2009.06.001

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2.6. Other locations . . . . . . . . . The physiological function of ICC from 3.1. ICC in neurotransmission . . . . 3.2. ICC as pacemakers . . . . . . . 3.3. Stretch sensors . . . . . . . . . 4. Pathological ICC and GIST . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . 3.

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1.

Introduction: the controversial origin of ICC

Between 1889 and 1893, Cajal published some articles describing a new type of cell that he classified as a primitive neuron. This type of cell was located in the stroma of the villi (Figs. 1A, 2), in the Auerbach's plexus (Figs. 1A, 3), deep muscular plexus (Figs. 1A, 4A), circular muscular layer of the intestine (Figs. 1A, 4B–D), and around the acini and blood vessels of the pancreas (Fig. 5). Following Cajal's first descriptions, these cells were identified using different names, including: células simpáticas intersticiales (sympathetic interstitial cells, 1891); células simpáticas (sympathetic cells, 1892); neuronas simpáticas intersticiales (sympathetic interstitial neurons); or células intersticiales (interstitial cells, 1899–1904). However, Dogiel subsequently called them –Cajal'sche zellen – and more than 100 years after their discovery the name of Interstitial Cells of Cajal (ICC) is still used. At that time, there was considerable controversy about the nature of these cells and while some researchers, including Cajal and his colleagues (LaVilla, 1897), thought they were neurons, others, such as Kölliker and Dogiel, classified them as fibroblasts. This debate was somewhat clouded by the ongoing discussion as to whether neurons were individual structures or if they simply formed a syncitium. According to the reticularist point of view, neurons were thought to form an interconnected continuous network built up of either axons and dendrites (Gerlach's), or exclusively of axons (Golgi's). Cajal's first paper on the nervous system (Cajal, 1888) proposed that neurons end freely, and that they connect with each other by contiguity and not by continuity. This relevant observation was the first description of the neuronal doctrine: neurons are independent units from a morphological and even physiological point of view. However, Cajal's description of the ICC as neurons was in contradiction with his neuron doctrine as he was unable to recognize the axonal process in these cells that characteristically establishes the typical network. In this respect, he recognized: “I am neither exclusive nor dogmatic. I am proud of retaining a mental flexibility which is not afraid of correction. Neuronal discontinuity, extremely evident in innumerable examples, could sustain some exceptions. I myself have mentioned some of them, for example those probably existing in the glands, vessels and intestines (my interstitial neurons)” (Cajal, 1933). During the twentieth century, there has been a longstanding dogmatic division regarding the nature of these cells (Jabonero, 1960; Thuneberg, 1990; for a review see Thuneberg (1999)). When

analysed by light and electron microscopy, Taxi referred these cells as neuronoids in an attempt to distinguish them from neurons, Schwann cells, smooth muscle cells, fibroblasts and macrophages, although he recognised their tendency to costain with nerves (Taxi, 1952, 1965; for a review see Thuneberg, (1999)). Following these findings, ultrastructural studies on the ICC suggested that they were primitive muscle cells (Imaizumi and Hama, 1969; Faussone-Pellegrini et al., 1977) or fibroblastlike cells (Richardson, 1958; Komuro, 1989). The most important advance in this area came with the discovery that ICC express the tyrosine kinase receptor (c-Kit: Maeda et al., 1992), which permitted them to be chemically differentiated from other cell types sharing similar morphological characteristics in the tunica muscularis (Thuneberg, 1982; Ward and Sanders, 2001a). The use of this specific marker allowed the mesenchyma to be identified as the source of ICC (Lecoin et al., 1996) and indeed, the detection of c-Kit expression in aneural explants confirmed that ICC are not of neural crest origin in mammals (Young et al., 1996). Moreover, it was shown that both smooth muscle cells and ICC have a common mesodermal origin (Torihashi et al., 1997; Kluppel et al., 1998). However, it is noteworthy that a subset of ICC might be of neural origin, since the ICC of the circular muscular layer originate from cells that emerge from the ventral neural tube (VENT cells: Sohal et al., 2002), a source of neurons, glia and ICC precursors that differ from the neural crest cells. Hence, the neuronal origin of ICC suggested by Cajal could be at least partially true. VENT cells originate in the ventral part of the hindbrain neural tube and they migrate through the site of attachment of the cranial nerves to colonize the gastrointestinal tract, particularly the duodenum and stomach (Sohal et al., 1996; Bockman and Sohal, 1998). Significantly, not all ICC express c-Kit, such as the ICCDMP (deep muscular plexus, see Fig. 1A) in the human small intestine (Torihashi et al., 1999; Wang et al., 2003). Moreover, there are many different cell types besides ICC that express cKit, such as mast cells, melanocytes, neurons and glia (Zhang and Fedoroff, 1997). Thus, ultrastructural analysis has proved to be essential to finally determine whether a particular cell belongs to the ICC family. The ultrastructural characteristics of ICC have been well defined (Faussone-Pellegrini and Thuneberg, 1999; Rumessen and Vanderwinden, 2003; Komuro, 1999) and they have been summarized as a gold standard (Huizinga et al., 1997) for ICC identification. ICC are generally characterized by a number of morphological aspects including the presence of: i) numerous mitochondria and caveolae; ii) a basal lamina, although discontinuous; iii) abundant intermediate filaments; iv) moderately developed Golgi apparatus, few ribosomes and a

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Fig. 1 – (A) Location of the different ICC subtypes according to Cajal and to the present nomenclature based on a semi-schematic drawing of Cajal (Cajal, 1899–1904) of a longitudinal section of the guinea pig small intestine stained by the Golgi method. According to Cajal: A, longitudinal muscle fibres; B, circular muscle fibres; C, submucose connective tissue in the Meissner plexus; D, Lieberkuhn glandules; E, intestinal villi; a, Auerbach plexus; g, Auerbach ganglion; b, deep muscular plexus; c, fibres from the Meissner plexus; e, periglandular plexus; f, intravillous plexus. According to the present nomenclature: ICC of the myenteric plexus (ICC-MP or ICC-MY); ICC of the circular muscle (ICC-CM) and ICC of the longitudinal muscle (ICC-LM), both referred to collectively as intramuscular ICC (ICC-IM); ICC of the deep muscular plexus (ICC-DMP); ICC of submucosa and submucosal plexus (ICC-SM and SMP). (B) Multipolar ICC-MP (asterisk) from the guinea pig small intestine evident through c-Kit immunohistochemistry. The cytoplasmic processes undergo repeated dichotomous branching and they make many contacts with those of the neighbours (Hanani et al., 2005). (C) Multipolar ICC-DMP of the guinea pig small intestine stained by c-Kit immunohistochemistry, with their secondary and tertiary slender processes mainly parallel to the axis of the circular muscle fibres (arrows: Hanani et al., 2005). (D) Bipolar ICC-CM from guinea pig small intestine demonstrated by c-Kit immunohistochemistry that emit only a few processes (Hanani et al., 2005). (E) Human exocrine pancreas. In the insterstitium, amongst the acini (a), note some spindle-shaped or triangular cells (arrows) with very long cytoplasmic processes (several tens of μm), indicated by dashed lines. The acini marked by asterisks appear to be surrounded by periacinar pICC processes. Methylene blue staining (Popescu et al., 2005).

rough and smooth endoplasmic reticula; and v) close contacts established with nerve varicosities and the formation of numerous gap junctions, both with each other and with smooth muscle cells.

2.

Location and morphology of ICC

Cajal described ICC at different sites in the intestinal tube. Apart from the classical Meissner plexus (located in the submuscular

connective tissue) and the Auerbach plexus (located between the longitudinal and circular smooth muscle fibres), Cajal found them in three more plexi: the deep muscular plexus, the periglandular and the intravillous plexi (summarized in Fig. 1A). At these sites, he found small fusiform and triangular cells with little protoplasm that had a number of varicose anastomosed processes, often ramifying at a right angle. These general characteristics of ICC varied at their different locations (Figs. 1B–E) and thus, it is worthwhile describing the characteristics of the ICC at the locations where Cajal observed them.

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Fig. 2 – (A) Drawing of the periglandular and intravillous plexi in the guinea pig intestine stained by the Golgi method (Cajal, 1899–1904): a, triangular cell; b, fusiform cell whose inner process result in fascicles of fibrils; c, triangular cell with a similar pattern; d, fusiform cell of the periglandular plexus; e, f, fusiform cell of the villi; g, layer of subglandular nerve fibre fascicles receiving processes of cells of the periglandular plexus. (B–D) Cajal's original histological slide from the intestine of the guinea pig impregnated by the Golgi technique. (B) Periglandular and fusiform cell of the villous plexi. (C) Fusiform cells of the villous plexus. (D) Triangular cell of the periglandular plexus. Scale bar: 100 μm (B) and 50 μm (C, D).

2.1.

Intravillous and periglandular plexi

Cajal described this new type of cell for the first time in the intestinal villi (Cajal, 1889), situated either at the basal or the apical portion of the villi and forming the periglandular plexus (Figs. 2A–B). In the basal portion of the intestinal villi, the cells were long and fusiform, with two processes emanating in oppo-

site directions, up and down (Fig. 2C). By contrast, the cells were round, triangular or stellate in the apical portion, close to the lumen of the intestinal tract (Fig. 2A). The periglandular plexus has triangular or stellate cells (Fig. 2D), and these cells had numerous processes that ramified in a complex way. Cajal realized that the numerous processes anastomosed and he could not differentiate any axonal process (Cajal, 1893). In

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Fig. 3 – (A) Drawing of ICC from the frog Auerbach plexus stained by Ehrlich's method (Cajal, 1892): A, long cells; B, star shape cell; a, intercellular anastomosis; b, small terminal branches with varicosities; d, nucleiform protuberances; c, protoplasmatic granules]. (B) Drawing of ICC from the frog Auerbach plexus stained by Ehrlich's method: a, nerve cells; b, nerve fibres; c, bundle of nerve fibres; d, cellular processes ending in a bundle of nerve fibres; e, fusiform cell along a bundle of nerve fibres; f, ganglion formed by three cells; g, unstained cells in a ganglion; h, nuclei. (C) Drawing of ICC in the adult rabbit Auerbach plexus stained by Ehrlich's method (LaVilla, 1898): A, cells in the interganglionar mesh; B, anastomosis between two of these cells; C, marginal or periganglionar cells. D, ICC of the Auerbach plexus from one of Cajal's original histological preparation (Ehrlich's method). Scale bar: 50 μm.

Cajal's original histological preparations preserved in the Cajal Museum, we have found these cells in the basal portion of the villi and in the periglandular plexus but not in the apical portion. In this regard, Cajal said (1899–1904), that they ICC in the apical portion of the intestina villi are very difficult to stain. Besides these first observations, Güldner also found a connected system of fibroblasts in the villi of the duodenum (Güldner et al., 1972; for a review see Thuneberg (1999); Huizinga and Faussone-Pellegrini (2005)). These cells formed a cellular network establishing close contact with axons, smooth muscle cells and partially embracing the capillaries and terminal arteriole. Later, it was observed that the fibro-

blasts in the villi are connected through gap junctions (Komuro, 1990; Komuro and Hashimoto, 1990). In contrast to typical ICC, these myofibroblasts do not bear c-Kit (Vannucchi et al., 2002) but they do express NK1r. Moreover, since they are in close contact with one another and with nerve fibres (Vannucchi and Faussone-Pellegrini, 2000), they can still be considered as a class of ICC. Concerning the possible physiological role of these cells, it is thought that they may serve as a barrier/sieve, a flexible mechanical frame, mechanosensors and signal transduction machinery in the intestinal villi, regulated locally and dynamically by rapid changes in cell shape (Furuya et al., 2005; Furuya and Furuya, 2007).

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the nervous cells, Cajal also described his interstitial cells as small fusiform or triangular shaped cells with little protoplasm, a long and thick nucleus, and with very long and varicose processes (Fig. 3: Cajal, 1892; 1899–1904). The fusiform shaped cells give off processes from opposing poles while the multipolar ones had several cytoplasmic processes (Cajal, 1892; 1899–1904). With regard their connections, Cajal stated that these cells could establish associations either with Auerbach's plexus, with other ICC or with the muscle cells (Cajal, 1892). Nowadays, these cells are referred to as myenteric interstitial cells (ICC-MY). The distribution of ICCMY varies greatly between different parts of the gastrointestinal tract, and they are fewer in number and their cellular networks are relatively looser in the gastric corpus and colon than in the small intestine (see Komuro, 2006).

2.3.

Deep muscular plexus

Cajal also described ICC in the deep muscular plexus, located under the muscle tunic of circular fibres, in which the majority of fascicles course parallel to the contractile fibres (Cajal, 1893; 1899–1904). Here, the somata of the ICC are small and fusiform, with a triangular or stellate morphology. Indeed, they are multipolar cells, with secondary or tertiary branches oriented parallel to the axis of circular smooth muscle cells (Fig. 4A). These cells maintain a close relationship with both the muscles and the nerve fibres, and their processes often span about 200–300 μm. The network established by the processes covers the whole area of the intestinal wall in a large mesh predominantly composed of long parallel partially anastomosised lines (see Hanani et al., 2005). These cells are currently referred to as interstitial cells of the deep muscular plexus (ICC-DMP).

2.4.

Intramuscular plexus

Cajal observed bipolar ICC with small ramifications in the circular muscle layer (ICC-CM), parallel to the axis of muscle fibres (Figs. 4B–D: Cajal, 1892, 1893). “We have also noticed or believe to note some fusiform nervous corpuscle between the circular muscular fibres directed in the same direction as the muscular fibres” (Cajal, 1892). The morphology, distribution and density of ICC-CM differs considerably from organ to organ in a given species. ICC-CM of the small intestine often show secondary cytoplasmic branches and they are sparsely distributed in association with rather thicker nerve bundles, without forming their own cellular network. By contrast, ICC-CM of the stomach and colon have a simple elongated spindle shape and they are densely distributed along nerve bundles (see Komuro, 2006). Some other ICC are also found in the longitudinal muscle layer ICC-LM. These cells are similar to ICC-CM in shape but there are usually fewer in nearly the whole gastrointestinal tract (i.e. in the stomach, small intestine and colon: Komuro, 2004). ICC-CM located in the circular muscle layer and those located in the longitudinal muscle layer (ICC-LM) are referred to collectively as intramuscular ICC (ICC-IM).

Fig. 4 – (A) Drawing of ICC in deep muscle plexus from the guinea pig seen in a section parallel to the muscle layer and stained by the Golgi method, according to Cajal (1893): A, nerve cells. a, b, nerve cells of the interstitial plexus; e, arborization of one interstitial cell process; f, interstitial cell with long processes. (B) ICC under the layer of circular muscle in the rabbit stained by Ehrlichs' method (Cajal, 1893) (C–D) ICC-CM stained by Ehrlichs' method (C) and the Golgi method (D) from Cajal's original histological preparations. Scale bar: 25 μm (C, D).

2.2.

Auerbach plexus

Cajal studied the Auerbach's plexus in the frog with the help of methylene blue staining. He identified a network of stained thick, flexible and ramified fibres parallel to the circular muscular fibres (Cajal, 1892). This plexus is endowed with ganglions (2 to 12 cells) joined into anastomotic bundles. Besides

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Fig. 5 – (A) Terminal axonal plexus of the rabbit pancreas stained by the Golgi method (Cajal and Sala, 1891): A–F: ICC. (B) Terminal axonal plexus of the rabbit pancreas stained by the Golgi method. A, perivascular nerve cell; B, C, ICC; a, b, terminal branches between epithelial cells; D, neural plexus of an arteriole (Cajal and Sala, 1891).

2.5.

Pancreas

Cajal studied the distribution of ICC in the pancreas of different species with the aid of the Golgi method and he found that they were independent elements throughout the organ. These cells were fusiform, triangular or stellate, with 3 or more divergent processes (Fig. 5: Cajal and Sala, 1891), and processes from these cells formed a strong plexus around the acini or the blood vessels (Fig. 5B). Again, the ICC processes anastomized such that he could not discriminate a typical axon emanating from them. Recently, the presence of ICC in pancreas (pICC) was confirmed using non-conventional light microscopy, immunohistochemistry and transmission electron microscopy (Popescu et al., 2005). These studies suggested that pICC may play a role in neurotransmission/modulation through two possible strategies: a) by co-operating with acinar cells and with small vessels; and b) to engage mutual contact with pancreatic stellate cells or with Pacinian receptors. In addition, ICC could fulfil another hypothetical role in controlling normal mechanoreceptor physiology, since they were closely apposed to the Pacinian corpuscle. Interestingly, they also considered that stromal pancreatic tumours (SPT) might originate from a subset of pICC by analogy with GIST (see below).

3. The physiological function of ICC from Cajal to the present day
The history of gastrointestinal motility extends deep into the past. From the observations of gastric contractions (Beaumont, 1833) through to the discovery of spontaneous colon contractions in the cat tract using X-rays (Cannon, 1902), there have been many advances in this field. The implication of the Auerbach and Meissner plexi in the motility of the gastrointestinal tract was fully appreciated from the beginning of last century: “The presence of these centres (referring to the Meissner and Auerbach plexi) explains the automatism of intestinal movements” (Cajal, 1899–1904). However, the role of the ICC was less clear. Nevertheless, Cajal proposed these cells to be mediators of enteric transmission (Fig. 6: Cajal, 1899–1904): “It is not a risky conjecture, however, that the interstitial cells are subordinated to fibres of the autonomic ganglia. The impulse brought by these fibres would elicit a supplementary discharge in the interstitial cells, able to add strength to the contraction or increase its duration”. (Cajal, 1899–1904). Later in this text and in reference to the motor pathway of the autonomic system, Cajal stated: “Here, in all probability, the motor chain has two additional neurons: that of myenteric and mucosal plexi, and the interstitial or terminal cell”. (Cajal, 1899–1904). For Cajal, the ICC would function as mediators of neuronal transmission and subsequent studies supported this theory (Imaizumi and Hama, 1969; Yamamoto, 1977; Oki and Daniel, 1973; Daniel, 1977). Currently there is no doubt that interstitial cells serve as mediators of enteric transmission and indeed, interstitial cells were proposed as pacemakers by Keith in 1915 (Keith, 1915; for a review see Thuneberg (1999)) and this role in gastrointestinal pacemaking activity has since been further demonstrated. These different functions

2.6.

Other locations

ICC are also located outside the gastrointestinal tract and by applying the Golgi technique, some histologists even found them in the serose glands of the tongue (Krause, Fusari and Panasci) or in the myocardium (Berkley, 1893; review in Cajal, 1899–1904). With modern techniques, ICC have also been found in many other locations such as in the upper urinary tract (Lang and Klemm, 2005), urethra (Sergeant et al., 2006), myometrium (Ciontea et al., 2005), myocardium (Hinescu and Popescu, 2005; Popescu et al., 2006), uterus, fallopian tube (Popescu et al., 2007), human placenta (Suciu et al., 2007) and the ciliary muscle in monkeys (Paula et al., 2009). Thus, these findings confirm Cajal's conclusions that: “All or almost all glands have terminal neural plexi, similar to those of the intestine, made of Remak fibres originated in special autonomic ganglia, as well as fusiform or stellate cells of the previously described interstitial type” (Cajal, 1899–1904).

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3.1.

ICC in neurotransmission

Fig. 6 – Diagram of sensory and motor pathways of the autonomic system according to (Cajal, 1899–1904). A, sympathetic ganglion; B, ventral horn of the spinal cord; C, dorsal root ganglion; D, small intestine; E, pancreas; F, visceral ganglion; J, glandular interstitial cell; K, perivascular nerve cell; V, blood vessels; A, motor spino-gangliar fibres of preganglionic Langley fibres; b, another spino-sympathetic fibre terminating exclusively in a single ganglion; c, sympathetic axon coursing through two ganglia; d, sympathetic axon incorporated into a spinal nerve through the gray ramus communicans; e, autonomic axon ending on a blood vessel (postganglionic fibre of Langley); f, autonomic axon ending in the myenteric plexus of the intestine; g, motor cell of a myenteric ganglion; h, sensory spinal fibre ending in the intestinal mucosa; m, ganglion of the myenteric plexus; I, motor fibre ending in a visceral ganglion.

(nervous transmission and pacemaking activity) are to some extent carried out by different types of ICC. While nervous transmission is mediated by ICC-IM, the pacemaking activity is preferentially mediated by ICC-MY even though ICC-IM may also regulate the frequency of the pacemaker.

Several studies have revealed a close and functional relationship between ICC and enteric nerve fibres, confirming that ICC participate in neurotransmission (Cajal, 1899–1904; Daniel and Posey-Daniel, 1984; see also Ward, 2000; Ward and Sanders, 2001b). The knock-out animals available for c-kit have been particularly useful in defining the role of ICC in neurotransmission (Burns et al., 1996), especially W/Wv mutant animals. The absence of ICC-IM in the murine fundus not only led to reduced NO (nitric oxide) dependent post-junctional responses (Burns et al., 1996; Ward et al., 1998) but also, it resulted in the loss of cholinergic excitatory responses (Ward et al., 2000). Immunohistochemical studies have revealed that isolated ICC are responsive to a variety of enteric transmitters, both excitatory and inhibitory. Nerve fibres stained with the primary transmitters of excitatory motor neurons, such as vesicular ACh transporter (VAChT) and substance P, are closely associated with cell bodies and processes of ICC-IM in the stomach (Beckett et al., 2002; Horiguchi et al., 2003; Song et al., 2005; Wang et al., 1999; Ward et al., 2000), and with ICCDMP in the small intestine (Faussone-Pellegrini, 2006; Iino et al., 2004; Lavin et al., 1998; Wang et al., 1999). Many inhibitory motor neurons that contain nitric oxide synthase (NOS), vasoactive intestinal polypeptide (VIP) or adenosine triphosphate (ATP) are closely associated with both the cell bodies and processes of ICC-IM (Beckett et al., 2002; Horiguchi et al., 2003; Song et al., 2005; Wang et al., 1999; Ward et al., 2000) and ICC-DMP (Toma et al., 1999; Wang et al., 1999). In addition, different neurotransmitter receptors are expressed by the ICC (See Box 1). These data demonstrate that ICC are densely innervated by excitatory and inhibitory enteric motor neurons. It should be noted that the close apposition of enteric nerve fibres (both excitatory and inhibitory) and ICC, as well as the presence of neurotransmitter receptors on these cells, does not imply that functional synaptic contacts are made between these structures. With the aid of electron microscopy, abundant close contacts (<25 nm) between varicose nerve terminals and ICC were demonstrated that support the existence of a specialized kind of transmission of neural information between enteric nerves and ICC (Daniel and Posey-Daniel 1984). These contacts have been confirmed (Wang et al., 1999; Ward et al., 2000) and the existence of these close interactions led to the recovery of the intercalation theory which favours the existence of nerve transmission through ICC (Cajal, 1899–1904; Daniel and Posey-Daniel, 1984; see also Ward, 2000; Ward and Sanders, 2001b). These synaptic specializations are functional, since the soluble N-ethylmaleimide-sensitive attachment protein receptors (SNARE) implicated in neurotransmitter release is located in varicosities associated with ICC-IM (Nirasawa et al., 1997; Aguado et al., 1999; Beckett et al., 2005; for a review see Ward and Sanders, (2006)). The postsynaptic densities are also functional since they contain typical postsynaptic proteins. There is also a decrease in the expression of postsynaptic density (PSD-93 and PSD-95) in kit mutant mice (W/Wv), whereas immunohistochemistry for the PDZ domain of the PSD-95 family and for Kit revealed some degree of co-localization (Beckett et al., 2005; for a review see Sanders and Ward (2006)).

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Box 1 ICC receptors. Receptors
5-HT, 5-HT3, 5-HT4 subtypes Bombesin, subtype-3 Cholecystokinin A G protein-coupled, Protein Kinase A (PKA), Protein Kinase C (PKC) Muscarinic acetylcholine, M2, M3 subtypes

ICC location

References

ICC-MY Glatzle et al. (2002); Liu et al. (2005); Poole et al. (2006); ICC-DMP Almost in all ICC Porcher et al. (2005) ICC ICC Patterson et al. (2001) Southwell (2003); Poole et al. (2004) Epperson et al. (2000); Iino and Nojyo (2006) Sternini et al. (1995); Grady et al. (1996); Portbury et al. (1996); Lavin et al. (1998); Epperson et al. (2000); Iino et al. (2004) Burnstock and Lavin (2002); Van Nassauw et al. (2006); Chen et al. (2007) Sternini et al. (1997) Epperson et al. (2000)

ICC-IM, ICC-MY ICC-DMP Neurokinin, NK1, NK3 subtypes ICC-IM, ICC-MY ICC-DMP Purinergic, P2Y1, P2Y4 subtypes P2X2, P2X5 ICC-IM, ICC-MY, subtypes ICC-DMP Somatostatin 2A ICC-DMP VIP ICC-IM, ICC-MY VPAC1 subtype

However, there is still little data regarding how the nervous impulse is transmitted from the ICC-IM to the smooth muscle cells. Although gap junctions were proposed to be involved in this process, recent research using gap junction blockers suggests that gap junctions are not necessary for pacing or nerve transmission to the circular muscle of the mouse intestine (Daniel, 2004; Daniel et al., 2007).

3.2.

ICC as pacemakers

The first suggestion that ICC may act as physiological pacemakers was made by Arthur Keith, the discoverer of the cardiac sino-atrial pacemaker organization (Keith, 1915; for a review see Thuneberg (1999)). “A series of sections through the ileo-caecal junction of the rat's bowel revealed a collar of peculiar tissue…there was also present a third element -numerous branching cells, not connective tissue in nature with processes which united with muscle cells, on the one hand, and with the processes from true ganglionic cells on the other. I regarded these intermediate cells as a possible representation of the nodal tissue of the heart”. (Keith, 1915); taken from (Thuneberg, 1999) Ambache was the first to show that electrical slow waves control intestinal contractions and to relate these slow waves to the ICC (Ambache, 1947; reviewed in Thuneberg (1999)). Several subsequent studies (using different approaches that included chemical lesions and dissection experiments, intracellular electrophysiological recording or mutant animals) indicated that ICC generated these slow waves. Slow waves are cyclic depolarizations of the membrane potential of smooth muscle cells. The cellular mechanisms involved in the generation of pacemaker potentials are not completely understood, although it seems clear that the release of Ca2+ from internal IP3-dependent stores plays a key part in their generation (Suzuki, 2000; for a review see Nakayama et al. (2007)). When rhythmic electrical oscillations reach the opening threshold of calcium channels, calcium enters the cell and triggers the contraction of smooth muscle cells.

Early evidence of the implication of ICC in the generation of slow waves came from photochemical ablation of ICC, whereby methylene blue followed by illumination blocks slow-wave activity (Thuneberg et al., 1983; Liu et al., 1993, 1994). Alternatively, others used rhodamine 123, a cytotoxic fluorescent dye that specifically accumulates in the ICC, although it may also accumulate in enteric neurons (Ward et al., 1990). Other studies have been critical to confirm the role of ICC in generating slow-wave activity. Intracellular electrode recording and methylene blue staining were used to confirm that slow waves are only observed in smooth muscle cells when the ICC are attached to the muscle layer registered (Suzuki et al., 1986). At the same time, intracellular recording of the longitudinal, inner and outer circular muscle layers of the dog, cat, rabbit, opossum and human small intestine demonstrated that the myenteric region is the dominant source of slow waves in the small intestine (Hara et al., 1986). By contrast, the pacemaker in the colon resides at the submucosal surface of the circular muscle layer, since removing ICC-SMP from the submucosal border blocks the generation of slow waves (Smith et al., 1987). In mice with c-kit mutations (W/Wv), the networks of ICC-MY are grossly underdeveloped in the small intestine where pacemaker activity was lacking (Ward et al., 1994; Huizinga et al., 1995), even though ICC are present in the DMP. In the latter experimental model, ICC-MY are evident in the stomach where slow-wave activity can be recorded (Burns et al., 1996; see also Huizinga, 2001). These data suggest that ICC-MY but not ICC-DMP are crucial for generating slow-wave activity (Ward et al., 1994, 1995; Huizinga et al., 1995; Huizinga et al., 2001). Similar experiments in rat mutants (Horiguchi and Komuro, 1998) or in steel-Dickie mutant mice (Sl/Sld), in which the gene encoding the c-Kit ligand (stem cell factor, SCF) is defective (Ward et al., 1995) confirmed these data. However, the generation of slow waves is not only mediated by ICC-MY. In the gastric corpus of the guinea pig where ICC-MY are absent, the dominant pacemaker activity that entrains activity in other regions of the stomach is provided by the ICC-IM (Hashitani et al., 2005). Furthermore, ICC-IM contribute to the amplification of pacemaker signals from ICC-MY by generating rhythmic oscillations known as unitary potentials,

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Fig. 7 – (A) Adult mouse duodenum physiologically distended by the intestinal contents according (Thuneberg and Peters, 2001). The electron micrograph shows the longitudinal muscle layer with five peg and socket junctions (*). Note the uniform, narrow space between peg and socket membranes, in contrast to simple folds of the cell surface. (B) Diagram of the distribution of the peg and socket junctions and the gap junctions in the muscularis of adult mouse small intestine (Thuneberg, 1999).

regenerating the depolarizing currents from ICC-MY or those that follow exposure to acetylcholine (Dickens et al., 2001; Hirst et al., 2002a,b; Edwards et al., 1999). Other studies have been carried out on isolated and/or cultured ICC. Single ICC are spontaneously active, generating electrical depolarization similar to slow waves recorded in intact smooth muscle cells, as demonstrated in patch clamp experiments on the canine colon (Langton et al., 1989). Indeed, single ICC generate a rhythmic inward current insensitive to Ltype calcium channel blockers that is crucial for the generation of slow waves in smooth muscle cells (Thomsen et al., 1998). But how the slow waves spread from the ICC-MY to the smooth muscle cells is still unclear. Although ICC-MY are coupled through gap junctions, there are no gap junctions between ICC-MY and smooth muscle cells of the longitudinal or circular muscle layer (Fig. 7). Thus, other mechanisms such as peg and socket connections, have been proposed that might provide electrical coupling through the accumulation of potassium in the narrow cleft between the peg and the socket under appropriate conditions (Vigmond et al., 2000). These peg and socket connections have also been proposed as stretch sensors, warranting a description of these structures and their possible implications.

coupling and the internal sensitivity of a muscular layer to stretch (Faussone-Pellegrini and Thuneberg, 1999; Thuneberg and Peters, 2001). However, the most solid physiological evidence supporting the functioning of ICC as stretch sensors was obtained by applying length ramps to the murine antral muscles, while recording intracellular electrical activity and isometric force (Won et al., 2005). Increasing the length caused membrane depolarization and an increase in the slow-wave frequency. The response was mediated by ICC-IM because no response was observed in antral muscles of c-kit mutants, W/Wv mice, which lack ICC-IM. The stretch sensor mechanism associated with the ICC is mediated by the cyclooxygenase enzyme COX-II, since stretch-dependent responses were inhibited by the COX-II inhibitor indomethacin and they were absent in COX-II deficient mice (Won et al., 2005). COX-II is constitutively expressed by ICC-IM (Porcher et al., 2002) and it is implicated in the prostaglandin cascade. Therefore, products of arachidonic acid metabolism, such as prostaglandin E2 (PGE2), are likely to mediate stretch-dependent responses (Won et al., 2005). Thus, ICC-IM seem to coordinate different neural and mechanical inputs to regulate gastric motility.

4.
3.3. Stretch sensors

Pathological ICC and GIST

The hypothesis that ICC could act as stretch sensors has been proposed repeatedly (Daniel, 1977; Thuneberg, 1989; Faussone-Pellegrini and Thuneberg, 1999), based on the existence of special structures called peg-and-socket junctions that may represent the part of muscle cells most vulnerable to such tension (Fig. 7). These peg-and-socket junctions are thought to consist of a peg of 0.5 to several-micrometers long, which extends from one smooth muscle cell into a narrow pocket or invagination of the plasma membrane of a neighbouring smooth muscle cell or ICC, excluding the connective tissue components from the space between the tightly apposed membranes. The morphology and fixed orientation of these structures suggests that they could serve as mechanical stretch sensors, regulating smooth muscle/interstitial cell

There is evidence of a correlation between alterations to ICC and some digestive pathologies. Indeed, ICC are lacking, reduced or damaged in some of the following digestive pathologies: idiopathic gastric perforation, hypertrophic pyloric stenosis, transient neonatal pseudo-obstruction, neonatal meoconium ileus, Hirshprung's disease, total colonic aganglionosis, intestinal neuronal dysplasia, hypoganglionosis, internal sphincter achalasia or congenital uretopelvic junction obstruction in children and achalasia of oesophagus, gastroparesis, chronic idiopathic intestinal pseudo-obstruction, diabetic gastroenteropathy, paraneoplastic dismotility, afferent loop syndrome, Chagas disease, or inflammatory bowel diseases such as ulcerative colitis or Crohn's disease in adults (for a review see Streutker et al. (2007)). While in the paediatric population some of these alterations may be caused by developmental delay, in

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the case of adults the causes are less well understood. Moreover, it is necessary to differentiate whether these alterations are the primary cause of the disease or just an outcome of it. ICC are also involved in the formation of GIST, the most common mesenchymal tumours of the gastrointestinal tract. Most GIST (50–60%) arise in the stomach, yet 20–30% arise in the small bowel, less than 10% develop in the colon and 1% in the oesophagus, while a small proportion are extragastrointestinal (5%). Prior to the availability of c-Kit immunohistochemistry, GIST were pathologically diagnosed as leiomyomas, leiomyoblastomas or leiomyosarcomas when they were considered to be of smooth muscle origin, or as schwannomas if they were considered to be of neural origin. For those tumours without smooth muscle or Schwann cells features (Mazur and Clark, 1983), the term GIST was introduced on the basis of immunohistochemical light and electron microscopy studies. It was not until 1998 that the relationship between GISTs and ICC was demonstrated (Hirota et al., 1998). Based on the evidence that loss of function mutations of the c-kit gene led to deficiencies in ICC and mast cells, and that gain-of-function c-kit mutations provoked the formation of mast cell tumours (Furitsu et al., 1993), it was speculated that ICC tumours could be induced by c-kit gain-of-function (Hirota et al., 1998; for a review see Hirota and Isozaki (2006)). While Kit expression was undetectable by immunohistochemistry in authentic leiomyoma and schwannomas, it was present in 94% of GIST analyzed. These immunohistochemical characteristics of GIST were also shared by ICC that express Kit (Maeda et al., 1992) and CD34 (Nishida et al., 1998). Accordingly, the complete coding region c-kit (from human chromosome 4) was sequenced from six GIST and in five cases there were mutations in the region between the transmembrane and the tyrosine kinase domains (the juxtamembrane domain encoded primarily by exon 11 and rarely by exons 9 and 13). The mutations led to the constitutive activation of Kit protein, even in the absence of the c-Kit SCF ligand. This mutant c-kit induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that GIST might originate from the ICC with mutations in the c-Kit receptor (Hirota et al., 1998), as later confirmed in other studies (Kindblom et al., 1998; SarlomoRikala et al., 1998; Sircar et al., 1999; Robinson et al., 2000). Nevertheless, it is still not clear whether GIST originate from ICC or from a precursor of these cells that differentiates into ICC during the pathological process (this later mechanisms follows Cajal's so-called “general doctrine of tissue composition”, for a review see Martinez et al. (2005)). Although most GIST bear mutations in kit, a subset (10–15%) express wild type kit (Taniguchi et al., 1999; Rubin et al., 2001). Indeed, 35% of the GIST that lack mutations in kit have intragenic activating mutations in the related receptor tyrosine kinase (Heinrich et al., 2003), platelet-derived growth factor receptor α (PDGFRA), and this proportion reached 65% in a later study (Hirota et al., 2003). These mutations in PDGFRA also produce constitutively active proteins, these receptors freely activating their Receptor Tyrosine Kinase and MitogenActivated Protein kinase (RTKs and MAP) targets independently of their ligands (Fig. 8A). When the specific locations of the mutations in kit were studied in mutational analysis: 66% are found in the intracellular/juxtamembranous region of exon 11 that fulfils physiological regulatory/autoinhibitory roles

Fig. 8 – (A) Scheme of Kit structure and of Kit activation by SCF binding: EC, extracellular; TM, transmembrane; JM, juxtamembrane; and TK, Tyrosine Kinase. The growth factor, SCF, causes dimerization of KIT, resulting in cell differentiation and proliferation via MAP kinase and the JAK/STAT signal transduction pathway. Modified from (Isozaki and Hirota, 2006). (B) Location and type of c-kit gene mutation in sporadic GIST according to Isozaki and Hirota (2006).

(Nishida et al., 1998; Lasota et al., 1999; Moskaluk et al., 1999; Taniguchi et al., 1999); 13% lie in exon 9 corresponding to the extracellular domain (Lux et al., 2000; Lasota et al., 2000; Hirota et al., 2001); less than 4% are located in the Tyrosine Kinase I (TKI) domain encoded by exon 13 (Lux et al., 2000; Lasota et al., 2000; Kinoshita et al., 2003); and less than 4% are in the TKII domain encoded by exon 17 (Lux et al., 2000; Lasota et al., 2000; Kinoshita et al., 2003: Fig. 8B). The mutations in the PDGFA gene were located at the JM domain encoded by exon 12 and the TKII domain encoded by exon 18 (Heinrich et al., 2003; Hirota et al., 2003), whereas mutations in exon 14 that encodes the TKI domain have only rarely been reported (Corless et al., 2005; Lasota et al., 2006). At least, 12 families with multiple GISTs and germ-line kit activating mutations have been reported (Nishida et al., 1998; O'Brien et al., 1999; Hirota et al., 2000; Isozaki et al., 2000; Maeyama et al., 2001; Beghini et al., 2001; Hirota et al., 2002; Robson et al., 2004; Carballo et al., 2005; Li et al., 2005; Kim et al., 2005; Hartmann et al., 2005; O'Riain et al., 2005; for a review see Isozaki and Hirota, (2006); Streutker et al., (2007)). The mutations of kit or PDGFRA in GIST tumours have permitted novel treatments to be developed that aim to inhibit the constitutively activated receptors in these tumours. Imatinib mesylate or Gleevec was developed as a specific inhibitor of PDGFRA and the chimeric fusion protein Bcrl–Abl, the activity of which is uncontrolled in myeologenus leukemia (CML). In preclinical models, imatinib mesylate was also shown to be efficient in inhibiting the mutant kit in GIST and the first patient to be treated with this oral treatment in 2001 displayed a strong response to the treatment (Joensuu et al., 2001). Since then, several trials have been carried out with excellent results (Demetri et al., 2002; Verweij et al., 2004; Scaife et al., 2003). More recently (Demetri et al., 2006; Goodman et al., 2007), a new multitargeted kinase inhibitor has been tested in patients with

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GIST resistant to Imatinib with promising results, while another novel inhibitor of Kit, PKC412 (Debiec-Rychter et al., 2005; Growney et al., 2005), also showed promising preclinical activity against certain imatinib-resistant mutations.

5.

Conclusion

The observations and interpretations of Cajal on the ICC remain valid today, especially his intercalation theory of ICC as mediators of nervous activity. Following Cajal's discoveries, other important physiological functions for ICC have been demonstrated, such as their activity as pacemakers or stretch sensors. The discovery of the c-Kit receptor in the ICC has not only permitted the development of strategic tools to study their physiological functions, but it also serves as a target for the development of accurate therapies to treat GIST.

Acknowledgments
We would like to acknowledge the inheritors of Santiago Ramón y Cajal © P. G-L. is supported by the Fundación Caixa Galicia. This work was supported by the Spanish Ministry of Science and Education (Grant SAF2007-60010) and the Instituto de Salud Carlos III (Grant RD06/0026/1001).
REFERENCES

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Please cite this article as: Garcia-Lopez, P., et al., Updating old ideas and recent advances regarding the Interstitial Cells of Cajal, Brain Res. Rev. (2009), doi:10.1016/j.brainresrev.2009.06.001

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