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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


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


Article history: Since their discovery by Cajal in 1889, the Interstitial Cells of Cajal (ICC) have generated
Accepted 1 June 2009 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: contemporary histologists like Kölliker and Dogiel categorized these cells as fibroblasts.
Cajal More recently, the role of ICC in the origin of slow-wave peristaltism has been elucidated,
Interstitial Cells of Cajal 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 non-
epithelial 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.


1. Introduction: the controversial origin of ICC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2. Location and morphology of ICC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. Intravillous and periglandular plexi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2. Auerbach plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3. Deep muscular plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4. Intramuscular plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.5. Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Corresponding author. Fax: +34 91 585 47 54.

E-mail address: (V. Garcia-Marin).
Both authors contributed equally to this article.

0165-0173/$ – see front matter © 2009 Elsevier B.V. All rights reserved.

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
2 B RA I N R E SE A RC H R E V IE W S X X (2 0 0 9 ) XX X– XX X

2.6. Other locations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

3. The physiological function of ICC from Cajal to the present day . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. ICC in neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. ICC as pacemakers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3. Stretch sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Pathological ICC and GIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction: the controversial origin of ICC analysed by light and electron microscopy, Taxi referred these
cells as neuronoids in an attempt to distinguish them from
Between 1889 and 1893, Cajal published some articles describing neurons, Schwann cells, smooth muscle cells, fibroblasts and
a new type of cell that he classified as a primitive neuron. This macrophages, although he recognised their tendency to co-
type of cell was located in the stroma of the villi (Figs. 1A, 2), in stain with nerves (Taxi, 1952, 1965; for a review see Thuneberg,
the Auerbach's plexus (Figs. 1A, 3), deep muscular plexus (Figs. (1999)). Following these findings, ultrastructural studies on the
1A, 4A), circular muscular layer of the intestine (Figs. 1A, 4B–D), ICC suggested that they were primitive muscle cells (Imaizumi
and around the acini and blood vessels of the pancreas (Fig. 5). and Hama, 1969; Faussone-Pellegrini et al., 1977) or fibroblast-
Following Cajal's first descriptions, these cells were identified like cells (Richardson, 1958; Komuro, 1989).
using different names, including: células simpáticas intersticiales The most important advance in this area came with the
(sympathetic interstitial cells, 1891); células simpáticas (sympa- discovery that ICC express the tyrosine kinase receptor (c-Kit:
thetic cells, 1892); neuronas simpáticas intersticiales (sympathetic Maeda et al., 1992), which permitted them to be chemically
interstitial neurons); or células intersticiales (interstitial cells, differentiated from other cell types sharing similar morpholo-
1899–1904). However, Dogiel subsequently called them –Ca- gical characteristics in the tunica muscularis (Thuneberg, 1982;
jal'sche zellen – and more than 100 years after their discovery the Ward and Sanders, 2001a). The use of this specific marker
name of Interstitial Cells of Cajal (ICC) is still used. allowed the mesenchyma to be identified as the source of ICC
At that time, there was considerable controversy about the (Lecoin et al., 1996) and indeed, the detection of c-Kit expression
nature of these cells and while some researchers, including Cajal in aneural explants confirmed that ICC are not of neural crest
and his colleagues (LaVilla, 1897), thought they were neurons, origin in mammals (Young et al., 1996). Moreover, it was shown
others, such as Kölliker and Dogiel, classified them as fibro- that both smooth muscle cells and ICC have a common
blasts. This debate was somewhat clouded by the ongoing mesodermal origin (Torihashi et al., 1997; Kluppel et al., 1998).
discussion as to whether neurons were individual structures or However, it is noteworthy that a subset of ICC might be of neural
if they simply formed a syncitium. According to the reticularist origin, since the ICC of the circular muscular layer originate from
point of view, neurons were thought to form an interconnected cells that emerge from the ventral neural tube (VENT cells: Sohal
continuous network built up of either axons and dendrites et al., 2002), a source of neurons, glia and ICC precursors that
(Gerlach's), or exclusively of axons (Golgi's). Cajal's first paper on differ from the neural crest cells. Hence, the neuronal origin of
the nervous system (Cajal, 1888) proposed that neurons end ICC suggested by Cajal could be at least partially true. VENT cells
freely, and that they connect with each other by contiguity and originate in the ventral part of the hindbrain neural tube and
not by continuity. This relevant observation was the first they migrate through the site of attachment of the cranial
description of the neuronal doctrine: neurons are independent nerves to colonize the gastrointestinal tract, particularly the
units from a morphological and even physiological point of view. duodenum and stomach (Sohal et al., 1996; Bockman and Sohal,
However, Cajal's description of the ICC as neurons was in 1998). Significantly, not all ICC express c-Kit, such as the ICC-
contradiction with his neuron doctrine as he was unable to DMP (deep muscular plexus, see Fig. 1A) in the human small
recognize the axonal process in these cells that characteristically intestine (Torihashi et al., 1999; Wang et al., 2003). Moreover,
establishes the typical network. In this respect, he recognized: there are many different cell types besides ICC that express c-
Kit, such as mast cells, melanocytes, neurons and glia (Zhang
“I am neither exclusive nor dogmatic. I am proud of and Fedoroff, 1997). Thus, ultrastructural analysis has proved to
retaining a mental flexibility which is not afraid of be essential to finally determine whether a particular cell
correction. Neuronal discontinuity, extremely evident in belongs to the ICC family. The ultrastructural characteristics of
innumerable examples, could sustain some exceptions. I ICC have been well defined (Faussone-Pellegrini and Thuneberg,
myself have mentioned some of them, for example those 1999; Rumessen and Vanderwinden, 2003; Komuro, 1999) and
probably existing in the glands, vessels and intestines (my they have been summarized as a gold standard (Huizinga et al.,
interstitial neurons)” (Cajal, 1933). 1997) for ICC identification. ICC are generally characterized by a
number of morphological aspects including the presence of: i)
During the twentieth century, there has been a longstanding numerous mitochondria and caveolae; ii) a basal lamina,
dogmatic division regarding the nature of these cells (Jabonero, although discontinuous; iii) abundant intermediate filaments;
1960; Thuneberg, 1990; for a review see Thuneberg (1999)). When iv) moderately developed Golgi apparatus, few ribosomes and a

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
B RA I N R E SE A R CH RE V IE W S X X ( 20 0 9 ) XX X– XX X 3

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 connective tissue) and the Auerbach plexus (located between
established with nerve varicosities and the formation of the longitudinal and circular smooth muscle fibres), Cajal found
numerous gap junctions, both with each other and with smooth them in three more plexi: the deep muscular plexus, the
muscle cells. 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
2. Location and morphology of ICC anastomosed processes, often ramifying at a right angle. These
general characteristics of ICC varied at their different locations
Cajal described ICC at different sites in the intestinal tube. Apart (Figs. 1B–E) and thus, it is worthwhile describing the characte-
from the classical Meissner plexus (located in the submuscular ristics of the ICC at the locations where Cajal observed them.

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
4 B RA I N R E SE A RC H R E V IE W S X X (2 0 0 9 ) XX X– XX X

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 site directions, up and down (Fig. 2C). By contrast, the cells were
round, triangular or stellate in the apical portion, close to the
Cajal described this new type of cell for the first time in the lumen of the intestinal tract (Fig. 2A). The periglandular plexus
intestinal villi (Cajal, 1889), situated either at the basal or the has triangular or stellate cells (Fig. 2D), and these cells had
apical portion of the villi and forming the periglandular plexus numerous processes that ramified in a complex way. Cajal
(Figs. 2A–B). In the basal portion of the intestinal villi, the cells realized that the numerous processes anastomosed and he
were long and fusiform, with two processes emanating in oppo- could not differentiate any axonal process (Cajal, 1893). In

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
B RA I N R E SE A R CH RE V IE W S X X ( 20 0 9 ) XX X– XX X 5

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 blasts in the villi are connected through gap junctions
Museum, we have found these cells in the basal portion of the (Komuro, 1990; Komuro and Hashimoto, 1990). In contrast to
villi and in the periglandular plexus but not in the apical portion. typical ICC, these myofibroblasts do not bear c-Kit (Vannucchi
In this regard, Cajal said (1899–1904), that they ICC in the apical et al., 2002) but they do express NK1r. Moreover, since they are
portion of the intestina villi are very difficult to stain. in close contact with one another and with nerve fibres
Besides these first observations, Güldner also found a (Vannucchi and Faussone-Pellegrini, 2000), they can still be
connected system of fibroblasts in the villi of the duodenum considered as a class of ICC. Concerning the possible
(Güldner et al., 1972; for a review see Thuneberg (1999); physiological role of these cells, it is thought that they may
Huizinga and Faussone-Pellegrini (2005)). These cells formed serve as a barrier/sieve, a flexible mechanical frame, mechan-
a cellular network establishing close contact with axons, osensors and signal transduction machinery in the intestinal
smooth muscle cells and partially embracing the capillaries villi, regulated locally and dynamically by rapid changes in cell
and terminal arteriole. Later, it was observed that the fibro- shape (Furuya et al., 2005; Furuya and Furuya, 2007).

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
6 B RA I N R E SE A RC H R E V IE W S X X (2 0 0 9 ) XX X– XX X

the nervous cells, Cajal also described his interstitial cells as

small fusiform or triangular shaped cells with little proto-
plasm, 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 ICC-
MY varies greatly between different parts of the gastrointes-
tinal 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 anastomo-
sised lines (see Hanani et al., 2005). These cells are currently
referred to as interstitial cells of the deep muscular plexus

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

Fig. 4 – (A) Drawing of ICC in deep muscle plexus from the nervous corpuscle between the circular muscular fibres
guinea pig seen in a section parallel to the muscle layer and directed in the same direction as the muscular fibres”
stained by the Golgi method, according to Cajal (1893): (Cajal, 1892).
A, nerve cells. a, b, nerve cells of the interstitial plexus;
e, arborization of one interstitial cell process; f, interstitial cell The morphology, distribution and density of ICC-CM differs
with long processes. (B) ICC under the layer of circular muscle considerably from organ to organ in a given species. ICC-CM of
in the rabbit stained by Ehrlichs' method (Cajal, 1893) the small intestine often show secondary cytoplasmic
(C–D) ICC-CM stained by Ehrlichs' method (C) and the Golgi branches and they are sparsely distributed in association
method (D) from Cajal's original histological preparations. with rather thicker nerve bundles, without forming their own
Scale bar: 25 μm (C, D). 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).
2.2. Auerbach plexus Some other ICC are also found in the longitudinal muscle
layer ICC-LM. These cells are similar to ICC-CM in shape but
Cajal studied the Auerbach's plexus in the frog with the help of there are usually fewer in nearly the whole gastrointestinal
methylene blue staining. He identified a network of stained tract (i.e. in the stomach, small intestine and colon: Komuro,
thick, flexible and ramified fibres parallel to the circular mus- 2004). ICC-CM located in the circular muscle layer and those
cular fibres (Cajal, 1892). This plexus is endowed with gang- located in the longitudinal muscle layer (ICC-LM) are referred
lions (2 to 12 cells) joined into anastomotic bundles. Besides to collectively as intramuscular ICC (ICC-IM).

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
B RA I N R E SE A R CH RE V IE W S X X ( 20 0 9 ) XX X– XX X 7

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
3. The physiological function of ICC from Cajal
Cajal studied the distribution of ICC in the pancreas of different to the present day
species with the aid of the Golgi method and he found that they
were independent elements throughout the organ. These cells The history of gastrointestinal motility extends deep into the
were fusiform, triangular or stellate, with 3 or more divergent past. From the observations of gastric contractions (Beau-
processes (Fig. 5: Cajal and Sala, 1891), and processes from these mont, 1833) through to the discovery of spontaneous colon
cells formed a strong plexus around the acini or the blood contractions in the cat tract using X-rays (Cannon, 1902), there
vessels (Fig. 5B). Again, the ICC processes anastomized such that have been many advances in this field. The implication of the
he could not discriminate a typical axon emanating from them. Auerbach and Meissner plexi in the motility of the gastro-
Recently, the presence of ICC in pancreas (pICC) was confirmed intestinal tract was fully appreciated from the beginning of
using non-conventional light microscopy, immunohistoche- last century:
mistry and transmission electron microscopy (Popescu et al.,
2005). These studies suggested that pICC may play a role in “The presence of these centres (referring to the Meissner
neurotransmission/modulation through two possible strate- and Auerbach plexi) explains the automatism of intestinal
gies: a) by co-operating with acinar cells and with small vessels; movements” (Cajal, 1899–1904).
and b) to engage mutual contact with pancreatic stellate cells or
with Pacinian receptors. In addition, ICC could fulfil another However, the role of the ICC was less clear. Nevertheless,
hypothetical role in controlling normal mechanoreceptor phy- Cajal proposed these cells to be mediators of enteric transmis-
siology, since they were closely apposed to the Pacinian sion (Fig. 6: Cajal, 1899–1904):
corpuscle. Interestingly, they also considered that stromal
pancreatic tumours (SPT) might originate from a subset of “It is not a risky conjecture, however, that the interstitial
pICC by analogy with GIST (see below). cells are subordinated to fibres of the autonomic ganglia.
The impulse brought by these fibres would elicit a sup-
2.6. Other locations plementary discharge in the interstitial cells, able to add
strength to the contraction or increase its duration”. (Cajal,
ICC are also located outside the gastrointestinal tract and by 1899–1904).
applying the Golgi technique, some histologists even found
them in the serose glands of the tongue (Krause, Fusari and Later in this text and in reference to the motor pathway of
Panasci) or in the myocardium (Berkley, 1893; review in Cajal, the autonomic system, Cajal stated:
1899–1904). With modern techniques, ICC have also been
found in many other locations such as in the upper urinary “Here, in all probability, the motor chain has two
tract (Lang and Klemm, 2005), urethra (Sergeant et al., 2006), additional neurons: that of myenteric and mucosal plexi,
myometrium (Ciontea et al., 2005), myocardium (Hinescu and and the interstitial or terminal cell”. (Cajal, 1899–1904).
Popescu, 2005; Popescu et al., 2006), uterus, fallopian tube
(Popescu et al., 2007), human placenta (Suciu et al., 2007) and For Cajal, the ICC would function as mediators of neuronal
the ciliary muscle in monkeys (Paula et al., 2009). Thus, these transmission and subsequent studies supported this theory
findings confirm Cajal's conclusions that: (Imaizumi and Hama, 1969; Yamamoto, 1977; Oki and Daniel,
1973; Daniel, 1977). Currently there is no doubt that inter-
“All or almost all glands have terminal neural plexi, similar stitial cells serve as mediators of enteric transmission and
to those of the intestine, made of Remak fibres originated indeed, interstitial cells were proposed as pacemakers by
in special autonomic ganglia, as well as fusiform or stellate Keith in 1915 (Keith, 1915; for a review see Thuneberg (1999))
cells of the previously described interstitial type” (Cajal, and this role in gastrointestinal pacemaking activity has
1899–1904). since been further demonstrated. These different functions

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
8 B RA I N R E SE A RC H R E V IE W S X X (2 0 0 9 ) XX X– XX X

3.1. ICC in neurotransmission

Several studies have revealed a close and functional relation-

ship 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 neurotransmis-
sion (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 ICC-
DMP 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
It should be noted that the close apposition of enteric nerve
fibres (both excitatory and inhibitory) and ICC, as well as the
Fig. 6 – Diagram of sensory and motor pathways of the presence of neurotransmitter receptors on these cells, does
autonomic system according to (Cajal, 1899–1904). not imply that functional synaptic contacts are made between
A, sympathetic ganglion; B, ventral horn of the spinal cord; these structures. With the aid of electron microscopy,
C, dorsal root ganglion; D, small intestine; E, pancreas; abundant close contacts (<25 nm) between varicose nerve
F, visceral ganglion; J, glandular interstitial cell; terminals and ICC were demonstrated that support the
K, perivascular nerve cell; V, blood vessels; A, motor existence of a specialized kind of transmission of neural
spino-gangliar fibres of preganglionic Langley fibres; information between enteric nerves and ICC (Daniel and
b, another spino-sympathetic fibre terminating exclusively Posey-Daniel 1984). These contacts have been confirmed
in a single ganglion; c, sympathetic axon coursing through (Wang et al., 1999; Ward et al., 2000) and the existence of
two ganglia; d, sympathetic axon incorporated into a spinal these close interactions led to the recovery of the intercalation
nerve through the gray ramus communicans; e, autonomic theory which favours the existence of nerve transmission
axon ending on a blood vessel (postganglionic fibre of through ICC (Cajal, 1899–1904; Daniel and Posey-Daniel, 1984;
Langley); f, autonomic axon ending in the myenteric plexus see also Ward, 2000; Ward and Sanders, 2001b). These synaptic
of the intestine; g, motor cell of a myenteric ganglion; specializations are functional, since the soluble N-ethylma-
h, sensory spinal fibre ending in the intestinal mucosa; leimide-sensitive attachment protein receptors (SNARE)
m, ganglion of the myenteric plexus; I, motor fibre ending in implicated in neurotransmitter release is located in varicos-
a visceral ganglion. ities 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 func-
tional since they contain typical postsynaptic proteins. There
(nervous transmission and pacemaking activity) are to some is also a decrease in the expression of postsynaptic density
extent carried out by different types of ICC. While nervous (PSD-93 and PSD-95) in kit mutant mice (W/Wv), whereas
transmission is mediated by ICC-IM, the pacemaking activity immunohistochemistry for the PDZ domain of the PSD-95
is preferentially mediated by ICC-MY even though ICC-IM family and for Kit revealed some degree of co-localization
may also regulate the frequency of the pacemaker. (Beckett et al., 2005; for a review see Sanders and Ward (2006)).

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B RA I N R E SE A R CH RE V IE W S X X ( 20 0 9 ) XX X– XX X 9

Box 1
ICC receptors.
Receptors ICC location References

5-HT, 5-HT3, 5-HT4 subtypes ICC-MY Glatzle et al. (2002); Liu et al. (2005); Poole et al. (2006);
Bombesin, subtype-3 Almost in all ICC Porcher et al. (2005)

Cholecystokinin A ICC Patterson et al. (2001)

G protein-coupled, Protein Kinase A (PKA), ICC Southwell (2003); Poole et al. (2004)
Protein Kinase C (PKC)
Muscarinic acetylcholine, M2, M3 subtypes ICC-IM, ICC-MY Epperson et al. (2000); Iino and Nojyo (2006)
Neurokinin, NK1, NK3 subtypes ICC-IM, ICC-MY Sternini et al. (1995); Grady et al. (1996); Portbury et al. (1996); Lavin et al. (1998);
ICC-DMP Epperson et al. (2000); Iino et al. (2004)
Purinergic, P2Y1, P2Y4 subtypes P2X2, P2X5 ICC-IM, ICC-MY, Burnstock and Lavin (2002); Van Nassauw et al. (2006); Chen et al. (2007)
subtypes ICC-DMP
Somatostatin 2A ICC-DMP Sternini et al. (1997)
VIP ICC-IM, ICC-MY Epperson et al. (2000)
VPAC1 subtype

However, there is still little data regarding how the nervous Early evidence of the implication of ICC in the generation of
impulse is transmitted from the ICC-IM to the smooth muscle slow waves came from photochemical ablation of ICC, whereby
cells. Although gap junctions were proposed to be involved in methylene blue followed by illumination blocks slow-wave
this process, recent research using gap junction blockers sug- activity (Thuneberg et al., 1983; Liu et al., 1993, 1994). Alter-
gests that gap junctions are not necessary for pacing or nerve natively, others used rhodamine 123, a cytotoxic fluorescent dye
transmission to the circular muscle of the mouse intestine that specifically accumulates in the ICC, although it may also
(Daniel, 2004; Daniel et al., 2007). accumulate in enteric neurons (Ward et al., 1990).
Other studies have been critical to confirm the role of ICC in
3.2. ICC as pacemakers generating slow-wave activity. Intracellular electrode record-
ing and methylene blue staining were used to confirm that
The first suggestion that ICC may act as physiological pace- slow waves are only observed in smooth muscle cells when
makers was made by Arthur Keith, the discoverer of the the ICC are attached to the muscle layer registered (Suzuki
cardiac sino-atrial pacemaker organization (Keith, 1915; for a et al., 1986). At the same time, intracellular recording of the
review see Thuneberg (1999)). longitudinal, inner and outer circular muscle layers of the dog,
cat, rabbit, opossum and human small intestine demonstrated
“A series of sections through the ileo-caecal junction of the that the myenteric region is the dominant source of slow
rat's bowel revealed a collar of peculiar tissue…there was waves in the small intestine (Hara et al., 1986). By contrast, the
also present a third element -numerous branching cells, not pacemaker in the colon resides at the submucosal surface of
connective tissue in nature with processes which united the circular muscle layer, since removing ICC-SMP from the
with muscle cells, on the one hand, and with the processes submucosal border blocks the generation of slow waves
from true ganglionic cells on the other. I regarded these inter- (Smith et al., 1987). In mice with c-kit mutations (W/Wv), the
mediate cells as a possible representation of the nodal tissue networks of ICC-MY are grossly underdeveloped in the small
of the heart”. (Keith, 1915); taken from (Thuneberg, 1999) intestine where pacemaker activity was lacking (Ward et al.,
1994; Huizinga et al., 1995), even though ICC are present in the
Ambache was the first to show that electrical slow waves DMP. In the latter experimental model, ICC-MY are evident in
control intestinal contractions and to relate these slow waves the stomach where slow-wave activity can be recorded (Burns
to the ICC (Ambache, 1947; reviewed in Thuneberg (1999)). et al., 1996; see also Huizinga, 2001). These data suggest that
Several subsequent studies (using different approaches that ICC-MY but not ICC-DMP are crucial for generating slow-wave
included chemical lesions and dissection experiments, intra- activity (Ward et al., 1994, 1995; Huizinga et al., 1995; Huizinga
cellular electrophysiological recording or mutant animals) et al., 2001). Similar experiments in rat mutants (Horiguchi
indicated that ICC generated these slow waves. Slow waves and Komuro, 1998) or in steel-Dickie mutant mice (Sl/Sld), in
are cyclic depolarizations of the membrane potential of which the gene encoding the c-Kit ligand (stem cell factor, SCF)
smooth muscle cells. The cellular mechanisms involved in is defective (Ward et al., 1995) confirmed these data. However,
the generation of pacemaker potentials are not completely the generation of slow waves is not only mediated by ICC-MY.
understood, although it seems clear that the release of Ca2+ In the gastric corpus of the guinea pig where ICC-MY are
from internal IP3-dependent stores plays a key part in their absent, the dominant pacemaker activity that entrains activity
generation (Suzuki, 2000; for a review see Nakayama et al. in other regions of the stomach is provided by the ICC-IM
(2007)). When rhythmic electrical oscillations reach the open- (Hashitani et al., 2005). Furthermore, ICC-IM contribute to the
ing threshold of calcium channels, calcium enters the cell and amplification of pacemaker signals from ICC-MY by genera-
triggers the contraction of smooth muscle cells. ting rhythmic oscillations known as unitary potentials,

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10 B RA I N R E SE A RC H R E V IE W S X X (2 0 0 9 ) XX X– XX X

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 coupling and the internal sensitivity of a muscular layer to
that follow exposure to acetylcholine (Dickens et al., 2001; stretch (Faussone-Pellegrini and Thuneberg, 1999; Thuneberg
Hirst et al., 2002a,b; Edwards et al., 1999). and Peters, 2001).
Other studies have been carried out on isolated and/or However, the most solid physiological evidence supporting
cultured ICC. Single ICC are spontaneously active, generating the functioning of ICC as stretch sensors was obtained by
electrical depolarization similar to slow waves recorded in applying length ramps to the murine antral muscles, while
intact smooth muscle cells, as demonstrated in patch clamp recording intracellular electrical activity and isometric force
experiments on the canine colon (Langton et al., 1989). Indeed, (Won et al., 2005). Increasing the length caused membrane
single ICC generate a rhythmic inward current insensitive to L- depolarization and an increase in the slow-wave frequency.
type calcium channel blockers that is crucial for the genera- The response was mediated by ICC-IM because no response
tion of slow waves in smooth muscle cells (Thomsen et al., was observed in antral muscles of c-kit mutants, W/Wv mice,
1998). which lack ICC-IM. The stretch sensor mechanism associated
But how the slow waves spread from the ICC-MY to the with the ICC is mediated by the cyclooxygenase enzyme
smooth muscle cells is still unclear. Although ICC-MY are COX-II, since stretch-dependent responses were inhibited by
coupled through gap junctions, there are no gap junctions the COX-II inhibitor indomethacin and they were absent in
between ICC-MY and smooth muscle cells of the longitudinal COX-II deficient mice (Won et al., 2005). COX-II is constitu-
or circular muscle layer (Fig. 7). Thus, other mechanisms such tively expressed by ICC-IM (Porcher et al., 2002) and it is
as peg and socket connections, have been proposed that might implicated in the prostaglandin cascade. Therefore, products
provide electrical coupling through the accumulation of of arachidonic acid metabolism, such as prostaglandin E2
potassium in the narrow cleft between the peg and the socket (PGE2), are likely to mediate stretch-dependent responses
under appropriate conditions (Vigmond et al., 2000). These peg (Won et al., 2005). Thus, ICC-IM seem to coordinate different
and socket connections have also been proposed as stretch neural and mechanical inputs to regulate gastric motility.
sensors, warranting a description of these structures and their
possible implications.
4. Pathological ICC and GIST
3.3. Stretch sensors
There is evidence of a correlation between alterations to ICC and
The hypothesis that ICC could act as stretch sensors has been some digestive pathologies. Indeed, ICC are lacking, reduced or
proposed repeatedly (Daniel, 1977; Thuneberg, 1989; Faus- damaged in some of the following digestive pathologies:
sone-Pellegrini and Thuneberg, 1999), based on the existence idiopathic gastric perforation, hypertrophic pyloric stenosis,
of special structures called peg-and-socket junctions that may transient neonatal pseudo-obstruction, neonatal meoconium
represent the part of muscle cells most vulnerable to such ileus, Hirshprung's disease, total colonic aganglionosis, intest-
tension (Fig. 7). These peg-and-socket junctions are thought to inal neuronal dysplasia, hypoganglionosis, internal sphincter
consist of a peg of 0.5 to several-micrometers long, which achalasia or congenital uretopelvic junction obstruction in
extends from one smooth muscle cell into a narrow pocket or children and achalasia of oesophagus, gastroparesis, chronic
invagination of the plasma membrane of a neighbouring idiopathic intestinal pseudo-obstruction, diabetic gastroentero-
smooth muscle cell or ICC, excluding the connective tissue pathy, paraneoplastic dismotility, afferent loop syndrome,
components from the space between the tightly apposed Chagas disease, or inflammatory bowel diseases such as ulce-
membranes. The morphology and fixed orientation of these rative colitis or Crohn's disease in adults (for a review see
structures suggests that they could serve as mechanical Streutker et al. (2007)). While in the paediatric population some
stretch sensors, regulating smooth muscle/interstitial cell of these alterations may be caused by developmental delay, in

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B RA I N R E SE A R CH RE V IE W S X X ( 20 0 9 ) XX X– XX X 11

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 extra-
gastrointestinal (5%). Prior to the availability of c-Kit immu-
nohistochemistry, 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 intro- Fig. 8 – (A) Scheme of Kit structure and of Kit activation by
duced on the basis of immunohistochemical light and electron SCF binding: EC, extracellular; TM, transmembrane;
microscopy studies. It was not until 1998 that the relationship JM, juxtamembrane; and TK, Tyrosine Kinase. The growth
between GISTs and ICC was demonstrated (Hirota et al., 1998). factor, SCF, causes dimerization of KIT, resulting in cell
Based on the evidence that loss of function mutations of differentiation and proliferation via MAP kinase and the
the c-kit gene led to deficiencies in ICC and mast cells, and that JAK/STAT signal transduction pathway. Modified from
gain-of-function c-kit mutations provoked the formation of (Isozaki and Hirota, 2006). (B) Location and type of c-kit
mast cell tumours (Furitsu et al., 1993), it was speculated that gene mutation in sporadic GIST according to Isozaki and
ICC tumours could be induced by c-kit gain-of-function (Hirota Hirota (2006).
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 charac- (Nishida et al., 1998; Lasota et al., 1999; Moskaluk et al., 1999;
teristics of GIST were also shared by ICC that express Kit Taniguchi et al., 1999); 13% lie in exon 9 corresponding to the
(Maeda et al., 1992) and CD34 (Nishida et al., 1998). Accor- extracellular domain (Lux et al., 2000; Lasota et al., 2000; Hirota
dingly, the complete coding region c-kit (from human chromo- et al., 2001); less than 4% are located in the Tyrosine Kinase I
some 4) was sequenced from six GIST and in five cases there (TKI) domain encoded by exon 13 (Lux et al., 2000; Lasota et al.,
were mutations in the region between the transmembrane 2000; Kinoshita et al., 2003); and less than 4% are in the TKII
and the tyrosine kinase domains (the juxtamembrane domain domain encoded by exon 17 (Lux et al., 2000; Lasota et al., 2000;
encoded primarily by exon 11 and rarely by exons 9 and 13). Kinoshita et al., 2003: Fig. 8B). The mutations in the PDGFA gene
The mutations led to the constitutive activation of Kit protein, were located at the JM domain encoded by exon 12 and the TKII
even in the absence of the c-Kit SCF ligand. This mutant c-kit domain encoded by exon 18 (Heinrich et al., 2003; Hirota et al.,
induced malignant transformation of Ba/F3 murine lymphoid 2003), whereas mutations in exon 14 that encodes the TKI
cells, suggesting that GIST might originate from the ICC with domain have only rarely been reported (Corless et al., 2005;
mutations in the c-Kit receptor (Hirota et al., 1998), as later Lasota et al., 2006).
confirmed in other studies (Kindblom et al., 1998; Sarlomo- At least, 12 families with multiple GISTs and germ-line kit
Rikala et al., 1998; Sircar et al., 1999; Robinson et al., 2000). activating mutations have been reported (Nishida et al., 1998;
Nevertheless, it is still not clear whether GIST originate from O'Brien et al., 1999; Hirota et al., 2000; Isozaki et al., 2000;
ICC or from a precursor of these cells that differentiates into Maeyama et al., 2001; Beghini et al., 2001; Hirota et al., 2002;
ICC during the pathological process (this later mechanisms Robson et al., 2004; Carballo et al., 2005; Li et al., 2005; Kim et al.,
follows Cajal's so-called “general doctrine of tissue composition”, 2005; Hartmann et al., 2005; O'Riain et al., 2005; for a review see
for a review see Martinez et al. (2005)). Isozaki and Hirota, (2006); Streutker et al., (2007)). The
Although most GIST bear mutations in kit, a subset (10–15%) mutations of kit or PDGFRA in GIST tumours have permitted
express wild type kit (Taniguchi et al., 1999; Rubin et al., 2001). novel treatments to be developed that aim to inhibit the
Indeed, 35% of the GIST that lack mutations in kit have intra- constitutively activated receptors in these tumours. Imatinib
genic activating mutations in the related receptor tyrosine mesylate or Gleevec was developed as a specific inhibitor of
kinase (Heinrich et al., 2003), platelet-derived growth factor PDGFRA and the chimeric fusion protein Bcrl–Abl, the activity
receptor α (PDGFRA), and this proportion reached 65% in a later of which is uncontrolled in myeologenus leukemia (CML). In
study (Hirota et al., 2003). These mutations in PDGFRA preclinical models, imatinib mesylate was also shown to be
also produce constitutively active proteins, these receptors efficient in inhibiting the mutant kit in GIST and the first
freely activating their Receptor Tyrosine Kinase and Mitogen- patient to be treated with this oral treatment in 2001 displayed
Activated Protein kinase (RTKs and MAP) targets independently a strong response to the treatment (Joensuu et al., 2001). Since
of their ligands (Fig. 8A). When the specific locations of the then, several trials have been carried out with excellent results
mutations in kit were studied in mutational analysis: 66% are (Demetri et al., 2002; Verweij et al., 2004; Scaife et al., 2003).
found in the intracellular/juxtamembranous region of exon 11 More recently (Demetri et al., 2006; Goodman et al., 2007), a new
that fulfils physiological regulatory/autoinhibitory roles multitargeted kinase inhibitor has been tested in patients with

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
12 B RA I N R E SE A RC H R E V IE W S X X (2 0 0 9 ) XX X– XX X

GIST resistant to Imatinib with promising results, while Cajal, S.R., 1892. El plexo de Auerbach de los batracios. Trab. Lab.
another novel inhibitor of Kit, PKC412 (Debiec-Rychter et al., Histol. Facultad Med. Barcelona 23–28 Febrary.
Cajal, S.R., 1893. Los Ganglios y Plexos Nerviosos del Intestino de
2005; Growney et al., 2005), also showed promising preclinical
los Mamíferos.. Imprenta y Libreía de Nicolás Moya, Madrid.
activity against certain imatinib-resistant mutations. Cajal, S.R., 1899–1904. Textura del Sistema Nervioso del Hombre y
de los Vertebrados, 2 Vols, 1. Imprenta y librería de Nicolás
Moya, Madrid.
5. Conclusion Cajal, S.R., 1933. Neuronismo o Reticularimo?. Imprenta y Libreria
de Nicolás Moya, Madrid.
The observations and interpretations of Cajal on the ICC Cajal, S.R., Sala, C., 1891. Terminación de los nervios y tubos
glandulares del páncreas de los vertebrados. Trab. Lab. Histol.
remain valid today, especially his intercalation theory of ICC
Facultad Med. Barcelona 28, 1–5 Diciembre.
as mediators of nervous activity. Following Cajal's discoveries, Cannon, W.B., 1902. The movements of the intestines studied by
other important physiological functions for ICC have been means of the Röntgen rays. Am. J. Physiol. 6, 251–277.
demonstrated, such as their activity as pacemakers or stretch Carballo, M., Roig, I., Aguilar, F., Pol, M.A., Gamundi, M.J., Hernan,
sensors. The discovery of the c-Kit receptor in the ICC has not I., Martinez-Gimeno, M., 2005. Novel c-KIT germline mutation
only permitted the development of strategic tools to study in a family with gastrointestinal stromal tumors and
cutaneous hyperpigmentation. Am. J. Med. Genet., A 132,
their physiological functions, but it also serves as a target for
the development of accurate therapies to treat GIST.
Chen, H., Redelman, D., Ro, S., Ward, S.M., Ordog, T., Sanders, K.M.,
2007. Selective labeling and isolation of functional classes of
interstitial cells of Cajal of human and murine small intestine.
Acknowledgments Am. J. Physiol., Cell Physiol. 292, C497–C507.
Ciontea, S.M., Radu, E., Regalia, T., Ceafalan, L., Cretoiu, D.,
We would like to acknowledge the inheritors of Santiago Gherghiceanu, M., Braga, R.I., Malincenco, M., Zagrean, L.,
Hinescu, M.E., Popescu, L.M., 2005. C-kit immunopositive
Ramón y Cajal © P. G-L. is supported by the Fundación Caixa
interstitial cells Cajal-type in human myometrium. J. Cell. Mol.
Galicia. This work was supported by the Spanish Ministry of Med. 9, 407–420.
Science and Education (Grant SAF2007-60010) and the Insti- Corless, C.L., Schroeder, A., Griffith, D., Town, A., McGreevey, L.,
tuto de Salud Carlos III (Grant RD06/0026/1001). Harrell, P., Shiraga, S., Bainbridge, T., Morich, J., Heinrich, M.C.,
2005. PDGFRA mutations in gastrointestinal stromal tumors:
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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