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Interstitial cells of Cajal in the human fetal small
bowel as shown by c-kit immunohistochemistry
T Wester, L Eriksson, Y Olsson, L Olsen
Abstract
Background—Interstitial cells of Cajal
(ICCs) express the tyrosine kinase recep-
tor c-kit, which is required for their devel-
opment and spontaneous pacemaker
activity in the bowel. From murine models
it has been proposed that ICCs do not
develop until after birth, but more recent
findings indicate that c-kit is expressed
early in the embryonic period. The tem-
poral development of ICCs in the human
gut remains unknown.
Aim—To investigate ICCs in the human
fetal small bowel using c-kit immunohisto-
chemistry.
Subjects—Small bowel specimens were
obtained at post mortem examination of
16 fetuses and nine neonates, eight of
whom were premature, born at
gestational ages of 13 to 41 weeks, without
gastrointestinal disorders.
Methods—Immunohistochemical analysis
was performed on material fixed in for-
malin and embedded in paraYn. The
specimens were exposed to antibodies
raised against c-kit (an ICC marker) and
neurone specific enolase (a general neuro-
nal marker). The ABC complex method
was used to visualise binding of antibodies
to the corresponding antigens.
Results—c-kit immunoreactive cells were
visualised from 13 weeks of gestation. The
immunoreactivity was mainly localised in
association with the myenteric plexus.
From about 17–18 weeks of gestation, the
ICCs formed a layer along the myenteric
plexus, whereas this layer appeared to be
disrupted at 13–16 weeks of gestation.
Conclusions—ICCs are c-kit immuno-
reactive at least from a gestational age of
13 weeks in the human fetal small intes-
tine. From 17–18 weeks of gestation until
birth, they form a continuous layer
around the myenteric ganglia.
(Gut 1999;44:65–71)
Keywords: interstitial cells of Cajal; c-kit; myenteric
plexus; human; fetal; development
Although it is now more than a century since
the interstitial cells of Cajal (ICCs) first
attracted the interest of scientists,12 many
questions about these cells remain unan-
swered, particularly with respect to their func-
tion. Furthermore, the ontogeny and develop-
ment of ICCs, especially in the human
gastrointestinal tract, require further investiga-
tion, and these questions were addressed in the
present study.
In the human small bowel, the ICCs are
localised at the level of the myenteric plexus
between the longitudinal and circular muscle
layers, in the deep muscular plexus in the
innermost part of the circular muscle layer, and
within the circular muscle layer itself.3–5 They
are considered to be generators of spontaneous
pacemaker activity in the smooth muscle layers
of the gut.6–9 Furthermore, it has been sug-
gested that they may be involved in
neurotransmission.9A cytokine, steel factor,10
also termed stem cell factor (SCF)11 or mast
cell growth factor (MGF),12 has been identified
as the c-kit ligand. Huizinga et al13 showed that
ICCs associated with the myenteric plexus
express c-kit, which is a proto-oncogene
encoding a cell surface receptor tyrosine
kinase.14 Mice with mutations in the white
spotting (W) locus, resulting in kit gene muta-
tions, lack ICCs associated with the myenteric
plexus as well as intestinal pacemaker activity.
In conclusion, ICCs appear to have a key
role in the normal function of the intestine, and
alterations in these cells may well be involved in
various intestinal disorders. For instance, in
Hirschsprung’s disease there are considerably
fewer ICCs in the aganglionic segment than in
the ganglionic bowel.15 16 The absence or
reduction of c-kit immunoreactive cells in
association with the myenteric plexus has also
been observed in infantile hypertrophic pyloric
stenosis.17 Recently, Isozaki et al18 reported two
cases of myopathic chronic intestinal pseudo-
obstruction with decreased numbers of c-kit
immunoreactive cells associated with the my-
enteric plexus.
To our knowledge, the temporal develop-
ment of ICCs in the human gastrointestinal
tract has not been systematically investigated
previously. The purpose of this study was
therefore to map c-kit immunoreactivity as an
ICC marker in the small intestine from human
fetuses at diVerent gestational ages. Neurone
specific enolase (NSE) immunohistochemistry
was used as a marker of the neuronal
component, which has already been well
defined in the human fetal small bowel.19
Information on the ICCs may contribute to our
understanding of the development of small
bowel motility in premature babies in whom
this motility appears immature in the fasting
state,20 21 although it has been reported that
premature babies respond appropriately to
feeding.22 Furthermore, knowledge of ICC
development may help to clarify the aetiology
Abbreviations used in this paper: ICC, interstitial
cells of Cajal; SCF, stem cell factor; MGF, mast cell
growth factor; NSE, neurone specific enolase; PBS
phosphate buVered saline.
Gut 1999;44:65–71 65
Department of
Paediatric Surgery,
University Children’s
Hospital, S-751 85
Uppsala, Sweden
T Wester
L Olsen
Laboratory of
Neuropathology,
Department of
Genetics and
Pathology, University
Hospital, Uppsala,
Sweden
L Eriksson
Y Olsson
Correspondence to:
Dr T Wester.
Accepted for publication
22 July 1998
and pathophysiology of disorders characterised
by a deficiency of ICCs.
Methods
Specimens from the mid part of the small
bowel were collected for diagnostic purposes at
routine post mortem examination of 16 fetuses
and nine newborns, eight of whom were born
prematurely. The gestational age ranged from
13 to 41 weeks (table 1). The liveborn babies
died between the first and 17th day of life.
Seven of these were born at 21–27 weeks of
gestation. Post mortem examination was per-
formed one to six days after death. Mild mac-
eration was found in three of the fetuses who
died in utero; stillbirths with severe maceration
were not included. Furthermore, fetuses and
infants displaying grossly pathological condi-
tions of the gastrointestinal tract were not
included. The morphology of the bowel wall
was normal in all cases at routine histopatho-
logical examination of haematoxylin and eosin
stained sections, although the mucosa showed
autolytic alterations in several subjects. Speci-
mens were also obtained from the rectum in
five cases at 13, 19, 19, 23, and 31 weeks of
gestation. As control tissue, specimens from
the distal ileum were collected at the time of
ileocaecal resection in three cases. The resec-
tions were performed because of colonic
cancer, villous adenoma, and perforated ap-
pendicitis, and the patients were 63,75, and 78
years old.
The study was approved by the ethics
committee of the Faculty of Medicine of Upp-
sala University.
TISSUE PREPARATION
The specimens were fixed in 10% formalin and
embedded in paraYn. Sections 5 µm thick were
cut, placed on poly-L-lysine coated slides, and
incubated at 37°C overnight. All sections were
deparaYnised in xylene and hydrated.
IMMUNOHISTOCHEMISTRY
Antigen retrieval by microwave oven heating was
performed for both antibodies. The sections
were boiled (750 W) in citric acid buVer (10
mM, pH 6.0) for five (NSE) or ten (c-kit) min-
utes. The sections were allowed to cool to room
temperature in the buVer and then rinsed in
phosphate buVered saline (PBS, pH 7.4). The
endogenous peroxidase activity was blocked in
2% hydrogen peroxide in distilled water for five
minutes and the sections were then rinsed in
PBS. Thereafter they were incubated with
normal swine serum (Dako, Glostrup, Den-
mark; dilution 1:5) for c-kit or normal goat
serum (Dako; dilution 1:5) for NSE in PBS for
20 minutes at room temperature. Incubation
with the primary antibody took place overnight
at 4°C (c-kit) or for one hour at room tempera-
ture (NSE). Table 2 provides a further descrip-
tion of the primary antibodies. After being
rinsed in PBS, the slides were incubated with a
biotinylated secondary antibody, goat anti-
mouse (Dako, product number E0433; dilution
1:200) for NSE or swine anti-rabbit (Dako,
product number E0353; dilution 1:300) for
c-kit, for 30 minutes at room temperature. The
sections were then incubated in Vectastain elite
ABC kit (Vector Laboratories, Burlingame,
California, USA) for 30 minutes and developed
in 3,3’-diaminobenzidine tetrahydrochloride
(Sigma, London, UK) for about six minutes.
Counterstaining with haematoxylin was per-
formed. Finally, the sections were dehydrated,
cleared in xylene and mounted in Pertex
(Histolab, Göteborg, Sweden).
Immunoreactivity was absent in negative
controls in which the primary antibody was
omitted. For c-kit, the immunostaining was
also abolished by a blocking peptide (1.0 µg/ml;
#sc-168p; Santa Cruz Biotechnology, Santa
Cruz, California, USA), incubated with c-kit
antibody (0.01 µg/ml) for two hours at room
temperature, before the specific immunohisto-
chemical procedure, according to instructions
provided by the suppliers.
The slides were analysed by light microscopy.
Table 1 Data on the subjects
Case
Gestational age
(weeks)
Age at death
(days)/death in utero
(iu) Diagnosis
1 13 iu Anencephaly
2 15 iu Anencephaly
3 15 iu Amnion band syndrome
4 16 iu Anencephaly
5 17 iu Fragile X syndrome
6 17 iu Unknown*
7 18 iu Ablatio placentae, chorioamnionitis
8 18 iu Dysplastic kidneys
9 20 iu Down’s syndrome
10 20 iu Unknown
11 21 1 Cerebral haemorrhage
12 21 1 Pulmonary haemorrhage, cerebral
haemorrhage
13 23 15 Aortic thrombosis, renal infarction,
cerebral haemorrhage
14 25 1 RDS, cerebral haemorrhage
15 25 2 Septicaemia, pulmonary haemorrhage
16 25 14 Pneumonia, septicaemia
17 26 17 Septicaemia, cerebral haemorrhage
18 31 iu Unknown
19 31 iu Meckel-Gruber syndrome
20 34 iu Unknown
21 35 iu Unknown
22 36 2 Polycystic kidney disease
23 36 iu Asphyxia in utero
24 41 iu Unknown
25 41 4 Pulmonary hypertension, bilateral
pneumothorax
*Unknown means that the cause of death was not established at autopsy.
RDS, respiratory distress syndrome.
Table 2 Sur vey of the antibodies used
Antibody Clone/product no Characteristics Source Dilution
c-kit # sc-168 Polyclonal, rabbit, anti-human, raised
against peptide corresponding to
amino acids 958-976 within carboxy
terminal domain of human c-kit
Santa Cruz Biotechnology 0.1 µg/ml
NSE BBS/NC/VI-H14 Monoclonal, mouse, anti-human Dako 1:100
NSE, neurone specific enolase.
66 Wester, Eriksson, Olsson, et al
Figure 1 (A) NSE immunohistochemistry showing immunoreactive ganglion cells in the myenteric plexus (arrow) and in
the inner and outer submucous plexuses (arrowheads) of the small bowel in an infant born at 26 weeks of gestation who
died at the age of 17 days. Nerve fibres associated with the ganglia and in the circular muscle layer are also stained.
Original magnification ×66. (B) NSE immunohistochemistry of the small bowel at 13 weeks of gestation displays the
myenteric plexus (arrow), whereas no immunoreactive ganglion cells were present in the submucosa. Original magnification
×40. (C) From 17–18 weeks of gestation, the ICCs form a continuous layer along the myenteric plexus of the small bowel.
This is illustrated in a case at 20 weeks of gestation using c-kit immunohistochemistry.Original magnification ×80. (D)
c-kit immunoreactive cells are elongated in shape and have an ovoid nucleus as in this case at 20 weeks of gestation. The
cell processes do not seem to penetrate into the ganglia. Original magnification ×200. (E) From 13 to 16 weeks of
gestation, the layer of c-kit immunoreactive ICCs associated with the myenteric plexus of the small bowel appears to be
disrupted. In the submucosa, isolated round c-kit immunoreactive cells, interpreted as mast cells, are seen (arrows). In this
case the submucous plexus had not yet developed at 13 weeks of gestation,as shown in (B). Original magnification ×80.
(F) From 17 weeks of gestation, the processes of the ICCs are often seen to penetrate into the circular muscle layer,whereas
isolated ICCs in this layer are only rarely observed. Original magnification ×50. Abbreviations: LM, longitudinal muscle
layer; CM, circular muscle layer; SM, submucosa.
Development of interstitial cells of Cajal 67
Results
NSE IMMUNOHISTOCHEMISTRY
NSE immunohistochemistry clearly showed
the myenteric and submucous plexuses. NSE
immunoreactivity was observed in the nerve
cell bodies and also in nerve fibres in the inter-
muscular space and submucosa (fig 1A). The
myenteric plexus was established in all cases.
On the other hand, the submucous plexus was
absent in the earliest case (13 weeks of
gestation, fig 1B). In several of the early
subjects submucous ganglia were identifiable,
butitwasdiYcult to distinguish an inner and
outer plexus and most of the immunoreactive
cells were observed close to the circular muscle
layer. In the older subjects, separate inner and
outer plexuses were established and clearly
visualised (fig 1A). We did not observe any
NSE immunoreactive cells with morphological
features characteristic of ICCs.
C-KIT IMMUNOHISTOCHEMISTRY
c-kit immunoreactivity was observed in all but
two cases, at gestational ages of 31 and 35
weeks. NSE immunoreactivity was normal in
these cases. There was no obvious reason for
the negative results, but post mortem changes
may have contributed as these fetuses were
mildly macerated. Both fetuses died in utero
and the cause of death could not be established
atpostmortem examination.Thec-kitimmuno-
reactive cells were situated in the intermuscular
space, and most of the c-kit positive cells were
thin and elongated and had an ovoid nucleus,
surrounding the myenteric ganglia and nerve
fascicles (figs 1C and D). In subjects older than
about 17–18 weeks of gestation, a continuous
layer of c-kit immunoreactive cells was usually
observed around the myenteric plexus (fig 1C).
On the other hand, at a gestational age of
13–16 weeks this layer of cells appeared to be
disrupted, and immunoreactive cells with a
round nucleus and short processes were found.
Furthermore, in these cases the immunoreac-
tivity was weak and few immunopositive cells
were seen (fig 1E). In almost all cases, round
immunoreactive cells were observed in the
submucosa without any association with the
submucous ganglia; these were interpreted as
mast cells, which are known to be c-kit immuno-
reactive (fig 1E).23 Although the c-kit positive
cells often extended into the smooth muscle
layers (fig 1F), isolated immunopositive cells
were rarely seen in the muscle layers. No
diVerences between the liveborn neonates and
the fetuses who died in utero could be
distinguished. In the rectum specimens, similar
findings were encountered. However, at 13
weeks of gestation no c-kit immunoreactivity
could be observed around the myenteric plexus
(fig 2A). At 19 weeks of gestation c-kit immu-
noreactive cells were rare in one of the cases,
whereas in the second case, the myenteric gan-
glia were outlined by c-kit immunoreactive
ICCs (fig 2B). The latter pattern was also
observed at 23 and 31 weeks of gestation. In the
adult small intestine, large numbers of ICCs
were found around the myenteric ganglia. The
number of ICCs in the circular muscle layer was
larger than in the fetal cases (fig 2C).
Discussion
The morphology and distribution of ICCs have
previously been diYcult to study, as standard
staining procedures for conventional light
microscopy do not disclose this cell type.
Figure 2 (A) At 13 weeks of gestation no c-kit
immunoreactivity can be seen in association with the
myenteric plexus of the rectum. Original magnification ×
50. (B) A layer of c-kit immunoreactive ICCs is seen
around the myenteric plexus of the rectum at 19 weeks of
gestation. Original magnification ×50. (C) In the adult
small bowel, c-kit immunoreactive ICCs surround the
myenteric ganglia. ICCs are also frequently found in the
circular muscle layer.Or iginal magnification ×25.
68 Wester, Eriksson, Olsson, et al
Consequently, electron microscopy has been
the method of choice for investigations of the
distribution of ICCs, and several ultrastruc-
tural studies have in fact been performed on
human small bowel using this technique.3–5
Ultrastructurally, ICCs associated with the
myenteric plexus are arranged in bundles
surrounding the ganglia and nerve fascicles,
with which they are always in close contact.
The processes of ICCs are long and usually do
not branch. Characteristically, the ICC proc-
esses contain a well developed smooth endo-
plasmic reticulum and a dense meshwork of
intermediate filaments. The perinuclear cyto-
plasm also contains many intermediate fila-
ments, but less abundant smooth endoplasmic
reticulum. The chromatin pattern of the ICC
nucleus is similar to that observed in smooth
muscle cells. However, in contrast with smooth
muscle cells, ICCs do not contain myosin
filaments.4
It has been shown in mouse,24 guinea pig,25
and human bowel15 that the morphology of the
c-kit immunoreactive cells associated with the
myenteric plexus correlates with the ultrastruc-
tural descriptions of ICCs. ICCs are interca-
lated between varicose nerve endings and
smooth muscle cells. Two types of varicosities
have been identified in the nerve endings. The
first may be cholinergic, whereas the second,
which is more commonly encountered in
association with the deep muscular plexus
ICCs than in those associated with the
myenteric plexus, is morphologically similar to
varicosities seen in inhibitory non-adrenergic
non-cholinergic neurones.9These findings in-
dicate that ICCs may play a role in inhibitory
neurotransmission, which was further investi-
gated by Publicover et al,26 who proposed that
these cells may amplify the inhibitory nitric
oxide signalling in canine colon. The demon-
stration of nitric oxide synthase, the endothelial
isoform, in ICCs indicates that this cell type is
able to synthesise nitric oxide.27
Maeda et al23 found that c-kit plays a major
role in the development of the pacemaker sys-
tem in the gut and proposed that ICCs were
involved. Administration of an antagonistic
anti-c-kit antibody to newborn mice resulted in
abnormal intestinal motility.23 Several other
investigators have presented results supporting
the role of ICCs in generating spontaneous
pacemaker activity. For instance, removal of
the submucosa from the circular muscle layer,
disrupting the submucosa-circular muscle in-
terface which is the location of one class of
ICCs, was found to abolish slow waves in the
canine colonic circular muscle.7Methylene
blue perfusion combined with illumination of
intestinal smooth muscle preparations resulted
in selective damage to the ICCs and loss of
slow wave activity.6Furthermore, exposure of
ICCs to rhodamine 123, which is a fluorescent
dye taken up by ICCs and enteric neurones but
not by smooth muscle cells, altered the electri-
cal rhythmicity of canine colonic circular mus-
cle preparations.28
The embryonic origin of ICCs has been
debated. Recently, however, Lecoin et al29
investigated the origin of the c-kit positive cells
in avian bowel. Quail neural crest was grafted
to chicken embryos at embryonic day 2. The
experiment showed that all enteric neurones
and glial cells were of quail origin, whereas all
c-kit immunoreactive cells originated from the
chick. The authors concluded that the c-kit
positive ICCs have a mesenchymal origin.
In an ultrastructural study of murine small
bowel, Faussone-Pellegrini30 reported that
ICCs were not detected in term fetuses, but
appeared during the first two weeks of life. On
the other hand, Torihashi et al24 detected c-kit
immunoreactivity in the murine small intestine
at embryonic day 12 (E12). At this stage the
c-kit positive cells were found at the outer sur-
face of the bowel wall just beneath the serosal
layer. These cells could not be characterised as
either ICCs or smooth muscle cells. The ICC
network associated with the myenteric plexus
developed between days E15 and E18. The
authors suggested that a population of cells
that were c-kit positive at day E12 diVerenti-
ated into smooth muscle cells, losing the c-kit
immunoreactivity, whereas others continued to
express c-kit immunoreactivity and diVerenti-
ated into ICCs associated with the myenteric
plexus. The c-kit immunoreactivity did not
co-localise with the neuronal marker c-ret,
indicating that ICCs are not of neuronal origin.
The ICCs associated with the deep muscular
plexus developed after birth. The development
of ICCs in the human fetal bowel remains
unclear, which was the reason for the present
study. Matsuda et al31 investigated c-kit expres-
sion in normal adult and fetal human tissue
and found c-kit immunoreactivity in enteric
nervous plexuses in adult tissue, but not in fetal
tissue. On the other hand, they observed c-kit
immunoreactive cells in the brain in both
tissues. Vanderwinden et al15 mentioned that
c-kit immunoreactive ICCs appeared in the
human foregut at gestational week 14 and in
the hindgut at 23 weeks of gestation but with-
out further description. Horie et al32 found c-kit
immunoreactivity in the smooth muscle layers
of human fetal oesophagus, small bowel, and
colon at 18 and 20 weeks of gestation.
We observed c-kit immunoreactivity in elon-
gated cells with an ovoid nucleus around the
myenteric ganglia. The typical localisation and
morphology of the c-kit immunoreactive cells
visualised in our study indicate that they are
ICCs. It has previously been shown that ICCs
associated with the myenteric plexus express
the c-kit tyrosine kinase receptor.13 Prosser et
al33 reported that some ICCs associated with
the myenteric plexus were NSE immunoreac-
tive in the rat intestine. However, these findings
were not corroborated in our study, as we did
not observe NSE immunoreactive cells with
morphological features or localisations charac-
teristic of ICCs. Our findings indicate that
ICCs express c-kit at least as early as at 13
weeks of gestation in the human fetal small
bowel, although the morphology and distribu-
tion of the ICCs at this stage suggest that they
are still immature. At a gestational age of 13–16
weeks, few dispersed ICCs were observed in
the intermuscular space and some of the indi-
vidual cells had short processes and a round
Development of interstitial cells of Cajal 69
nucleus. In the rectum specimens,no immuno-
reactivity was observed at this gestational age.
From 17–18 weeks of gestation a continuous
layer of c-kit immunoreactive ICCs was
observed around the myenteric ganglia and
nerve fascicles in the small bowel, and we
detected no further alterations from this
gestational age until full term. From about 19
weeks of gestation, c-kit immunoreactive ICCs
had developed in association with the rectal
myenteric ganglia. We did not observe any c-kit
immunoreactive cells in the region of the deep
muscular plexus in the fetal cases, although
ICCs have been observed at this site in
ultrastructural studies of adult human small
bowel.5One explanation for the absence of
c-kit immunoreactive ICCs in the deep muscu-
lar plexus in the fetal cases may be that ICCs of
this type develop after birth, as in the murine
small bowel.24 However, Isozaki et al18 only
found a few c-kit immunoreactive cells in the
deep muscular plexus in human adults, which
may indicate that it is mainly the ICCs associ-
ated with the myenteric plexus that are c-kit
positive in the human small bowel. We found
numerous c-kit positive ICCs in the circular
muscle layer in the adult cases, but it was diY-
cult to distinguish a separate deep muscular
plexus.
In the murine small bowel, it has been shown
that the onset of electrical rhythmicity corre-
lates with the development of ICCs. At E16
and E17 spontaneous electrical activity was
absent, whereas slow waves could be recorded
at E19 when the ICCs and the longitudinal
muscle layers had diVerentiated into two
distinct entities.24 In mice, the slow wave
frequency has been shown to correlate with
variations in the intraluminal pressure, which
results in propulsive peristalsis as shown by
radiological methods.34 McLain35 investigated
human fetal gastrointestinal motility by amni-
ography and could not show any emptying of
contrast from the stomach before about 30
weeks of gestation. However, from 30 weeks of
gestation, the rate of propagation of contrast
increased with increasing gestational age.
Bisset et al20 studied small intestinal pressures
in preterm infants from 28 weeks of gestation
until term. Before 31 weeks of gestation a dis-
organised activity pattern with low amplitude
was found. Between 31 and 34 weeks of gesta-
tion, clustered phasic activity appeared, and
from 34 to 37 weeks of gestation prolonged
phasic activity was observed propagating in
aboral direction. At term a well defined fasting
motor activity with migrating motor complexes
was discernible. However, Berseth22 showed
that preterm infants respond appropriately to
feeding administered as infusion, by develop-
ing persistent activity.The responses to feeding
among prematures did not diVer from that of
term infants. The slow wave frequency which
has been associated with ICC function in-
creases with gestational age from 10.5 cycles
per minute at 28 weeks of gestation to 12.5
cycles per minute at term.20
It is diYcult to investigate normal human
fetal development. Ethical aspects of collecting
and using material must be considered. Fur-
thermore, the great variation seen in human
material as opposed to animal models may
make interpretation diYcult. Our material
comprised specimens obtained at autopsy after
induced termination or spontaneous abortion
and specimens from liveborn babies who died
within the first weeks of life. A wide range of
malformations and disorders were encoun-
tered, but we could not distinguish any abnor-
malities in the expression of NSE or c-kit
immunoreactivity which could be related to
these conditions. However, the absence of c-kit
immunoreactivity in two of our cases may well
be explained by post mortem changes or events
occurring before death. It has previously been
pointed out that events before death, such as
hypoxaemia, may influence the staining prop-
erties of enteric ganglia in studies using silver
impregnation36 or NADPH diaphorase
histochemistry.37 The eVects of autolysis are
always a concern when autopsy material is
used, but it has been reported that many anti-
gens are surprisingly resistant to post mortem
changes.38
In conclusion, ICCs associated with the
myenteric plexus in the human fetal small
bowel express the c-kit tyrosine kinase receptor
at least from 13 weeks of gestation. From about
17–18 weeks of gestation the c-kit immuno-
reactive ICCs form a layer of cells surrounding
the myenteric ganglia and nerve fascicles.
However, at 13–16 weeks this cell layer
appeared to be disrupted, which may indicate
that ICCs are still in a phase of development at
that stage.
This work was supported by the HRH Crown Princess Louisa’s
Association for Child Medical Care and the Ollie and Elof Eric-
sson Foundation for Scientific Research. We are also grateful to
Gunilla Tibbling and Frank Bittkowski for their photographic
assistance and to Bengt Sandstedt who contributed specimens.
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