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Heme oxygenase carbon monoxide and interstitial cells of Cajal

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Embryological Origin of Interstitial Cells of Cajal
Department of Anatomy and Cell Biology, University of Melbourne, Parkville, 3052, VIC, Australia
Kit; neural crest; mesenchyme; developmental origin
Until recently, the embryological origin of the interstitial cells of Cajal (ICC) within
the intestine was unclear. An origin from the neural crest or from the mesenchyme was considered
possible because ICC possess some characteristics in common with neural crest-derived cells, and
some characteristics in common with cells derived from the mesenchyme. Experiments in both
mammalian and avian species, in which segments of embryonic gut were removed prior to the
arrival of neural crest cells and grown in organ culture, have now shown that ICC do not arise from
the neural crest. It appears that ICC and smooth muscle cells arise from common mesenchymal
precursor cells. From mid-embryonic stages, ICC precursors express Kit, which is a receptor
tyrosine kinase. Both ICC and many smooth muscle cell precursors initially express Kit, and then
the cells destined to become smooth muscle cells down-regulate Kit and up-regulate the synthesis of
myofilament proteins, whereas cells destined to differentiate into ICC maintain their expression of
Kit. Adult mice with mutations that block the activity of Kit have disrupted arrays of ICC, whereas
normal ICC are present until shortly after birth in such mice. It, therefore, appears that the Kit
signalling pathway in not necessary for the embryonic development of ICC, but rather the post-natal
proliferation of ICC. Microsc. Res. Tech. 47:303–308, 1999. r 1999 Wiley-Liss, Inc.
The gastrointestinal tract is formed from cells derived from all three embryonic germ layers. The endoderm gives rise to the epithelial cells lining the lumen
and the glands opening into the lumen, the mesoderm
gives rise to blood and lymphatic vessels, smooth
muscle cells, and connective tissue, and the ectoderm is
the source of neural crest cells that migrate into the
gastrointestinal tract and give rise to enteric neurons
and glial cells. Although the interstitial cells of Cajal
(ICC) were first described toward the end of the last
century, until recently the embryological origin of ICC
was uncertain. Because ICC have some characteristics
in common with cells of neural crest origin (neurons
and glial cells) and some characteristics in common
with cells of mesenchymal origin (fibroblasts and smooth
muscle cells; see below), it was unclear whether ICC
arise from the neural crest or from the mesenchyme.
Finally, in 1996, studies using chickens and quail
(Lecoin et al., 1996) and mice (Young et al., 1996)
demonstrated that ICC do not arise from the neural
crest, and it was proposed that they arise from the
mesenchyme. More recent studies in mice have shown
that ICC appear to have a common developmental
origin with smooth muscle cells (Klüppel et al., 1998;
Torihashi et al., 1997).
Although cells with similar characteristics do not
necessarily have similar developmental origins, similarities between ICC and neurons, neuronal support cells,
fibroblasts and smooth muscle cells had raised the
possibilities that ICC could be either of neural crest or
mesenchymal origin. Cajal thought that ICC were
neural in nature because, like neurons, they could be
stained with methylene blue or with silver chromate,
and they also formed intimate relationships with nerves
(see Christensen, 1992). Early ultrastructural studies
suggested that ICC could be either specialised neuronal
support cells, fibroblasts, or smooth muscle cells (see
Thuneberg, 1982, 1989). More recent studies have
shown that ICC in different locations differ in their
appearance and the expression of particular antigens
(Christensen, 1992; Thuneberg, 1989; Torihashi et al.,
1994). However, ICC in all locations can be distinguished from other cell types by their ultrastructure
and the expression of cell-specific markers (Christensen, 1992; Thuneberg, 1989;). There have been no
reports of ICC in any location expressing glial fibrillary
acidic protein (GFAP) or S100, which are selective
markers of glial and Schwann cells, respectively, or
pan-neuronal markers, such as neuron-specific enolase
or PGP9.5 (protein gene product 9.5). Although ICC at
the level of the myenteric plexus show some similarities
to fibroblasts, they can be clearly distinguished from
fibroblasts using ultrastructural criteria, such as inconspicuous Golgi apparatus, incomplete or no basal
lamina, and numerous surface caveolae (Thuneberg,
1989). ICC associated with the inner margin of the
circular muscle layer show some features in common
with smooth muscle cells, such as smooth muscle actinand myosin light chain-immunoreactivity, but they
differ from smooth muscle cells in that contractile
filaments are less abundant and desmin is not ex-
Contract grant sponsor: NHMRC (Australia).
*Correspondence to: Dr. H.M. Young, Department of Anatomy and Cell Biology,
University of Melbourne, Parkville, 3052, VIC, Australia.
Received 20 December 1999; accepted in revised form 29 April 1999
pressed at detectable levels (Torihashi et al., 1993,
1994). Hence, ICC represent a cell type clearly different
from neurons, glia, fibroblasts, and smooth muscle
cells, and whose developmental origin cannot be assumed from their morphological and histological characteristics.
Like studies of many aspects of mature ICC, studies
of the embryological origin of ICC were hampered by a
lack of specific, reliable markers of ICC. It was only
following the discovery that ICC can be specifically
localised within the gastrointestinal tract using probes
or antibodies to the receptor tyrosine kinase, Kit (Huizinga et al., 1995; Maeda et al., 1992; Torihashi et al.,
1995; Ward et al., 1994), that studies were performed to
examine the developmental origin of ICC. There is now
strong evidence in both avian and mammalian species,
and using a variety of experimental approaches, that
ICC do not arise from the neural crest.
Enteric neurons and glial cells arise from the neural
crest (Yntema and Hammond, 1954). The vast majority
of enteric neurons in the stomach and intestine arise
from the ‘‘vagal’’ level (somites 1–7) neural crest cells,
which enter the foregut and migrate rostrocaudally (Le
Douarin and Teillet, 1973, 1974; Yntema and Hammond, 1954). In mice and birds, there is an interval of
3–4 days between the time that the neural crest cells
first enter the foregut and when they reach the most
caudal part of the hindgut (Allan and Newgreen, 1980;
Burns and Le Douarin, 1998; Kapur et al., 1992; Young
et al., 1998a). In birds, cells from sacral-level neural
crest (caudal to somite 28) also give rise to some enteric
neurons in the hindgut, but they do not enter the
hindgut until approximately the same time that vagallevel neural crest cells reach the hindgut (Burns and Le
Douarin, 1998). In mice, it is unclear whether sacrallevel neural crest cells give rise to some enteric neurons
in the hindgut. However, if sacral-level neural crest
cells do populate the hindgut, it appears that they
either do not enter the hindgut, or do not differentiate
into enteric neurons, until after the vagal neural crest
cells have reached the hindgut (Kapur et al., 1992;
Young et al., 1998a).
Lecoin et al. (1996) were the first to show that ICC in
the avian intestine do not arise from the neural crest.
They performed two types of experiments. In the first
set of experiments, they exploited the fact the nuclei of
quail cells can be distinguished from those of chicken
cells (Le Douarin, 1973); quail-chick chimeras were
constructed in which the vagal-level neural tubes of
chick embryos were replaced by vagal-level neural
tubes from equivalent stage quail embryos, and the
chimeras were left to grow for about a week before the
gut was sectioned and processed to determine whether
any of the quail cells within the intestine were positive
to a c-kit nucleic acid probe. Although there were
numerous c-kit-positive cells (ICC) within the gut surrounding the myenteric ganglia of the chimeras, none of
the quail cells within the myenteric plexus (which were
all presumably enteric neurons and glial cells) expressed c-kit. In the second series of experiments,
Lecoin et al. (1996) utilised the knowledge that neural
crest–derived cells do not reach the hindgut until 2–3
days after they colonise the fore- and mid-guts (see
above). While they are migrating through the gut
mesenchyme, neural crest–derived cells do not express
a neuronal or glial phenotype, and thus to determine if
neuronal or glial cell precursors are present in a
particular segment of embryonic gut, it must be removed and grown in isolation for several days before
being analysed for the presence of neurons or glial cells.
In both chick (Lecoin et al., 1996) and mouse (Torihashi
et al., 1997) embryos, ICC precursors do not express
c-kit until after neural crest-derived cells have almost
colonised the entire gut, and thus the chronological
appearance of c-kit-positive cells cannot be used to
ascertain whether ICC arise from the neural crest.
Lecoin and her colleagues removed segments of hindgut
from embryonic day 3.5 (E3.5) chick embryos prior to
the arrival of neural crest-derived cells and grew them
on the chorioallantoic membrane (CAM) of host embryonic chicks for 7 days, before the explants were processed for in situ hybridisation or electron microscopy.
Confirming previous studies (Allan and Newgreen,
1980; Smith et al., 1977), no enteric neurons were found
within the hindgut explants grown on the CAM. However, c-kit-positive cells, and cells with the ultrastructural characteristics of ICC were observed in the explants lacking neural crest-derived cells, thus
confirming the results from the chick-quail chimeras,
that ICC do not arise from the neural crest.
Shortly afterwards, it was also shown that ICC in the
mouse gut do not arise from the neural crest (Young et
al., 1996). This study involved the removal of segments
of embryonic mouse gut either before or after the
arrival of neural crest-derived cells; the explants were
grown under the kidney capsule of adult host mice for
3–6 weeks before being examined for the presence of
neurons and Kit-immunoreactive ICC. These experiments were, therefore, very similar to the experiments
of Lecoin et al. (1996) described above, in which segments of embryonic chick gut were removed and grown
on the CAM. As in chick embryos, the presence of ICC in
the explants of embryonic mouse gut grown under the
kidney capsule was independent of the presence of
enteric neurons, and Kit-immunoreactive ICC were
present in all explants, regardless of the developmental
stage and region from which they were removed. In
contrast, enteric neurons were only present in explants
containing neural crest–derived cells at the time of
removal (Kapur et al., 1992 Nishijima et al., 1990).
Since ICC develop in explants of embryonic chicken or
mouse gut lacking neural crest–derived cells, it was
concluded that ICC arise from the local mesenchyme.
Recently a technique has been devised in which
segments of embryonic mouse intestine can be grown in
organ culture under conditions in which it retains its
3-dimensional shape, and growth and differentiation of
the different cell types proceed (Fig. 1A–C; Hearn et al.,
1999; Young et al., 1998a). Consistent with the results
obtained when segments of embryonic chicken hindgut
are grown on the CAM of host chicken embryos (Lecoin
et al., 1996) or when segments of embryonic mouse
intestine are grown under the kidney capsule of host
adult mice (Young et al., 1996), when segments of
hindgut from embryonic mouse hindgut are removed
prior to the arrival of neural crest cells and grown in
organ culture for 6 days, Kit-immunoreactive ICC are
present in the explants (Fig. 1D,E; Hearn et al., 1999).
There are a number of spontaneous mouse mutants,
and also mice that have been generated by genetargetting techniques, which lack neural crest-derived
cells in parts of the gastrointestinal tract (see Gershon,
1997, 1998 for reviews). The presence of ICC has been
examined in the intestine of mice lacking Ret and in
ls/ls mice (Wu et al., 1996). Ret is a receptor tyrosine
kinase, and is the receptor for glial-derived neurotrophic factor (GDNF), and in ret-/- mice there are no
neural crest-derived cells in the gastrointestinal tract
caudal to the stomach (Schuchardt et al., 1994). In ls/ls
mice, the gene encoding endothelin 3 is disrupted and
there are no neural crest–derived cells in the caudal
part of the large intestine (Baynash et al., 1994).
However, Kit-immunoreactive ICC are present in both
the intestine of embryonic ret-/- mice and in the large
intestine of ls/ls mice (Wu et al., 1996), again indicating
that ICC do not arise from the neural crest.
Additional evidence corroborating a non-neural crest
origin of ICC is that ICC do not express any of the
currently known markers of neural crest-derived cells.
Neural crest-derived cells within the developing gut
express a number of different markers including Ret
(Durbec et al., 1996; Pachnis et al., 1993, 1998; Tsuzuki
et al., 1995; Watanabe et al., 1997), the low affinity
neurotrophin receptor, p75 (Chalazonitis et al., 1994;
Lo and Anderson, 1995), and the transcription factor,
Phox2b (Pattyn et al., 1997; Young et al., 1998a).
However, ICC do not express Ret (Torihashi et al.,
1997), p75 (Figs. 1F, F’), or Phox2b (Young et al., 1998a).
Faussone-Pellegrini (1984, 1985) examined the ultrastructural histogenesis of ICC at the level of the
myenteric plexus and the deep muscular plexus in the
mouse small intestine. She identified ICC precursor
cells in early post-natal mice that were closely associated with nerve fibres of the myenteric plexus, but she
was unable to determine whether the precursors cells
were of neural crest or of mesenchymal origin. The
results from two more recent studies (Klüppel et al.,
1998; Torihashi et al., 1997) suggest that ICC arise
from mesenchymal cells and have common precursors
with smooth muscle cells.
Torihashi et al. (1997) looked at the development of
immunoreactivity to Kit, smooth muscle markers (actin, myosin, desmin) and a marker of neural crestderived cells (Ret) in the small intestine of embryonic
and neonatal mice. They found that Kit-immunoreactive cells were first detected in the outer layers of the
gut of E12.5 mice, and these cells were undifferentiated
in appearance and lacked the morphological feature of
both ICC and muscle cells. Kit-positive cells were
peripheral to, and did not overlap with, the developing,
Ret-immunoreactive myenteric ganglion cells. At E15,
cells in the putative circular muscle layer, which was
internal to the myenteric plexus, started to show actinand myosin-immunoreactivity, whereas cells in the
location of the future longitudinal muscle layer were
Kit-positive, but actin- and myosin-negative. By late
embryonic stages, it appeared that a sub-population of
Kit-positive cells began to develop into smooth muscle
cells (and showed immunoreactivity to the myofilament
proteins), and subsequently no longer showed detectable levels of Kit immunoreactivity. The authors speculated that ICCs and longitudinal smooth muscle cells
develop from common, Kit-positive precursor cells in
the peripheral layers of the gut, and that those cells in
which the Kit receptor is activated by contact with stem
cell factor-expressing neural cells (see below) will differentiate into ICCs, whereas those cells without direct
appositions with neural cells will differentiate into
longitudinal smooth muscle cells and down-regulate
the expression of Kit.
The study by Klüppel et al. (1998) also suggests
strongly that ICCs and smooth muscle cells arise from
common precursor cells. In this study, the expression of
mRNA for c-kit and smooth muscle myosin heavy chain
(SMMHC) in the embryonic and post-natal mouse gut
was examined. Unlike Torihashi et al. (1997), they
found co-expression of c-kit and SMMHC by cells of the
circular muscle layer and the future longitudinal muscle
layer, and then c-kit expression was lost first from
circular smooth muscle cells, and then subsequently
also from longitudinal smooth muscle cells, whereas
cells destined to become ICCs retained their expression
of c-kit, but down-regulated expression of SMMHC.
Thus, although the results of the studies by Torihashi et
al. (1997) and Klüppel et al. (1998) differ somewhat,
probably due to technical differences, the main conclusions are the same, that is, ICCs have a common
precursor with smooth muscle cells.
In mice, all ICC appear to express c-kit. W/Wv mice,
which have a mutation that reduces but does not
abolish the tyrosine kinase activity of Kit, lack particular sub-populations of ICC (Huizinga et al., 1995; Ward
et al., 1994). Moreover, when the normal action of the
Kit receptor is blocked with neutralising antibodies
during a critical post-natal period, there is a dramatic
reduction in the number of myenteric ICC (Maeda et
al., 1992; Torihashi et al., 1995). The natural ligand for
Kit is stem cell factor (SCF, also known as steel factor,
Kit ligand, or mast cell growth factor), and mice with
mutations affecting the gene encoding SCF display
many phenotypic changes similar to W mutants (Ward
et al., 1995). It was, therefore, suggested that the
SCF-Kit signalling pathway is critical for the development and/or survival of ICC (Sanders, 1996; Torihashi
et al., 1995; Ward et al., 1995).
Kit expression can be detected in cells in the outer
mesenchyme of the gut of mid-stage embryonic mice
(Bernex et al., 1996; Klüppel et al., 1998; Torihashi et
al., 1997). However, electrophysiological experiments
in the small intestine of late embryonic mice have
shown that slow waves, which are mediated by myenteric ICC (Huizinga et al., 1995; Ward et al., 1994),
cannot be detected until about one day before birth
(Torihashi et al., 1997), and using ultrastructural criteria, ICC at the level of the myenteric plexus cannot be
identified until the first post-natal week (FaussonePellegrini, 1985). Hence, the Kit-positive cells observed
during the embryonic period are ICC precursors, and
Fig. 1.
cells functionally and morphologically recognisable as
myenteric ICC do not develop until around birth.
Similarly, melanocyte precursor cells express Kit before
they begin to differentiate into melanocytes (Bernex et
al., 1996). The differentiation of ICC at the inner
margin of the circular muscle (whose function is still
uncertain) lags behind the myenteric ICC by several
days (Torihashi et al., 1997).
Since mice with mutations in the genes encoding Kit
or its ligand, SCF, lack particular sub-populations of
ICC (see above), it was proposed that the SCF-Kit
signalling pathway is necessary for the development of
ICC (Sanders, 1996; Torihashi et al., 1995). However,
there is now evidence from studies of WlacZ/WlacZ mice
(Bernex et al., 1996) and Wbd/Wbd mice (Klüppel et al.,
1998) that suggests that Kit is not necessary for the
development of ICC precursors, but rather for the
post-natal survival and proliferation of ICC. WlacZ/
WlacZ mice have been genetically engineered to express the lacZ reporter gene under the control of c-kit,
so the expression of lacZ reflects normal expression of
c-kit (Bernex et al., 1996). Mice homozygous for the
mutation (WlacZ/WlacZ mice) do not express c-kit
mRNA or Kit protein and die shortly after birth.
However, ICC are present in the gut of newborn WlacZ/
WlacZ mice with a similar distribution to that observed
in WlacZ/⫹ newborn mice, indicating that the SCF-Kit
signalling pathway is not necessary for the survival of
ICC precursors during embryonic development. Wbd/
Wbd mice have a regulatory W mutation, which affects
c-kit expression (Klüppel et al., 1997). There is no
expression of c-kit within the mesenchyme of the
intestine of embryonic Wbd/Wbd mice, and adult Wbd/
Wbd mice possess only sparse ICC (Klüppel et al.,
1998). Surprisingly, however, post-natal day-5 Wbd/
Wbd mice do possess a normal network of ICC. Unfortunately, the presence of slow waves has not been examined in these early post-natal Wbd/Wbd mice. It was
Fig. 1. A: Explant of midgut from an E11.5 mouse after growth in
catenary organ culture for 7 days. The explant was suspended between
the 2 sides of a ‘V’ cut into a small piece of filter paper, and during the
time in culture the explant increased 2.5⫻ in length, underwent gross
morphological changes including coiling, and the cells continued to
differentiate and proliferate (see Hearn et al., 1999). Scale bar ⫽ 500
mm. B,C: After growth in organ culture for several days, PGP9.5immunoreactive neurons (arrows) can be observed in segments of
midgut from E11.5 mice (B), indicating that neural crest cells were
present in the midgut at the time of explantation. However, neurons
cannot be detected in explants of E11.5 hindgut (C), even after growth
in organ culture for up to 2 weeks. Thus, neural crest–derived cells are
not present in the hindgut of E11.5 mice (Young et al., 1998a; Hearn et
al., 1999). Scale bars (B, C) ⫽ 20 mm. D: Although Kit-immunoreactive
cells cannot be detected in the hindgut of E11.5 mice, following growth
in organ culture for 3–10 days, Kit-immunoreactive cells (arrows) are
found in the cultured explants. Since there are no neural crest–derived
cells in the hindgut of E11.5 mice, the Kit-positive cells cannot arise
from the neural crest. The Kit-positive cells present in the organcultured explants of E11.5 gut (D) are similar in appearance to the
Kit-positive cells observed in the gut of control E15.5 mice (E) (see also
Hearn et al., 1999). Scale bars (D, E) ⫽ 20 mm. F, F8: Paired
micrographs of a wholemount preparation of circular muscle from an
adult mouse that had been processed for both p75- and Kitimmunoreactivity. Within the circular muscle, Kit-immunoreactive
cells (F8) are ICC, whereas the p75 antibody labels glial cells (F,
asterisk), which are not labelled by the Kit antiserum. The asterisk in
F8 indicates the location of the p75-positive glial cell. The processes of
the glial cells and ICC often run in the same bundles. Scale bar ⫽
20 mm.
calculated that, unlike wild-type mice in which there is
an 11-fold increase in the number of ICC after postnatal day 5, there is no increase in the number of ICC in
post-natal Wbd/Wbd mice. Thus, it appears that only
the post-natal proliferation of ICC is dependent on the
SCF-Kit signalling pathway, and the Kit-positive ICC
precursor cells present in embryonic mice do not require this pathway for survival, or to differentiate along
the ICC lineage (Bernex et al., 1996: Klüppel et al.,
The ligand for Kit is SCF (see above). To date, there
are no antisera available that specifically localise SCF
in mice. However, in mice that have been genetically
engineered to express lacZ under the regulation of the
cell-specific promotor for SCF, enteric neurons appear
to be the sole source of SCF (Torihashi et al., 1996;
Young et al., 1998b). If enteric neurons are the sole
source of SCF, and the SCF-Kit signalling pathway is
essential for ICC proliferation, then ICC should not
develop normally in segments of intestine lacking enteric neurons. However, apparently normal numbers of
Kit-positive cells, which have the morphological characteristics of ICC, do develop in segments of both chicken
and mouse intestine that lack enteric neurons (Lecoin
et al., 1996; Wu et al., 1996; Young et al., 1996; see
above), suggesting that enteric neurons may not be the
only source of SCF. Interestingly, however, aganglionic
segments of colon of humans with Hirschsprung’s disease have reduced the numbers of ICC compared to the
normal colon (Vanderwinden et al., 1996; Yamataka et
al., 1995). Although the reduction in the number of ICC
in the aganglionic segments of Hirschsprung’s patients
is not necessarily a direct result of an absence of enteric
neurons, there is also a high incidence of Hirschsprung’s
disease in humans with the pigment disorder, piebaldism (see Kapur, 1993). Since piebaldism results from
the mutations in the c-kit gene (Fleishman, 1992;
Spritz et al., 1992), it appears that sometimes there can
be a correlation between abnormalities in c-kit expression and neural crest derivatives.
ICC do not arise from the neural crest, but from
precursor cells in the outer mesenchyme of the embryonic gut that express the receptor tyrosine kinase, Kit.
However, some of the Kit-positive mesenchymal cells
are destined to become smooth muscle cells, and such
cells down-regulate the expression of Kit and upregulate the expression of myofilament proteins. ICC
maintain their expression of Kit, even in mature animals. The factors responsible for the decision to become
an ICC or a smooth muscle cell are unknown. The
SCF-Kit signalling pathway does not appear to be
essential for the initial development of ICC precursors
or for cells to differentiate along the ICC lineage, but is
essential for the post-natal proliferation of ICC.
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monoxide, interstitial, cajal, oxygenase, heme, carbon, cells
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