Interstitial Cells of Cajal
SEAN M. WARD AND KENTON M. SANDERS
University of Nevada School of Medicine
electrical slow waves Phasic electrical activity under-
lying generation of spontaneous mechanical
activity.
gastrointestinal stromal tumors The most common
mesenchymal tumors in the gastrointestinal tract.
interstitial cells of Cajal Responsible for the generation of
slow-wave activity and serve as intermediaries in enteric
motor neurotransmission.
Kit Type III tyrosine kinase receptor expressed on popula-
tions of interstitial cells of Cajal throughout the
gastrointestinal tract.
omental mesenchymal tumors Thought to represent
gastrointestinal stromal tumors of the omentum.
The interstitial cells of Cajal are specialized cells distrib-
uted in speci®c locations within the tunica muscularis of
the gastrointestinal tract; these cells serve as electrical
pacemakers, as active propagation pathways for slow
waves, and as mediators of enteric neurotransmission.
Mutations in these cells are also thought to be responsible
for the generation of tumors within the tunica muscularis
and omentum of the gastrointestinal tract.
INTRODUCTION
Until recently, evidence supporting a functional role
of the interstitial cells of Cajal (ICCs) in pacemaking
and neurotransmission within the gastrointestinal tract
was indirect. Electron microscopy has now revealed
ICCs within the tunica muscularis in sites where elec-
trical slow waves are thought to originate. Morpholog-
ical studies have also revealed close relationships
between ICCs and varicose nerve ®bers, and immuno-
histochemical techniques have shown that ICCs possess
receptors for several neurotransmitters and display
responses to neurotransmitters. Using a variety of spe-
ci®c molecular markers and mutant animal models,
more direct physiological evidence now supports the
hypothesis that speci®c populations of these cells are
responsible for the generation of electrical slow waves;
discrete populations of ICCs also act as intermediates
between enteric nerves and smooth muscle cells in
motor neurotransmission within the gastrointestinal
(GI) tract.
Encyclopedia of Gastroenterology
LOSS OF ICCs, SLOW WAVES, AND
NEUROTRANSMISSION IN KIT
MUTANT MICE
Several classes of ICCs of the mouse and other species
express a type III tyrosine kinase receptor (Kit). Acti-
vation of Kit by its ligand, stem cell factor, or ``steel''
factor, is important in the development of ICCs because
blockade of Kit with neutralizing antibodies or muta-
tions in c-kit or steel impair the development of ICCs.
Loss of ICCs in the myenteric plexus region (ICC-MY)
of the small intestine, for example, causes abnormal
electrical activity that includes total loss of electrical
slow-wave activity. In the white spotting mutation
(W/WV), ICCs within the circular and longitudinal
muscle layers (ICC-IM) of the stomach and lower
esophageal and pyloric sphincters fail to develop. Cho-
linergic excitatory and nitrergic inhibitory motor neu-
rotransmissions are compromised in tissues of these
animals, providing functional evidence for the idea,
originally proposed by Cajal, that ICCs mediate enteric
neurotransmission.
ICCs ARE DISRUPTED IN PATIENTS
WITH GI MOTILITY DISORDERS
The discovery that ICCs express Kit has allowed simple
morphological identi®cation of these cells with light
microscopy. Labeling of Kit receptors or c-kit mRNA
has provided an ef®cient means of identifying ICCs
throughout the GI tracts of several species, including
humans. Kit labeling combined with confocal laser
imaging techniques has improved our understanding
of the structure and distribution of ICC networks (see
Fig. 1) and has enhanced our perception of the anato-
mical relationships between ICCs and with other cell
types, such as enteric neurons and smooth muscle
cells. Kit labeling of ICCs has allowed pathologists to
determine the viability of ICCs in a variety of GI motility
disorders. ICC networks are disrupted in several
motility disorders, including achalasia, hypertrophic
pyloric stenosis, chronic idiopathic intestinal pseudo-
obstruction, ulcerative colitis, Crohn's disease, and
439 Copyright 2004, Elsevier (USA). All rights reserved.