Interstitial cells of Cajal in the human fetal small bowel as shown by c-kit immunohistochemistry

BackgroundInterstitial cells of Cajal (ICCs) express the tyrosine kinase receptor c-kit, which is required for their development 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 temporal development of ICCs in the human gut remains unknown.AimTo investigate ICCs in the human fetal small bowel using c-kit immunohistochemistry.SubjectsSmall 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.MethodsImmunohistochemical analysis was performed on material fixed in formalin and embedded in paraffin. The specimens were exposed to antibodies raised against c-kit (an ICC marker) and neurone specific enolase (a general neuronal marker). The ABC complex method was used to visualise binding of antibodies to the corresponding antigens.Resultsc-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.ConclusionsICCs are c-kit immunoreactive at least from a gestational age of 13 weeks in the human fetal small intestine. From 17–18 weeks of gestation until birth, they form a continuous layer around the myenteric ganglia.

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Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants

AJP Cell Physiology ◽

10.1152/ajpcell.1995.269.6.c1577 ◽

1995 ◽

Vol 269 (6) ◽

pp. C1577-C1585 ◽

Cited By ~ 187

Author(s):

S. M. Ward ◽

A. J. Burns ◽

S. Torihashi ◽

S. C. Harney ◽

K. M. Sanders

Keyword(s):

Small Intestine ◽

Gastrointestinal Tract ◽

Tyrosine Kinase ◽

Myenteric Plexus ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Slow Waves ◽

Tyrosine Kinase Receptor ◽

Steel Factor ◽

Cells Of Cajal

Electrical rhythmicity in the gastrointestinal tract may originate in interstitial cells of Cajal (IC). Development of IC in the small intestine is linked to signaling via the tyrosine kinase receptor, c-kit. IC express c-kit protein, and disruption of c-kit signaling causes breakdown in IC networks and loss of slow waves. We tested whether mutations in steel factor, the ligand for c-kit, affect the development of IC networks. IC were found in the region of the myenteric plexus (IC-MY) in mice with steel mutations (i.e., Sl/Sld) at 5-10 days postpartum, but these cells formed an abnormal network. IC-MY were not observed in adult Sl/Sld animals. IC in the deep muscular plexus (IC-DMP) appeared normal in Sl/Sld animals. Electrical slow waves, normally present in the small intestine, were absent in Sl/Sld animals (10-30 days postpartum). Neural inputs were intact in Sl/Sld animals. Steel factor appears important for the development of certain classes of IC, and IC-MY appear to be involved in the generation of electrical rhythmicity in the small intestine.

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A Close Relationship Between Networks of Interstitial Cells of Cajal and Gastrointestinal Transit In Vivo

Frontiers in Pharmacology ◽

10.3389/fphar.2020.587453 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Kazuhisa Kishi ◽

Moe Kamizaki ◽

Noriyuki Kaji ◽

Satoshi Iino ◽

Masatoshi Hori

Keyword(s):

Myenteric Plexus ◽

Immunohistochemical Staining ◽

Interstitial Cells Of Cajal ◽

Gastrointestinal Transit ◽

Interstitial Cells ◽

Pacemaker Activity ◽

Specific Marker ◽

Gi Transit ◽

Cells Of Cajal

The interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are located in the same area as the myenteric plexus. ICC-MP networks are linked to the generation of electrical pacemaker activity that causes spontaneous gastrointestinal (GI) contractions; however, its role in GI transit is not clear. The aim of this study was to comprehensively investigate the effect of ICC-MP disruption on GI transit in vivo using W/Wv mice, partially ICC-deficient model mice. In this study, we measured GI transit using a 13C-octanoic acid breath test, an orally administered dye and a bead expulsion assay. ICC were detected by immunohistochemical staining for c-Kit, a specific marker for ICC. Interestingly, we found that gastric emptying in W/Wv mice was normal. We also found that the ability of small intestinal and colonic transit was significantly reduced in W/Wv mice. Immunohistochemical staining using whole-mount muscularis samples revealed that c-Kit-positive ICC-MP networks were formed in wild-type mice. In contrast, ICC-MP networks in W/Wv mice were maintained only in the gastric antrum and were significantly reduced in the ileum and colon. No significant changes were observed in the nerve structures of the myenteric plexus in W/Wv mice. These findings suggest that ICC-MP contribute to GI transit as a powerful driving function in vivo.

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Effects of Lubiprostone on Pacemaker Activity of Interstitial Cells of Cajal from the Mouse Colon

Korean Journal of Physiology and Pharmacology ◽

10.4196/kjpp.2014.18.4.341 ◽

2014 ◽

Vol 18 (4) ◽

pp. 341 ◽

Cited By ~ 5

Author(s):

Han-Yi Jiao ◽

Dong Hyun Kim ◽

Jung Suk Ki ◽

Kwon Ho Ryu ◽

Seok Choi ◽

...

Keyword(s):

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Pacemaker Activity ◽

Mouse Colon ◽

Cells Of Cajal

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Effects of ATP on Pacemaker Activity of Interstitial Cells of Cajal from the Mouse Small Intestine

Chonnam Medical Journal ◽

10.4068/cmj.2018.54.1.63 ◽

2018 ◽

Vol 54 (1) ◽

pp. 63

Author(s):

Il Koo Park ◽

Jin Ho Kim ◽

Chan Guk Park ◽

Man Yoo Kim ◽

Shankar Prasad Parajuli ◽

...

Keyword(s):

Small Intestine ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Pacemaker Activity ◽

Mouse Small Intestine ◽

Cells Of Cajal

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Action potential generation in the small intestine of W mutant mice that lack interstitial cells of Cajal

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1996.271.3.g387 ◽

1996 ◽

Vol 271 (3) ◽

pp. G387-G399 ◽

Cited By ~ 21

Author(s):

J. Malysz ◽

L. Thuneberg ◽

H. B. Mikkelsen ◽

J. D. Huizinga

Keyword(s):

Small Intestine ◽

Action Potentials ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

K Channel ◽

Pacemaker Activity ◽

Channel Blockade ◽

Auerbach’S Plexus ◽

Cells Of Cajal ◽

Auerbach's Plexus

The small intestine of W/Wv mice lacks both the network of interstitial cells of Cajal (ICC), associated with Auerbach's plexus, and pacemaker activity, i.e., it does not generate slow-wave-type action potentials. The W/Wv muscle preparations showed a wide variety of electrical activities, ranging from total quiescence to generation of action potentials at regular or irregular frequency with or without periods of quiescence. The action potentials consisted of a slow component with superimposed spikes, preceded by a slowly developing depolarization and followed by a transient hyperpolarization. The action potentials were completely abolished by L-type Ca2+ channel blockers. W/Wv mice responded to K+ channel blockade (0.5 mM Ba2+ or 10 mM tetraethylammonium chloride) with effects on amplitude, frequency, rate of rise, and duration of the action potentials. In quiescent tissues from W/Wv mice, K+ channel blockade evoked the typical spikelike action potentials. Electron microscopy identified few methylene blue-positive cells in the W/Wv small intestine associated with Auerbach's plexus as individual ICC. Numbers of resident macrophage-like cells (MLC) and fibroblast-like cells (FLC) were significantly changed. Neither FLC nor MLC were part of a network nor did they form specialized junctions with neighboring cells as ICC do. Hence no cell type had replaced ICC at their normal morphological position associated with Auerbach's plexus. ICC were present in W/Wv mice at the deep muscular plexus in normal organization and numbers, indicating that they are not dependent on the Kit protein and do not take part in generation of pacemaker activity.

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Abnormalities of the intestinal pacemaker cells, enteric neurons, and smooth muscle in intestinal atresia

Journal of Laboratory Physicians ◽

10.4103/jlp.jlp_94_18 ◽

2019 ◽

Vol 11 (03) ◽

pp. 180-185 ◽

Cited By ~ 1

Author(s):

Radhika krishna OH ◽

Mohammed Abdul Aleem ◽

Geetha Kayla

Keyword(s):

Nervous System ◽

Small Bowel ◽

Enteric Nervous System ◽

Gastrointestinal Motility ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Enteric Neurons ◽

Small Bowel Atresia ◽

Bowel Atresia ◽

Cells Of Cajal

Abstract BACKGROUND: Small bowel atresia is a congenital disorder that carves a substantial morbidity. Numerous postoperative gastrointestinal motility problems occur. The underlying cause of this motility disorder is still unclear. Interstitial cells of Cajal (ICC) play a major role in gastrointestinal motility. AIMS AND OBJECTIVES: To investigate the morphological changes of enteric nervous system and ICC in small bowel atresia. MATERIAL AND METHODS: Resected small bowel specimen from affected patients (n=15) were divided into three parts (proximal, distal, atretic). Standard histology and immunohistochemistry with anti C-KIT receptor antibody (CD117), calretinin and α-SMA was carried out. The density of myenteric ICCs in the proximal, atretic and distal parts was demonstrated by CD 117 while Calretinin was used for ganglion cells and nerve bundles, α-SMA highlighted muscle hypertrophy. RESULT AND CONCLUSION: The proximal and distal bowel revealed clear changes in the morphology and density of enteric nervous system and interstitial cells of Cajal..

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Molecular markers expressed in cultured and freshly isolated interstitial cells of Cajal

AJP Cell Physiology ◽

10.1152/ajpcell.2000.279.2.c529 ◽

2000 ◽

Vol 279 (2) ◽

pp. C529-C539 ◽

Cited By ~ 131

Author(s):

Anne Epperson ◽

William J. Hatton ◽

Brid Callaghan ◽

Philip Doherty ◽

Rebecca L. Walker ◽

...

Keyword(s):

Smooth Muscle ◽

Small Intestine ◽

Interstitial Cells Of Cajal ◽

Expression Profiles ◽

Interstitial Cells ◽

Gastric Fundus ◽

Soluble Form ◽

Pacemaker Activity ◽

Murine Small Intestine ◽

Cells Of Cajal

Located within the tunica muscularis of the gastrointestinal (GI) tract are networks of cells known as interstitial cells of Cajal (ICC). ICC are critical for important basic functions of GI motility such as generation and propagation of slow-wave pacemaker activity and reception of regulatory inputs from the enteric nervous system. We have developed a novel procedure to identify and isolate individual ICC from freshly dispersed cell preparations of the murine small intestine and gastric fundus and to determine differential transcriptional expression We have compared the expression profiles of pacemaker ICC isolated from the murine small intestine (IC-MY) and ICC involved in neurotransmission from the gastric fundus (IC-IM). We have also compared expression profiles between ICC and smooth muscle cells (SMC) and between freshly isolated ICC and cultured ICC. Cultured ICC express smooth muscle myosin, whereas freshly dispersed ICC do not. All cell types express muscarinic receptor types M2and M3, neurokinin receptors NK1and NK3, and inhibitory receptor VIP-1, whereas only cultured ICC and SMC express VIP-2. Both cultured and freshly dispersed IC-IM and IC-MY express the soluble form of stem cell factor, whereas SMC from the gastric fundus express only the membrane-bound form.

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Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine

AJP Cell Physiology ◽

10.1152/ajpcell.00361.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. C710-C720 ◽

Cited By ~ 67

Author(s):

Yoshihiko Kito ◽

Sean M. Ward ◽

Kenton M. Sanders

Keyword(s):

Interstitial Cells Of Cajal ◽

Circular Muscle ◽

Muscle Cells ◽

Interstitial Cells ◽

Slow Waves ◽

Pacemaker Activity ◽

Dependent Manner ◽

Plateau Potential ◽

Pacemaker Potentials ◽

Cells Of Cajal

Pacemaker potentials were recorded in situ from myenteric interstitial cells of Cajal (ICC-MY) in the murine small intestine. The nature of the two components of pacemaker potentials (upstroke and plateau) were investigated and compared with slow waves recorded from circular muscle cells. Pacemaker potentials and slow waves were not blocked by nifedipine (3 μM). In the presence of nifedipine, mibefradil, a voltage-dependent Ca2+ channel blocker, reduced the amplitude, frequency, and rate of rise of upstroke depolarization (d V/d tmax) of pacemaker potentials and slow waves in a dose-dependent manner (1–30 μM). Mibefradil (30 μM) changed the pattern of pacemaker potentials from rapidly rising, high-frequency events to slowly depolarizing, low-frequency events with considerable membrane noise (unitary potentials) between pacemaker potentials. Caffeine (3 mM) abolished pacemaker potentials in the presence of mibefradil. Pinacidil (10 μM), an ATP-sensitive K+ channel opener, hyperpolarized ICC-MY and increased the amplitude and d V/d tmax without affecting frequency. Pinacidil hyperpolarized smooth muscle cells and attenuated the amplitude and d V/d tmax of slow waves without affecting frequency. The effects of pinacidil were blocked by glibenclamide (10 μM). These data suggest that slow waves are electrotonic potentials driven by pacemaker potentials. The upstroke component of pacemaker potentials is due to activation of dihydropyridine-resistant Ca2+ channels, and this depolarization entrains pacemaker activity to create the plateau potential. The plateau potential may be due to summation of unitary potentials generated by individual or small groups of pacemaker units in ICC-MY. Entrainment of unitary potentials appears to depend on Ca2+ entry during upstroke depolarization.

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