Interstitial cells of Cajal (ICC) are specialized mesenchyme-derived cells that regulate contractility and excitability of many smooth muscles with loss of ICC seen in a variety of gut motility disorders. Maintenance of ICC numbers is tightly regulated, with several factors known to regulate proliferation. In contrast, the fate of ICC is not established. The aim of this study was to investigate whether apoptosis plays a role in the regulation of ICC numbers in the normal colon. ICC were identified by immunolabeling for the c-Kit receptor tyrosine kinase and by electron microscopy. Apoptosis was detected in colon tissue by immunolabeling for activated caspase-3, terminal dUTP nucleotide end labeling, and ultrastructural changes in the cells. Apoptotic ICC were identified and counted in double labeled tissue sections. Apoptotic ICC were identified in all layers of the colonic muscle. In the muscularis propria 1.5 ± 0.2% of ICC were positive for activated caspase-3 and in the circular muscle layer 2.1 ± 0.9% of ICC were positive for TUNEL. Apoptotic ICC were identified by electron microscopy. Apoptotic cell death is ongoing in ICC. The level of apoptosis in ICC in healthy colon indicates that these cells must be continually regenerated to maintain intact networks.
The English spotting coat color locus in rabbits, also known as Dominant white spotting locus, is determined by an incompletely dominant allele (En). Rabbits homozygous for the recessive wild-type allele (en/en) are self-colored, heterozygous En/en rabbits are normally spotted, and homozygous En/En animals are almost completely white. Compared to vital en/en and En/en rabbits, En/En animals are subvital because of a dilated (“mega”) cecum and ascending colon. In this study, we investigated the role of the KIT gene as a candidate for the English spotting locus in Checkered Giant rabbits and characterized the abnormalities affecting enteric neurons and c-kit positive interstitial cells of Cajal (ICC) in the megacolon of En/En rabbits. Twenty-one litters were obtained by crossing three Checkered Giant bucks (En/en) with nine Checkered Giant (En/en) and two en/en does, producing a total of 138 F1 and backcrossed rabbits. Resequencing all coding exons and portions of non-coding regions of the KIT gene in 28 rabbits of different breeds identified 98 polymorphisms. A single nucleotide polymorphism genotyped in all F1 families showed complete cosegregation with the English spotting coat color phenotype (θ = 0.00 LOD = 75.56). KIT gene expression in cecum and colon specimens of En/En (pathological) rabbits was 5–10% of that of en/en (control) rabbits. En/En rabbits showed reduced and altered c-kit immunolabelled ICC compared to en/en controls. Morphometric data on whole mounts of the ascending colon showed a significant decrease of HuC/D (P<0.05) and substance P (P<0.01) immunoreactive neurons in En/En vs. en/en. Electron microscopy analysis showed neuronal and ICC abnormalities in En/En tissues. The En/En rabbit model shows neuro-ICC changes reminiscent of the human non-aganglionic megacolon. This rabbit model may provide a better understanding of the molecular abnormalities underlying conditions associated with non-aganglionic megacolon.
The morphogenesis of the special layer and the interstitial cells of Cajal (ICC) related to the plexus muscularis profundus (PMP) of mouse intestinal muscle coat has been studied in foetuses at term, neonates not yet fed, suckling animals, weaning animals and adult animals. In foetuses at term, the special layer is absent, but presumed myoblasts of this layer are recognized in the tela submucosa facing the developing circular layer. The ICC, too, are not differentiated and presumed ICC-blasts are tentatively identified in submucosal cells related to nerve fibers. These nerve fibers are considered to belong to the developing PMP. In neonates, the special layer, ICC and PMP are recognizable, but are made up of poorly differentiated elements. In suckling animals, these three structures develop but become almost fully differentiated only at the end of the weaning period, whereas the other components of the muscular coat are already developed.
A layer of muscle cells consisting of 1–3 rows is present on the inner part of the circular layer of mouse colon. These muscle cells are thinner, with a denser cytoplasm and more caveolae than those of the main portion of the circular layer. A connective interstice divides the two parts of the circular layer and is occupied by a nerve plexus rich in varicosities. Groups of cells, identified as interstitial cells of Cajal, and a nerve plexus rich in varicosities are located on the border between the innermost circular layer and the tela submucosa. The interstitial cells have many cytological features in common with muscle cells (caveolae, basal lamina, thin filaments, smooth endoplasmic reticulum, glycogen particles) and touch each other and the nerve endings frequently and the muscle cells of the innermost layer rarely.
The muscular coat of human small intestine is constituted by a ‘special’ layer, by the main component of the circular layer, by the region between the circular and the longitudinal layers and by the longitudinal layer. The ‘special’ layer is made up of the innermost 4–6 rows of muscle cells of the circular layer and is separated from the main component of the circular layer by a space in which an abundant connective tissue and numerous nerve fibers rich in nerve endings are located. Cells identified as interstitial cells of Cajal are located inside the ‘special’ layer, the space between it and the main component of the circular layer and in the region between the circular and the longitudinal layers. In this region small bundles of obliquely orientated muscle cells, apparently bridging the circular to the longitudinal layer, are found.
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