Survival dependency of intramuscular ICC on vagal afferent nerves in the cat esophagus

Abstract

cells of Cajal (ICC) have been proposed as stretch receptors for vagal afferent nerves in the stomach based on immunohistochemical studies. The aim of the present study was to use electron microscopy and the anterograde degeneration technique to investigate ultrastructural features and survival dependency of ICC associated with vagal afferent innervation of the cat esophagus. This is the first report on the ultrastructural characteristics of ICC in the cat esophagus. Intramuscular ICC (ICC-IM) were identified throughout the musculature, whereas ICC in the myenteric plexus were rare. ICC-IM were particularly numerous in septa aligned with smooth muscle bundles. They were in synapse-like contact with nerve varicosities and in gap junction contact with smooth muscle cells. Smooth muscle cells also made contact with ICC through peg and socket junctions. Precision damage through small-volume injection of saline in the center of the nodose ganglion from the lateral side, known to selectively affect sensory nerves, was followed within 24 h by degeneration of a subset of nerve varicosities associated with ICC-IM, as well as degeneration of the associated ICC-IM. Smooth muscle cells were not affected. Nerves of Auerbachs plexus and associated ICC were not affected. In summary, ICC-IM aligning the esophageal muscle bundles form specialized synapse-like contacts with vagal afferent nerves as well as gap junction and peg-and-socket contacts with smooth muscle cells. This is consistent with a role of ICC-IM as stretch receptors associated with vagal afferent nerves; the ICC-vagal nerve interaction appears essential for the survival of the ICC. interstitial cells of Cajal; esophagus; stretch receptor; vagus; afferent innervation; intramuscular interstitial cells of Cajal FOR NORMAL ESOPHAGEAL function, the vagus nerves provide the major sensory and motor innervation to both striated and smooth muscle portions of the esophagus. Sensory pathways from the esophagus have been studied both electrophysiologically (40, 41) and by nerve tracing techniques (4,11,28). However, the precise location and structure of the sensory receptor(s) involved in control of esophageal motor function remain controversial. It is likely that more than one structurally and functionally distinct type of mechanoreceptor exists within the esophagus (4, 5, 8). As early as 1929, intraganglionic laminar nerve endings (IGLE) were considered candidates for esophageal stretch receptors (34). In an elegant study by Berthoud and Powley (4), intramuscular vagal afferents were shown to be positioned and structured as likely candidates for the gastric stretch receptor. Intramuscular arrays (IMA) enter circular or longitudinal muscle layers, run parallel to respective muscle fibers, and bifurcate to create an array of parallel terminal elements in stomach and sphincters (28). In the stomach, these terminal elements consist of interconnected parallel axonal telodendria that are arrayed in close proximity to one another and that form appositions with interstitial cells ...

Vagal intramuscular array afferents form complexes with interstitial cells of Cajal in gastrointestinal smooth muscle: analogues of muscle spindle organs?

“…Previous observations have indicated that IMA varicosities contacting ICCs form synapse-like contacts (vesicles, prejunctional thickenings, etc.) with ICCs (Powley et al, 2008; see also Huizinga et al, 2008), and the present observations now illustrate how numerous such varicosities are (see, for example, Figures 1, 2 and 3). The extensive numbers of contact sites of IMAs with ICCs underscore the possibility that IMAs may carry stretch or length signals that originate or are transduced within the ICC-muscle-fiber apparatus of the gut (Huizinga et al, 2010).…”

“…Since small bundles of heterogeneous axons run in proximity to ICCs (e.g., Gabella, 1989; Mitsui and Komuro, 2002; Huizinga et al, 2008) and since we observed--in a recent ultrastructural study that included tracer-labeled IMAs--these bundles frequently contain only one or two IMA fibers and several axons unlabeled with dextran (Powley et al, 2008; also see Figures 4A and 5A), we evaluated a series of specimens in which IMAs were labeled with dextran, or ICCs were processed for c-Kit, and immunohistochemistry was used to identify CGRP+ neurites.…”

“…Zagorodnyuk et al, 2010) as well as, of course, IGLEs (e.g., Lawrentjew, 1929; Rodrigo et al, 1975; Zagorodnyuk et al, 2001; Raab and Neuhuber, 2004; Brookes et al, 2005) , and, arguably, they will be equally critical in the case of IMAs. Thus, we have performed a series of double labeling experiments that seemed particularly relevant in light of ultrastructural evidence that IMAs, as they arborize and innervate ICCs, are found in small bundles of axons of unknown origins and phenotypes (Powley et al, 2008; also see Huizinga et al, 2008). Presumably, and as also argued by others (e.g., Zagorodnyuk et al, 2010), such a fuller understanding of the structural organization of the vagal mechanoreceptor endings is needed and may provide observations that will help in the development of future neurophysiological and functional assessments of the afferent enigmas called IMAs.…”

Decrease of Nitrergic Innervation in the Esophagus of Patients with Chagas Disease: Correlation with Loss of Interstitial Cells of Cajal

“…A morphometric analysis revealed an equally significant decrease in the density of CD117-IR ICCs in both groups of individuals infected, with and without megaesophagus (Figure 4). and differentiation of ICCs [32], the denervation process may be one of multiple causal factors that lead to ICCs loss in the esophagus of T. cruzi infected individuals.…”

Vagal Intramuscular Arrays: The Specialized Mechanoreceptor Arbors That Innervate the Smooth Muscle Layers of the Stomach Examined in the Rat

“…6 and 5B; also see Powley and Phillips, 2011). Furthermore, IMA-ICC associations have also been examined ultrastructurally, and IMA varicosities form synapse-like contacts (i.e., the varicosities of the IMA branches exhibit prejunctional thickenings and contain vesicles) with ICCs (Powley et al, 2008; see also Huizinga et al, 2008). In addition, both of these nonneural elements of the muscularis externa, i.e., ICC-IMs and smooth muscle, that complex with IMAs express mechanoreceptive channels (Mazet, 2015).…”