Physiology, injury, and recovery of interstitial cells of Cajal: basic and clinical science

Abstract

In the last 15 years, our understanding of the cellular basis of gastrointestinal function has been altered irreversibly by the discovery that normal gastrointestinal motility requires interstitial cells of Cajal (ICC). Research in this relatively short time period has modified our original concept that the core unit that controls motility is made up of nerves and smooth muscle, to one that now includes ICC. This concept has now expanded to beyond the gastrointestinal tract, suggesting that it may be a fundamental property of the regulation of smooth muscle function that requires rhythmic contraction. ICC are distributed throughout the gastrointestinal tract, have important functions in the control of gastrointestinal motility and are often abnormal in diseased states. Recently, significant steps forward have been made in our understanding of the physiology of ICC as well as mechanisms of injury and recovery. These advances will be the focus of this review.

Figure 1. Subtypes and distribution of ICC along the GI tract as shown by various morphological techniques

a: whole mount light microscopy b: cross sections light microscopy c: electron microscopy 1. The esophagus has only ICC-IM (1a from mouse LES, 1b&c from human esophagus). These ICC-IM (arrows in 1a&b) exhibit a spindle shaped body with processes emerging from both cellular extremes (1a). Ultrastructural characteristics of ICC (* in 1c) are: electron dense cytoplasm, oval nucleus with heterochromatin distributed in the periphery and abundant mitochondria. ICC in the esophagus can establish close connections (arrows in 1c) with nearby smooth muscle cells (SM). Small arrows: caveolae. 2. There are two main classes of ICC networks in the stomach: ICC-IM, including septal ICC in larger animals, and ICC associated with the myenteric (Auerbach’s) plexus (2a from mouse corpus; 2b&c from human stomach). 2a shows ICC-IM with typical spindle shaped bodies (arrows) and myenteric pacemaker ICC with characteristic stellar bodies (arrowheads) in the wholemount preparation. 2b demonstrates ICC (arrowheads) and ICC-IM (arrows) scattered among smooth muscle cells in both muscle layers. 2c shows a longitudinal section of a myenteric ICC (*). N: nerves; SM: smooth muscle cells. 3. There are three main ICC populations in the small bowel (3a–c, all from human): ICC-IM (arrows in 3b), myenteric pacemaker ICC (arrowheads in 3a and 3b) and ICC-DMP, which are ICC, associated with the deep muscular plexus located between the outer and inner circular muscle layer (OCM&ICM). ICC-IM are distributed both within the musculature (arrows) and in the septa (double arrows) in 3a. ICC-DMP show weak Kit staining compared to other ICC and can be better identified by electron microscopy (3c). An ICC-DMP (*) in 3c establishes simultaneous close contact with a nearby nerve terminal (N) and a neighboring outer circular smooth muscle cell (OCM). Upper right inset in 3c shows a contact with the smooth muscle cell and lower left inset shows a synapse like contact with the nerve terminal. ICM: inner circular muscle. Small arrows in 3c: caveolae; Arrowheads in 3c: basal lamina. 4. Three different subtypes of ICC are present in the colon (4a–c, all from human). ICC-IM (arrows in 4a&b), myenteric pacemaker ICC (arrowheads 4a&b) and ICC-SM (* in 4c), which are ICC, associated with the submuscular plexus. Arrows in 4c: caveolae along the membrane; Arrowheads in 4c: basal lamina. CM: circular muscle cells; LM: longitudinal muscle cells; AP: Auerbach's plexus. Acknowledgements: Figure 4c was obtained with permission from Shigeko Torihashi . Figure 2c was obtained with permission from Simonetta Faussone-Pellegrini .

Figure 2. ICC are associated with the enteric nervous system

a. A dense network of myenteric pacemaker ICC surrounds the myenteric plexus ganglia in the small intestine. b. ICC of the deep muscular plexus in the small intestine are bipolar and aligned with smooth muscle cells. Many ICC are fully aligned with enteric nerves (shown here are nitrergic nerves). The confocal scanning thickness was 4 µm. C-kit staining of ICC (green), neural plexus is stained with nNOS antibody (red).

Figure 3. Proposed paradigm for the control of ICC networks