Interstitial cells of Cajal in gastrointestinal inflammatory diseases

Abstract

The gastrointestinal (GI) tract is a vital organ that digests food, absorbs nutrients, and excretes waste. Normal GI motility is the basis for these functions. The interstitial cells of Cajal (ICC) in the GI muscularis layer promote GI motility together with the enteric nervous system and smooth muscle cells. Since GI motility results from complex coordination of these heterogeneous cells, failure of any one of them can lead to GI dysmotility. Knowledge about ICC in physiological conditions has accumulated in recent decades, while the pathophysiology of ICC in GI inflammatory diseases, such as inflammatory bowel disease, is not well understood. In this review, we summarize the previous studies about the pathophysiological changes of ICC in inflammatory diseases and discuss the inflammatory mediators that induce ICC dysfunction.

Keywords: gastrointestinal motility; inflammation; interstitial cells of Cajal.

Fig. 1.

Interstitial cells of Cajal in inflammatory bowel disease. Schematic overview of the pathophysiological changes of interstitial cells of Cajal (ICC) in humans and experimental animals with inflammatory bowel disease (IBD). The ultrastructure of ICC at the colonic submuscular plexus and the small intestinal myenteric plexus (ICC-MY) showed abnormalities in patients with ulcerative colitis (UC) and Crohn’s disease (CD), respectively. Experimental animals with IBD also showed ultrastructural destruction of colonic ICC-MY. Patients with CD and UC showed a reduced number of small intestinal and colonic c-Kit⁺ ICC-MY, respectively. Experimental animals with IBD showed a reduced number of colonic c-Kit⁺ ICC-MY and disrupted pacemaker activity. The human and rodent symbols in the scheme mean that the pathophysiological changes of ICC have been reported in humans and experimental animals, respectively.

Fig. 2.

Interstitial cells of Cajal in Hirschsprung’s disease. Schematic overview of the pathophysiological changes of interstitial cells of Cajal (ICC) in humans and experimental animals with Hirschsprung’s disease (HD). In patients with HD, the ultrastructure of ICC at the colonic myenteric plexus (ICC-MY) showed abnormalities, including the swelling of mitochondria, and dilated rough endoplasmic reticulum (ER). Patients with HD and an animal model of HD showed a reduced number of colonic c-Kit⁺ ICC-MY. A study suggested that progenitors of ICC may be injured in patients with HD, which resulted in disrupted c-Kit⁺ ICC networks. Experimental animals with HD showed disrupted pacemaker activity of ICC. The human and rodent symbols in the scheme mean that the pathophysiological changes of ICC have been reported in humans and experimental animals, respectively.

Fig. 3.

Interstitial cells of Cajal in sepsis. Schematic overview of the pathophysiological changes of interstitial cells of Cajal (ICC) in rodent models of sepsis. The ultrastructure of ICC at the small intestinal myenteric plexus (ICC-MY) showed abnormalities, including the loss of lysosomes and reduced rough endoplasmic reticulum (ER). An immunohistological analysis revealed a reduced number of c-Kit⁺ ICC-MY in this animal model. A disruption of slow wave activity has been reported in this model animal.

Fig. 4.

Interstitial cells of Cajal after surgical manipulation. Schematic overview of the pathophysiological changes of interstitial cells of Cajal (ICC) in rodents after surgical manipulation, including resection and anastomosis. The ultrastructure of ICC at the small intestinal myenteric plexus (ICC-MY) showed abnormalities including abnormal cytoplasmic vacuoles. An immunohistological analysis revealed a reduced number of c-Kit⁺ ICC-MY in this animal model. A disruption of slow wave activity and propagation of pacemaker potentials has been reported in this model animal.

Fig. 5.

Summary of pathophysiological changes of interstitial cells of Cajal in gastrointestinal inflammatory diseases. Schematic overview of the pathophysiological changes of interstitial cells of Cajal (ICC) in gastrointestinal (GI) inflammatory diseases. Ultrastructural abnormalities of ICC, reduced number of c-Kit⁺ ICC, and pacemaker dysfunction of ICC were seen in these diseases. TNF-α, IL-6, and nitric oxide (NO) may be responsible for the pathophysiological changes of ICC seen in inflammation. Several experiments have shown that ICC may rapidly change their phenotypes in response to inflammatory conditions. It is not known whether ICC can redifferentiate into the pacemaker phenotype.