Delayed development of interstitial cells of Cajal in the ileum of a human case of gastroschisis

Abstract

The Interstitial Cells of Cajal (ICC) are responsible for rhythmic electrical activity. A paralytic ileus is present in gastroschisis (GS), a malformation due to a defective closure of the abdominal wall through which part of the intestine herniates during pregnancy. In experimental GS, ICC morphological immaturity was shown in the rat foetus at-term but it could not be demonstrated whether differentiation is accomplished post-natally. For this purpose we morphologically investigated ICC, as well as enteric neurons and smooth muscle cells, in a case of human GS at birth and 1 month later when peristaltic activity had initiated. A 36 weeks gestation female was born by c/section with prenatal diagnosis of GS and possible volvulus of the herniated intestine. At birth, the necrotic intestine was resected and both ileostomy and colostomy were performed. The intestine continuity was restored after 4 weeks. Intestinal specimens, taken during both operations at the level of the proximal stoma, were immunostained with c-kit, neuron-specific-enolase and α-smooth-muscle-actin antibodies and some processed for electron microscopy. ICC were present at the myenteric plexus only. At birth, these cells were rare and ultrastructurally immature; 1 month later, when partial enteral feeding was tolerated, they formed rows or groups and many of them were ultrastructurally differentiated. Neurons and smooth muscle cells, immature at birth, had developed after 1 month. Therefore, ICC differentiation, as well as that of neurons and smooth muscle cells, is delayed at birth and this might explain the paralytic ileus in GS. One month later, differentiation quickly proceeded at all cellular levels paralleling the increasing tolerance of enteral nutrition.

A Model to Study the Phenotypic Changes of Interstitial Cells of Cajal in Gastrointestinal Diseases

“…5,6 Loss of ICC function can lead to symptoms that might traditionally have been considered defects in myogenic or neurogenic control mechanisms. However, KIT labeling showed that the structural integrity of ICC is aberrant in a variety of GI dysmotilities, including achalasia, 7,8 diabetic gastroenteropathy, 9–11 hypertrophic pyloric stenosis, 12 gastroschisis, 13 intestinal pseudoobstruction, 14–17 slow transit constipation, 18–20 Hirschsprung’s disease, 21,22 Crohn’s disease, 23,24 and inflammatory bowel disease. 25–27 …”

Enteric Nervous System Impairment in Gastroschisis

“…Further support for this cause of delayed intestinal motility comes from a clinical case that showed delayed maturation of the ICC network and enteric neurons at birth in a specimen of normal-looking small bowel from a human neonate with gastroschisis who required resection because of bowel ischemia. 22 Interestingly, examination of a second specimen taken 1 month later during surgery to restore continuity showed improved maturation of the ICC network and enteric neurons. 22 Similarly, decreased expression of c-kit has been consistently observed in the proximal segment of small bowel with intestinal atresia in a large series of 23 patients 15 Impairment of ICC morphology and network in our experimental gastroschisis study may thus be secondary to functional obstruction.…”

“…22 Interestingly, examination of a second specimen taken 1 month later during surgery to restore continuity showed improved maturation of the ICC network and enteric neurons. 22 Similarly, decreased expression of c-kit has been consistently observed in the proximal segment of small bowel with intestinal atresia in a large series of 23 patients 15 Impairment of ICC morphology and network in our experimental gastroschisis study may thus be secondary to functional obstruction.…”

Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5

“…In addition to serving as a chemotactic factor for eosinophils, eotaxin may be involved in recruiting T cells that express the eotaxin receptor CCR3 to the intestine (50) and may adversely affect bowel motility (51). Locally, T cell infiltration and inflammatory cytokine production in the intestines may contribute to bowel dysmotility by multiple mechanisms, including damaging the interstitial cells of Cajal (52), which have been shown to be developmentally delayed in gastroschisis (53). …”