Intestinal pacemaker C-KIT+ cells and synapses in allied Hirschsprung's disorders.

The cause of bowel dysmotility in allied Hirschsprung's disorders (AHDs) such as hypoganglionosis (HYPG), immature ganglia (IMG) and neuronal intestinal dysplasia (NID) remains unexplained. Recent experimental studies in mice have shown that c-kit gene product positive (C-KIT+) cells are responsible for intestinal pacemaker activity and that c-kit is also closely involved in synapse formation. To further understand the pathophysiology of AHDs, the authors used immunohistochemistry to study the distribution of C-KIT+ cells and synapses in the muscle layers of normal bowel from controls (12 cases) and bowel from patients with AHDs (10 patients; mean age, 3.0 years; 5 HYPG, 3 NID, 2 IMG). Anti-human C-KIT serum and monoclonal antibody 171B5 (a novel marker of synapses) were used for visualization of C-KIT+ cells and 171B5+ synapses, respectively. In normal bowel from controls and patients with AHDs, moderate to many C-KIT immunoreactive (C-KIT-IR+) cells were observed in the muscle layers. Myenteric plexuses were clearly demarcated by C-KIT-IR+ cells. 171B5 immunoreactive (171B5-IR+) synapses were abundant in the muscle layers and within the myenteric plexuses. In contrast, the number of C-KIT-IR+ cells or 171 B5-IR+ synapses was reduced in the muscle layers of bowel affected by AHDs, except within the myenteric plexuses, where there was a moderate to large number of 171B5-IR+ synapses identified. A lack of intestinal pacemaker C-KIT+ cells may be of great significance with respect to the bowel dysmotility associated with AHDs and also to the abnormal synapse formation seen in the muscle layers of bowel affected by these disorders.