The Mechanism and Spread of Pacemaker Activity Through Myenteric Interstitial Cells of Cajal in Human Small Intestine

Background & Aims: It has been generally assumed that interstitial cells of Cajal (ICC) in the human gastrointestinal tract have similar functions to those in rodents, but no direct experimental evidence exists to date for this assumption. This is an important question because pathologists have noted decreased numbers of ICC in patients with a variety of motility disorders, and some have speculated that loss of ICC could be responsible for motor dysfunction. Our aims were to determine whether myenteric ICC (ICC-MY) in human jejunum are pacemaker cells and whether these cells actively propagate pacemaker activity. Methods: The mucosa and submucosa were removed, and strips of longitudinal muscle were peeled away to reveal the ICC-MY network. ICC networks were loaded with the Ca²⁺ indicator fluo-4, and pacemaker activity was recorded via high-speed video imaging at 36.5°C ± 0.5°C. Results: Rhythmic, biphasic Ca²⁺ transients (6.03 ± 0.33 cycles/min) occurred in Kit-positive ICC-MY. These consisted of a rapidly propagating upstroke phase that initiated a sustained plateau phase, which was associated with Ca²⁺ spikes in neighboring smooth muscle. Pacemaker activity was dependent on inositol 1,4,5-triphosphate receptor-operated stores and mitochondrial function. The upstroke phase of Ca²⁺ transients in ICC-MY appeared to result from Ca²⁺ influx through dihydropyridine-resistant Ca²⁺ channels, whereas the plateau phase was attributed to Ca²⁺ release from inositol 1,4,5-triphosphate receptor-operated Ca²⁺ stores. Conclusions: Each ICC-MY in human jejunum generates spontaneous pacemaker activity that actively propagates through the ICC network. Loss of these cells could severely disrupt the normal function of the human small intestine.