Establishment of pacemaker activity in tissues allotransplanted with interstitial cells of Cajal

Abstract

Background: Loss or disruption of Kit(+) -interstitial cells of Cajal (ICC) capable of generating pacemaker activity has been implicated in the development of numerous gastrointestinal motility disorders. We sought to develop a model where ICC could be allotransplanted into intestines naturally devoid of these cells.

Methods: Enzymatically dispersed cells from the intestinal tunica muscularis of Kit(+/copGFP) and Kit(V558Δ) /+ gain-of-function mice were allotransplanted into myenteric plexus regions of W/W(V) mutant intestines that lack ICC at the level of the myenteric plexus (ICC-MY) and pacemaker activity. Immunohistochemical analysis fate mapped the development of ICC-MY networks and intracellular microelectrode recordings provided evidence for the development of functional pacemaker activity.

Key results: Kit(+) -ICC developed into distinct networks at the level of the myenteric plexus in organotypic cultures over 28 days and displayed robust rhythmic pacemaker activity.

Conclusions & inferences: This study demonstrates the feasibility of allotransplantation of ICC into the myenteric region of the small intestine and the establishment of functional pacemaker activity into tissues normally devoid of ICC-MY and slow waves, thus providing a possible basis for the therapeutic treatment of patients where ICC networks have been disrupted due to a variety of pathophysiological conditions.