Tissue-Specific Mathematical Models of Slow Wave Entrainment in Wild-Type and 5-HT2B Knockout Mice with Altered Interstitial Cells of Cajal Networks

Abstract

Gastrointestinal slow waves are generated within networks of interstitial cells of Cajal (ICCs). In the intact tissue, slow waves are entrained to neighboring ICCs with higher intrinsic frequencies, leading to active propagation of slow waves. Degradation of ICC networks in humans is associated with motility disorders; however, the pathophysiological mechanisms of this relationship are uncertain. A recently developed biophysically based mathematical model of ICC was adopted and updated to simulate entrainment of slow waves. Simulated slow wave propagation was successfully entrained in a one-dimensional model, which contained a gradient of intrinsic frequencies. Slow wave propagation was then simulated in tissue models which contained a realistic two-dimensional microstructure of the myenteric ICC networks translated from wild-type (WT) and 5-HT2B knockout (degraded) mouse jejunum. The results showed that the peak current density in the WT model was 0.49 μA mm−2 higher than the 5-HT2B knockout model, and the intracellular Ca2+ density after 400 ms was 0.26 mM mm−2 higher in the WT model. In conclusion, tissue-specific models of slow waves are presented, and simulations quantitatively demonstrated physiological differences between WT and 5-HT2B knockout models. This study provides a framework for evaluating how ICC network degradation may impair slow wave propagation and ultimately motility and transit.