Development of the aganglionic colon following surgical rescue in a cell therapy model of Hirschsprung disease in rat

Abstract

Patients with Hirschsprung Disease lack enteric ganglia in the distal colon and propulsion of colorectal content is substantially impaired. Proposed stem cell therapies to replace neurons require surgical bypass of the aganglionic bowel during re-colonisation, but there is inadequate knowledge of the consequences of bypass. We performed bypass surgery in Ednrb-/- Hirschsprung rat pups. Surgically rescued rats failed to thrive, an outcome reversed by supplying electrolyte and glucose enriched drinking water. Histologically, the bypassed colon had normal structure, but grew substantially less in diameter than the functional region proximal to the bypass. Extrinsic sympathetic and spinal afferent neurons projected to their normal targets, including arteries and the circular muscle, in aganglionic regions. However, although axons of intrinsic excitatory and inhibitory neurons grew into the aganglionic region, their normally dense innervation of circular muscle was not restored. Large nerve trunks that contained TH, CGRP, nNOS, VIP and tachykinin immunoreactive axons occurred in the distal aganglionic region. We conclude that the rescued Ednrb-/- rat provides a good model for the development of cell therapies for the treatment of Hirschsprung disease.

Guardians of the gut: influence of the enteric nervous system on the intestinal epithelial barrier

“…It also interacts with stromal cells, interstitial cells of Cajal, and immune cells, including scattered single glial cells throughout the enteric tissue. Thus, there has been a growing interest in understanding the neuronal regulation of the immune system in the context of intestinal inflammatory disorders and for the advancement of cell-based therapies for aganglionic gut motility disorders (3,4). To facilitate a better understanding of the currently recognized enteric neuronal subtypes, we have provided a comparative Table 1 as a reference guide for neuronal subtypes identified by singlecell transcriptomic studies.…”