Skip segment Hirschsprung disease: modelling the trans-mesenteric origin of the enteric nervous system in the human colon

Abstract

Skip segment Hirschsprung disease is a difficult to explain human enteric neuropathy where a ganglionated region lies within a region of total colonic aganglionosis.. Recently, trans-mesenteric migration was described in the mouse intestine whereby neural crest cells migrate via the mesentery across a U-shape gut loop from the midgut to the hindgut: this could explain skip segment Hirschsprung disease. To investigate this, human intestinal growth parameters were derived from published sources and correlated with enteric neural crest cell migration. These processes were then simulated using agent based mathematical models scaled to human intestinal growth. A Hirschsprung-associated slowing of migration was imposed and trans-mesenteric migration was allowed. From the developmental anatomy we conclude that trans-mesenteric migration is unlikely in normal human embryogenesis, but with a Hirschsprung-associated slowing of enteric neural crest cell migration it could occur at Carnegie stages 17 and 18. By varying the division rate of enteric neural crest agents we could reproduce full colonisation, short segment, long segment and skip segment Hirschsprung and hypoganglionic segments.Summary StatementSkip segment Hirschsprung disease in humans challenges current explanations. Mathematical modelling shows how this birth defect could develop.

Mesenteric Neural Crest Cells Are the Embryological Basis of Skip Segment Hirschsprung’s Disease

“…Moreover, based on the developmental anatomy of human intestine, recent work has implicated that transmesenteric migration is unlikely to occur in normal human embryogenesis. 70 The main difference between our model and the tmNCC model lies in the hypothesized origin of the NCCs within the gut mesentery. Based on the location of mNCCs within the gut mesentery, Nishiyama et al 35 preliminarily concluded that tmNCCs were derived from midgut eNCCs.…”