PT  - JOURNAL ARTICLE
AU  - Arturo Tozzi
TI  - Reaction-Diffusion Mechanisms Underlying Hirschprung’s Disease and their Practical Impications
AID  - 10.1101/492884
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 492884
4099  - http://biorxiv.org/content/early/2018/12/10/492884.short
4100  - http://biorxiv.org/content/early/2018/12/10/492884.full
AB  - The erratic extent of aganglionic and hypoganglionic segments in Hirschsprung’s disease (HD) makes it difficult to predict the amount of the intestine to remove in order to restore the proper functional motility. Our aim was to assess whether the embryonic rostro-caudal intestinal colonization by neuroblasts from the neural crest follows a predictable pattern in HD. In touch with Turing’s reaction diffusion model (RD), which describes biological patterns (such as leopard spots and lung branching morphogenesis) in terms of interactions/competitions between activating and inhibiting factors, we hypothesized that intestinal neural density could be triggered by local gut factors that counteract the proximal-distal embryonic progression of neural progenitors. While the neuronal number is approximately the same throughout the whole intestine in healthy subjects, in HD neural density decreases rostro-caudally towards the rectal region, due to an augmented activity and concentration of distal local inhibitors. In order to prove our hypothesis of HD’s nervous rostro-caudal adjustments driven by Turing-like processes, we compared the neuronal density patterns achieved through RD models’ simulations with the neuronal numbers detected in different colonic regions from affected children. We showed that the virtual and the real plots display fully overlapping and matching features. The fact that neuronal decreases in impaired colons match Turing equations’s previsions points towards the human intestine (both healthy and sick) as colonized through a diffusive proximal-distal neural pattern that is predictable, allowing us to straightforwardly calculate the length of the gut to resect during surgical procedures for HD.