Investigating the Interaction of the Enteric Nervous System With the Extrinsic Nervous System and the Immune System in Children and Development of Cell Therapies for Hirschsprung's Disease

The gastrointestinal (GI) tract is responsible for many functions essential to life such as digestion, absorption and excretion, all of which are under the control of its own intrinsic nervous system, the enteric nervous system (ENS). The ENS is part of the autonomic peripheral nervous system and provides the intrinsic innervation of the bowel - the submucosal and myenteric plexuses are the two networks that comprise the ENS and consist of bundles of enteric neurons and glia - the enteric ganglia that are connected by nerve fibres. The ENS is essential for the autonomic regulation of gastric motility and secretion.

Hirschsprung's disease (HSCR) is a gut motility disorder, affecting 1 in 5000 people worldwide. HSCR is characterised by the absence of ganglia and nerve fibres of the ENS to various extents of the bowel: 80% of cases affect the distal colon and internal anal sphincter, but 10% of cases have total colonic aganglionosis and 1% total intestinal aganglionosis. Between the ganglionic and aganglionic bowel there is a transition zone. The transition zone is abnormally innervated due to a reduced number of enteric ganglia.

Initial presentation of neonates with HSCR typically includes distal intestinal obstruction, with symptoms including abdominal distention or vomiting and/or failure to pass meconium within the first 48hrs of life. Children with HSCR can also have difficulty feeding, severe constipation, and symptoms of HSCR- associated enterocolitis (HAEC).

Due to its lack of ENS, the aganglionic region of HSCR bowel is tonically contracted. This results in constipation and without treatment is fatal. The current gold-standard treatment for HSCR is a surgical pull-through procedure in which the aganglionic region and TZ is resected in an attempt to restore normal function.

The investigators have previously demonstrated the presence of enteric nervous system progenitor cells (ENSPCs) in the aganglionic bowel of children with HSCR. ENSPCs have both a multipotent nature and proliferative capacity. There has been a significant amount of research into the feasibility of using ENSPCs to reduce or correct bowel dysmotility in mouse and rat models of ENS neuropathies. ENSPCs have commonly been cultured as neurospheres. Neurospheres are free-floating cultures of neural stem cells that also contain neurons and glia and in the case of enteric neurospheres, ENSPCs.