Hirschsprung disease, or aganglionic megacolon, is a congenital defect that affects 1 out of 5,000 live births and is characterized by a failure to form enteric nervous system (ENS) in a variable length of the hindgut ADDIN EN.CITE Newgreen200231143114311417D. NewgreenH.M. YoungEnteric nervous system: development and developmental disturbances - Part 1Pediatric and Developmental Pathology224-24752002[1] . This potentially fatal condition results in an inability to coordinate peristaltic movements of the bowel and is most commonly caused by mutations that reduce signaling through the glial cell line-derived neurotrophic factor (GDNF) or endothelin-3 (EDN3) signaling pathways ADDIN EN.CITE Gariepy200137843784378417Gariepy, C. E.Department of Pediatrics, Pediatric Gastroenterology and Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA. Gariepy@utsw.swmed.eduIntestinal motility disorders and development of the enteric nervous systemPediatr Res605-13495AnimalsChildEnteric Nervous System/*growth &development*Gastrointestinal MotilityHumansInfant, NewbornIntestinal Diseases/*physiopathologyResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.2001May11328941www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11328941[2] . Both the GDNF receptor, Ret, and the EDN3 receptor Endothelin receptor B (EDNRB) are expressed by the neural crest stem cells (NCSCs) that give rise to the ENS ADDIN EN.CITE ADDIN EN.CITE.DATA [3] . These signaling pathways interact to regulate the proliferation and migration of NCSCs and other neural crest progenitors that colonize the gut, though questions remain about whether the primary role of EDN3 signaling is to inhibit premature differentiation or to promote migration ADDIN EN.CITE ADDIN EN.CITE.DATA [3-10] . Neural crest cells never migrate into the aganglionic portion of the gut in animals affected by Ret or Ednrb deficiency ADDIN EN.CITE ADDIN EN.CITE.DATA [3,6] . These observations raise the possibility of improving the treatment of Hirschsprung disease by combining traditional surgical approaches with cell therapy in which NCSCs are transplanted directly into the aganglionic portion of the gut to generate enteric ganglia by bypassing the migration/proliferation defects ADDIN EN.CITE ADDIN EN.CITE.DATA [3,6,11,12] . Consistent with this possibility, we and others have shown that NCSCs isolated from the fetal rodent gut can engraft and form enteric neurons after transplantation into the aganglionic region of the gut from rodent models of Hirschsprung disease ADDIN EN.CITE ADDIN EN.CITE.DATA [6,11-13] . Nonetheless, before such a therapy can be contemplated for patients it will be necessary to obtain human NCSCs in quantities adequate for clinical use. Since human fetal tissue is very limited and of inconsistent quality for clinical use ADDIN EN.CITE Bjorklund200036463646364617Bjorklund, A.Lindvall, O.The authors are at the Wallenberg Neuroscience Center, Lund University, Solvegatan 17, S-223 62 Lund, Sweden. anders.bjorklund@mphy.lu.seCell replacement therapies for central nervous system disordersNat NeurosciNat NeurosciNature neuroscience537-4436AnimalsBrain/*cytology/embryologyCell Transplantation/methods/*trendsCentral Nervous System Diseases/*therapyCerebrovascular Accident/therapyClinical TrialsEpilepsy/therapyHumansHuntington Disease/therapyNeurons/*transplantationParkinson Disease/therapyRatsRecovery of FunctionSeizures/prevention &control*Stem Cell TransplantationSwine2000Jun10816308www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10816308[14] , it would be ideal to derive NCSCs with enteric characteristics from human embryonic stem (hES) cells. Having extensively characterized mouse and rat enteric NCSCs, we propose to optimize culture conditions to derive human NCSCs with similar properties from hES cells. We will inject these human NCSCs into the aganglionic hindgut of Ednrb mutant rats to test the ability of these cells to form neurons and glia in vivo. These studies will test whether NCSCs with specific regional characteristics can be derived from hES cells and whether these cells engraft in the gut of an animal model of Hirschsprung disease.
Public Health Relevance
This proposal is designed to better understand the mechanisms that underlie the development of Hirschsprung disease in humans, and to develop a cell therapy for this disease. Hirschsprung disease is a congenital defect associated with the failure of neural crest cells to form enteric nervous system (aganglionosis) in a variable length of the hindgut. This leads to gut dysmotility that can be fatal without surgery to remove the affected segment of gut. Our research aims to use human embryonic stem cells to derive the neural crest stem cells that normally give rise to the enteric nervous system, to study their response to factors implicated in Hirschsprung disease, and to test whether their transplantation into aganglionic gut can restore gut function.
