![]() Furthermore, reinnervation of the gut has been observed just seven days following BAC treatment 22. A chemically induced model of aganglionosis, which relies on benzalkonium chloride (BAC), is hampered by off-target effects, with non-specific ablation of smooth muscle cells and interstitial cells of Cajal 20, 21. The short lifespan prevents long-term follow-up after cell therapy. Each of these models, however, has limitations for long-term studies since the animals die within the first several weeks of life due either to bowel obstruction or development of enterocolitis. These include rodent models with mutations in genes essential for ENS development, such as members of the Ret tyrosine kinase receptor pathway 11, 12, 13, the transcription factor Sox10 14, 15, or the Et3- Ednrb signaling pathway 16, 17, 18, 19. Several genetic models of intestinal aganglionosis are commonly used to explore the potential of cell therapy as a novel treatment for HSCR 8, 9, 10. New and more effective therapies for the treatment of HSCR are needed 3, 6, 7. Current treatment for HSCR involves surgical removal of the aganglionic segment, but the functional outcome is variable and often accompanied by long-term GI problems, including enterocolitis, constipation, fecal incontinence, and reduced quality of life. The incidence of HSCR is 1 in 5000 live births, of which 80% have short-segment HSCR, in which only the rectosigmoid colon lacks ganglion cells 4, 5. The uncolonized colon remains aganglionic and tonically contracted, resulting in functional obstruction and impaired GI motility. One of the best understood enteric neuropathies is Hirschsprung disease (HSCR), a congenital disorder in which enteric ganglia are absent along a variable length of the distal intestine due to failure of enteric neural crest-derived cells (ENCDCs) to complete their colonization of the intestine during development. One potential therapy is enteric neuronal cell transplantation 3. Enteric neuropathies, which are characterized by the congenital absence, acquired loss, or abnormal function of intrinsic enteric neurons, represent severe clinical GI disorders for which effective treatments are lacking because they do not address the underlying pathophysiology 1, 2. ![]() The ENS arises from neural crest-derived cells that migrate along the length of the developing GI tract. The enteric nervous system (ENS), which consists of neurons and glia arranged in networks of ganglia within the wall of the gastrointestinal (GI) tract, regulates multiple critical aspects of gut function, including motility. Transplantation of ENCDCs into this region leads to engraftment, migration, and differentiation of enteric neurons and glial cells, with restoration of normal architecture of the colonic epithelium and muscle, reduction in inflammation, and improved survival. Focal ENS ablation leads to increased smooth muscle and mucosal thickness, and localized inflammation. Local DT injection into the colon wall results in focal, specific, and sustained ENS ablation without altering GI transit or colonic contractility, allowing improved survival over other aganglionosis models. We have developed a novel model of aganglionosis in which enteric neural crest-derived cells (ENCDCs) express diphtheria toxin (DT) receptor. Cell therapy offers potential treatment but use of genetic models is limited by their poor survival. Despite removal of the aganglionic segment, gastrointestinal (GI) problems persist. Hirschsprung disease (HSCR) is characterized by absence of the enteric nervous system (ENS) in the distal bowel.
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