New Frontiers in the Treatment of Hirschsprung Disease

Abstract

Hirschsprung disease (HSCR) is the most common identifiable developmental disorder of the enteric nervous system (ENS), characterized by a failure of its formation in a variable segment of distal bowel. Currently available surgical therapies for HSCR, although lifesaving, are associated with an unsatisfactory long-term prognosis for many, highlighting the need for newer curative therapies. On the basis of our understanding of ENS development, 1 potential therapeutic tool relates to the cells that gave rise to the ENS during embryogenesis. Data from initial animal studies suggested that such "ENS stem cells" persist within postnatal gut, from which they can be harvested and used to replenish absent nerves within experimental models of gut aganglionosis. More recently, it has been shown that ENS stem cells can also be isolated from human postnatal gut. The early human studies, however, used full-thickness gut tissue obtained at surgery to generate ENS stem cells, which in clinical terms poses practical problems. In an effort to directly address such obstacles our latest research has shown that ENS stem cells can also be harvested from gut mucosal biopsies obtained at routine endoscopy. Such gut mucosal ENS stem cells are capable of appropriately and fully colonizing aganglionic gut tissue, including from HSCR, to generate components of a mature and functional ENS. Current evidence suggests that transplantation of ENS stem cells, sourced from easily accessible postnatal gut, could be a viable alternative treatment for HSCR and ultimately for a number of other congenital or acquired ENS disorders.