Leveraging our understanding of the embryonic ENS environment to enhance the success of enteric neuronal stem cell transplantation
The enteric nervous system (ENS) is a network of glial cells and neurons in the intestine wall that regulates secretion, absorption and motility of the gut. Abnormalities of the ENS include a wide spectrum of functional gastrointestinal disorders, including Hirschsprung disease, which is caused by the incomplete migration of enteric neural crest-derived cells and failure of these stem cells to populate the entire length of the gut. Current treatment involves surgical resection of the aganglionic large intestine, but many children suffer from constipation and enterocolitis. Stem cell-based therapy offers the potential to restore the abnormal ENS. However, the proliferation and migration of transplanted enteric neuronal stem cells (ENSC) remains limited. We hypothesize that the poor migration and integration of transplanted ENSCs can be overcome by modifying the stem cell’s interactions with its surrounding environment. To accomplish this we will first analyze the mesenchymal growth factors regulating ENS formation and characterize their extracellular environment before and after transplantation in the postnatal gut. Utilizing our knowledge of normal ENS development, we will then modify the hostile environment in a targeted manner to enhance ENSC migration. The strategy is highly innovative, as transplanted cells will be engineered with viral vectors and co-administered with growth factors to optimize the cell’s local environment for migration. This proposal has the potential to significantly improve the success of stem cell transplantation as a novel treatment for congenital enteric neuropathies.