PROJECT SUMMARY:
Congenital or acquired disruption of the enteric nervous system (ENS) leads to neurointestinal diseases,
including Hirschsprung disease, esophageal achalasia, gastroparesis, chronic intestinal pseudo-obstruction,
and others. Normal development of a functional ENS relies on the coordinated interaction between enteric
neural crest-derived cells and their microenvironment, including the extracellular matrix (ECM), as the enteric
neural crest-derived cells migrate rostrocaudally along the embryonic gut mesenchyme.1 These interactions
ensure proper cell migration, proliferation, and differentiation into the enteric neurons and glial cells that
regulate numerous gastrointestinal processes, including motor and sensory function. Numerous ECM and
ECM binding proteins have been shown to promote enteric neural crest-derived cell migration, while others
(including agrin and chondroitin sulfate proteoglycans) have been shown to inhibit migration, demonstrating a
critical role of the ECM in ENS formation. Despite an improving understanding of normal ENS development,
current therapies for neurointestinal diseases are lacking, as they target symptoms rather than the underlying
pathology of an absent or abnormal ENS. Our lab and others are investigating the potential of enteric neuronal
stem cell transplantation as a novel approach to restoring innervation and gut function in these patients, but
studies have been hampered by limited engraftment, migration, and proliferation of transplanted cells.1 Given
the reliance of ENS development on the local environment, we believe that successful development of enteric
neuronal stem cell transplantation relies on a permissive local ECM to support the transplanted cells. We
hypothesize that inhibitory ECM proteins (agrin and chondroitin sulfate proteoglycans) are over-expressed
following enteric neuronal stem cell transplantation, thwarting the migration of stem cells. In this grant we
therefore aim to identify ECM gene expression differences between the aganglionic and normal colon,
characterize ECM protein expression following enteric neuronal stem cell transplantation, and to leverage our
understanding of normal ENS development to modify the microenvironment after enteric neuronal stem cell
transplantation by knocking down ECM proteins that inhibit cell migration in order to enhance the migration of
transplanted cells.