Translational approach for the autologous stem cell therapy of gastrointestinal dysganglionosis.

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In the proposed project it is planned to eliminate weaknesses of currently undertaken approaches of neural stem cell transplantation in the gut. We are introducing a technique that allows flush neural stem cells in a locally defined gut segment using the mesenteric arteries, thus achieving a homogenous colonisation of the a- or hypoganglionic gut areas. Transplantation success will be evaluated measuring the reconstituted motility. First of all, experiments will be performed in ex-vivo mesenterially cannulated gut segments, that allow to investigate different concentrations of stem cells or different transplantation modi, such as cell suspensions or spheroids in an easily reproducible way. Transplantations will be performed with FACS sorted cell populations, isolated from the ENS of transgenic mice. So, the stem cell population with the most successful colonization result can be determined. As a proof of concept, transplantation will be performed in vivo in heterozygous Hirschsprungs disease mice. With these animals, we can establish the surgical routine, that will later be applied in a similar fashion in humans, as well as proof the reconstitution of the ENS defects, using motility measurements. Within the project we will demonstrate that the mesenteric transplantation approach leads to a homogenous colonization of larger gut segments in a way, that a substitutional network of myenteric and sub mucous ganglia is formed, and that gut function is established.