Year 4 (NCE)
Although stem cell-based therapies can potentially be used to treat numerous prevalent diseases, their successful clinical translation requires overcoming the problem of immune rejection. Given that self-identity is encoded by thymic epithelial cells (TECs), an appealing approach to manipulating immune tolerance in the context of stem cell therapies would be to reprogram the immune system through the generation of stem cell-derived TECs. To address this hypothesis, we have developed a method to generate in vitro differentiated stem cell-derived thymic epithelial progenitors (TEPs) that are transplanted into mice reconstituted with human immune cells. We also established a robust protocol to produce functional pancreatic beta cells using a genetically matched hESC line. Co-transplantation of matched TEPs and beta cells as well as genetically distinct cells will allow us to test the ability of stem cell-derived TECs to induce immune tolerance to genetically matched stem cell derivatives. In addition, these humanized mice will be used to study if expression of specific proteins by TECs can influence immune responses against this antigen. Taken together, our work provides unique tools to study stem cell derivatives immunogenicity following transplantation in humanized mice. These studies will also help demonstrate if hESC-derived TEPs can be used as a method for the induction of long lasting immune tolerance to specific antigens and to stem cell derivatives.