Year 3

Our overall project goal is to assess the immune response to tissues that are derived from embryonic stem cells. We are using mouse embryonic stem cells (ESC) and the adult mouse as a prototype of a cell-based therapy and a human patient who requires blood stem cells. We are also preparing to use adult diabetic mice as another disease model in the future.
In Years 1 and 2, we optimized our protocols to create embryonic stem cell – derived hematopoietic progenitors (ES-HP). This year (Year 3), we transplanted ES-HPs into an immune deficient mouse strain, and compared their engraftment, survival and immune cell developmental capacity to that or transplanted adult bone marrow cells. We observed that ES-HP survived up to 3 weeks post-transplantation, and that the ES-HP derived blood cells were located primary in the adult spleen and adult thymus. In contrast, adult bone marrow cells reconstituted the blood, bone marrow, spleen and thymus of the immune compromised hosts. Furthermore, mice receiving ES-HP displayed large spleens, which is indicative of a local immune response by macrophages. Mice receiving adult bone marrow cells did not display this phenotype. Recent papers in the scientific literature also suggest that the innate immune system (which includes macrophages) may respond to ESC-derived tissues. In addition, our observation that ES-HP derived cells were present in the recipient thymus and showed evidence of T cell maturation suggests that the adult thymus can support T cell development. Even though the presence in the thymus was transient, T cell development from ES-HP which would be a major step forward in the transplantation and induction of immune tolerance to ESC-derived tissues.
In Year 3, we have also extended our studies to ESC-derived insulin-producing cells (ESC-IPC), cells that have been suggested as a replacement for dysfunctional beta cells and a treatment for diabetes. We have been successful in culturing ESC-IPC and we have obtained similar functional and phenotypic data to that of other groups. Therefore, we are now ready to test the function and immunogenicity of ESC-IPC to investigate how well these cells might be tolerated after transplantation.
Two scientific articles and one invited review article related to this project was published by our laboratory in Year 3.