Year 5

We have derived blood progenitor cells and pancreatic-like cells from mouse embryonic stem cells (ESCs) in vitro. One of our goals this year was to identify whether the blood progenitors could be rejected by the immune system after transplantation into adult recipients, similar to what might occur in a bone marrow transplant. We discovered that macrophages, which are a component of the immune system, are a barrier to embryonic stem cell-derived hematopoietic progenitor (ES-HP) engraftment after transplant. We discovered this using a combination of cell culture assays as well as depletion of macrophages before ES-HP transplantation. These data suggest that host macrophages might need to be depleted or inhibited for ES-HP transplantation to be clinically successful. Another important goal of ours was to identify whether ESCs could be differentiated into insulin-producing cells (IPCs) and function as such after transplantation in vitro. Similar to other groups, we were able to differentiate ESCs into IPCs, but these cells did not seem to release insulin well, and formed teratomas in vivo, which would limit their clinical use. To circumvent this issue, we identified a ESC-derived population of cells that appeared similar to immature pancreatic progenitors (PPs) that are found in the developing mouse embryo. To our knowledge, no other group has described this ESC-PP in vitro. We isolated ESC-PPs and transplanted them into mice, and found that they expressed insulin and did not form teratomas. The next steps are to test the longevity and function of these ESC-PPs in response to hyperglycemia. These data may have relevance of the treatment of diabetes. These data have been shared at national and international immunology and stem cell conferences, and supported the training of a Ph.D. student as well as two undergraduate student researchers in the past year.