Immunobiology and differentiation potential of ES/iPS cells
Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells possess an unparalleled characteristic of being pluripotent and therefore able to differentiate into progenitor cells of any cell type. This opens up opportunities for establishing new therapies. Our laboratory seeks to exploit this property and derive hematopoietic cells and insulin producing cells from human ES and iPS cells. More importantly, we are interested in determining whether these cells are rejected in both the syngeneic and allogenic setting. We have recently reported that ES cell-derived hematopoietic cells poorly express MHC antigens, making them excellent targets for NK cells. However, in vitro they are not lysed by NK cells, a phenomenon that is quite intriguing. Using proteomics, we have discovered a “stem cell factor” that is only produced in vivo by the progenitor cells leading to recruitment of NK cells and rejection of the progenitor cells. Preliminary data show that this factor augments CD27 and Mac-1 on NK cells activating them to kill ES cell derived hematopoietic progenitor cells. We are currently elucidating the mechanisms that this factor uses to induce NK cell killing. Conversely, we have recently shown that these cells induce T cell anergy in alloreactive CD8+ cells allowing allogenic transplants.
A second aspect that we are interested in is to coax human iPS cells to differentiate into insulin producing cells for the treatment of diabetes. Our data show that we can convert near 100 % of the iPS cells into Pdx1-expressing cells that further differentiate into insulin producing cells. Pdx1 is a pancreatic transcription factor that regulates pancreatic development. Our goal is to establish iPS cells as a novel source to treat diabetes reducing the management costs of diabetic patients.
Current topics include:
1. Role of NK cells in the engraftment of ES-derived hematopoietic progenitor cells and T cell-mediated clonal deletion of allogenic ES-derived cells.
2. Induction of T cell anergy by ES-cell derived hematopoietic cells.
3. De novo generation of insulin producing cells from human iPS cells