Teratoma formation by Safe and Allo-Accepted Pluripotent Cells

Pluripotent stem cells are a promising alternative in cell and tissue transplantation as they have the potential to be differentiated into different cell types to treat various diseases. However, two major challenges have hindered their clinical application: concerns associated with risk of allogeneic rejection, in addition to safety issues related to uncontrolled proliferation and tumorigenicity. In this study, we utilised the H1 ESC line that was engineered to possess immune-evading properties to avoid rejection, and equipped with a "SafeCell" kill switch to selectively kill aberrantly proliferating cells. We used a humanised mouse model to demonstrate the successful generation of allogeneic tissues from SafeCell-AlloAccept (SC-AlloAccept) cells transplanted in the immune-active subcutaneous region of immunocompetent humanised mice. These cells formed teratomas and their growth was controlled with pro-drug ganciclovir that activated the kill switch, which successfully eliminated proliferating cells, rendering the remaining tissue dormant. This SC-AlloAccept-derived graft was harvested at 108 days post transplantation, highlighting their potential for long-term engraftment without rejection. We also showed that neither prior rejection of immunogenic parental H1 cells (sensitization) nor the presence of SC-AlloAccept tissue (potential immune compromise) affected the immune response to a subsequent, second transplant. This study validates the application of safe and AlloAccept human cells in transplantation, providing important insights into the immune status of the naive and sensitised human immune system of the host in a mouse model. These findings mark a key step towards the application of stem cells that can be universally accepted, towards cell-based regenerative therapies.