Author Correction: Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients

Background: Induced pluripotent stem cells (iPSCs) are promising candidates for regenerative cell-based therapies. Because autogenic iPSCs are not available for acute treatment procedures, allogeneic strategies have to be developed which evade immune rejection. We showed in this study that both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed. Methods: Hypoimmunogenic mouse (β2m-/-Ciita-/-Cd47tg miPSCs) and human (B2M-/-CIITA-/-CD47tg hiPSCs) iPSCs were generated via CRISPR/Cas9 technology and lentiviral overexpression. Unmodified and β2m-/-Ciita-/-Cd47tg miPSCs as well as their cell grafts were injected into syngeneic C57BL/6 or allogeneic BALB/c mice. Unmodified and B2M-/-CIITA-/-CD47tg hiPSCs and their cell grafts were injected into humanized mice. The cellular and antibody response was quantified and in vivo bioluminescence imaging were performed to assess cell survival. Results: FACS analysis showed normal expression of MHC I and MHC II on unmodified cells and depleted MHC I and MHC II on hypoimmunogenic cells. Surface expression of CD47 was 3-4 time increased in hypoimmunogenic cells compared to unmodified cells. After allogeneic transplantation, hypoimmunogenic cells showed a significantly decreased immune response in ELISPOT assays, comparable to the level of syngeneic transplants. No donor-specific antibodies were detected and the hypoimmunogenic cells were protected against innate response in in vivo innate cytotoxicity assays and in XCelligence assays. Additionally, 100% graft survival was achieved with hypoimmunogenic cells in vivo with an observation period of 50 days. Conclusion: Our results clearly demonstrate that the lack of immunogenicity is from MHC I and MHC II antigens and that the overexpression of the CD47 molecule prevents against innate immune responses. Thus, hypoimmunogenic iPSCs might serve as an unlimited cell source for the generation of universally compatible “off-the-shelf” cells grafts or tissues in future clinical applications.