Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach. Here we show 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. These hypoimmunogenic iPSCs retain their pluripotent stem cell potential and differentiation capacity. Endothelial cells, smooth muscle cells, and cardiomyocytes derived from hypoimmunogenic mouse or human iPSCs reliably evade immune rejection in fully MHC-mismatched allogeneic recipients and survive long-term without the use of immunosuppression. These findings suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation.
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We thank C. Pahrmann for cell culture work, imaging experiments and overall assistance and L. Li for his assistance. The in vivo BLI experiments were performed at the UCSF Pre-clinical Therapeutics Core (A. Fries; with special thanks to B.C. Hann). Special thanks go to J. Wu (Stanford Cardiovascular Institute, Stanford University School of Medicine) for providing the miPSCs and the help of his laboratory with developing the protocol for hiPSC differentiation into cardiomyocytes. We thank J.-F. Garcia-Gomez (City of Hope, Duarte) for the HLA typing of humanized BLT mice. We also thank E. Maltepe and H. Pektas for providing the syncytiotrophoblast cells. D.W. was supported by the Max Kade Foundation. A.W. received funding from the National Institutes of Health (grant AI123010). J.V.G. received funding from the National Institutes of Health (AI111899 and MH108179). The cardiomyocyte research was partly made possible by a grant from the California Institute for Regenerative Medicine (Grant Number DISC1-09984). Research related to cardiomyocyte immunobiology reported in this publication was supported by National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL140236. L.L.L. is an American Cancer Society Professor funded by NIH AI068129 and in part by the Parker Institute for Cancer Immunotherapy. S.S. and T.D. received funding for the cardiomyocyte research from the California Institute for Regenerative Medicine (Grant Number DISC1-09984) and for the immunobiology work from the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL140236. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, CIRM and other agencies of the State of California.