Generation of hypoimmunogenic human pluripotent stem cells

Significance To enable cell therapy on a broader scale, the development of universal donor stem cell products that can be administered to multiple patients in need has been proposed, yet a strategy controlling both adaptive and innate immune rejection has not been reported. In this study, we employed multiplex genome editing to selectively ablate the highly polymorphic HLA class Ia and class II molecules and introduced the immunoregulatory factors PD-L1, HLA-G, and CD47 to control T cell- and NK cell-mediated immune responses and macrophage engulfment in vitro and in vivo. Our strategy demonstrates the power of cell engineering and informs future studies aiming to generate “off-the-shelf” universal cell products that may make cell therapy available to a larger pool of patients.