Induced pluripotent stem (iPS) cells have emerged as a new source for cell based therapies. However, the safety of iPS cells in autologous recipients has been questioned after it was reported that iPS cells, but not ES cells, were rejected in syngeneic recipient mice. Due to inadequate mechanistic studies this observation has remained controversial. Here, we hypothesized that iPS cells, but not ES cells, readily differentiate into gamete-forming cells that express meiotic and spermatogenesis-associated antigens which trigger rejection. To address this, 129 Svj iPS cells or ESCs expressing luciferase were separately transplanted s.c. into syngeneic mice. Syngeneic mice injected with ESCs developed a robust luciferase signal, whereas the same mice injected with iPS cells lost the luciferase signal after 2 weeks. In addition, EBs from iPS cells highly express meiotic (Stra8, Mga), primordial (Prdm1, Vasa, Stella) and spermatogenesis genes (Dazl) compared to EBs from ES cells in vitro. These genes are involved in meiosis and spermatogenesis. Disruption of the expression of Stra8, which is “one of the master regulators of r meiosis”, in iPS cells, using shRNA led to significant delay of iPS cell rejection. Furthermore, the expression of Stella, which is high in iPS-EBs, was not upregulated in ES-EBs treated with retinoic acid and testosterone, supporting our hypothesis that GAPs expressed after the initiation of meiosis in iPS cells were responsible for rejection of iPS cell, not ES cells. However, iPS cell-derived hematopoietic cells derived from iPS cells engraft in immunocompetent mice long-term, suggesting that iPS cell derivatives lose the ability to express GAPs, and are therefore safe for transplantation in syngeneic recipients. Our findings, for the first time, provide a unifying explanation of why iPS cells, but not ES cells, are rejected in syngeneic recipients, ending the current controversy on the safety of iPS cells and their derivatives.

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