Specially Assigned Associate Professor Institute of Science Tokyo, Japan
Abstract: Naive pluripotent stem cells (PSCs) represent the earliest state of pluripotency, akin to the pre-implantation epiblast. While mouse and human naive PSCs exhibit differences in self-renewal requirements and extraembryonic differentiation potential, the conservation of these differences across higher primates remains unclear. To address this, we attempted to establish chimpanzee naive iPSCs (niPSCs). Initial efforts using standard human naive PSC culture conditions resulted in colonies that failed to propagate. However, we discovered that the addition of Activin, IL6, and, crucially, a Polycomb Repressive Complex 2 (PRC2) inhibitor (A6E condition) enabled efficient derivation and stable maintenance of chimpanzee niPSCs. These chimpanzee niPSCs displayed a global transcriptome profile closely resembling human naive PSCs and the pre-implantation epiblast, sharing the expression of key pluripotency transcription factors. Notably, chimpanzee niPSCs demonstrated the ability to differentiate into extraembryonic lineages, including trophectoderm and hypoblast, and formed tri-lineage blastoids, mirroring human blastoids. This highlights their potential as a valuable comparative model for studying pluripotency and early embryogenesis in higher primates. Furthermore, we found that PRC2 inhibition not only overcame the self-renewal barrier in chimpanzee niPSCs but also facilitated feeder-free propagation of human naive PSCs. This suggests that excess H3K27me3 deposition, mediated by PRC2, poses a significant obstacle to naive PSC self-renewal across species. Our findings provide crucial insights into the evolution of pluripotency and offer a promising avenue for generating ethically more acceptable models of early human development using chimpanzee niPSCs.
