Inhibition of PRC2 enables self-renewal of naïve pluripotent stem cells from chimpanzee

Naïve pluripotent stem cells (nPSCs) correspond to nascent epiblast in the pre-implantation embryo. nPSCs from mouse and human differ in self-renewal requirements and potency for trophectoderm generation. Here we investigated chimpanzee (Pan troglodytes) nPSCs. Naïve type colonies emerged after resetting or reprogramming but failed to expand. We found that the block to self-renewal is overcome by inhibition of EZH2, the enzymatic component of Polycomb repressor group 2 (PRC2). Chimpanzee nPSCs are euploid, produce teratomas, and can be capacitated for somatic lineage differentiation in vitro. They show transcriptome relatedness to human nPSCs and early epiblast, with shared expression of a subset of pluripotency transcription factors. Chimpanzee nPSCs differentiate to trophectoderm and form tri-lineage blastoids. We confirmed that PRC2 suppresses self-renewal by genetic deletions. Furthermore, we demonstrate that EZH2 inhibition facilitates feeder-free propagation of human nPSCs. In summary, chimpanzee nPSCs expand the repertoire of systems for studying primate pluripotency and early embryogenesis. To elucidate the developmental potential of chimpanzee naïve pluripotent stem cells (PSCs), we dissociated induced blastoids into single cells and performed single-cell RNA sequencing (scRNAseq). We then compared each single-cell transcriptome with human embryo scRNAseq datasets to identify the corresponding lineages.