Inhibition of PRC2 enables self-renewal of blastoid-competent naive pluripotent stem cells from chimpanzee
Summary
Naive pluripotent stem cells (PSCs) are counterparts of early epiblast in the mammalian embryo. Mouse and human naive PSCs differ in self-renewal requirements and extraembryonic lineage potency. Here, we investigated the generation of chimpanzee naive PSCs. Colonies generated by resetting or reprogramming failed to propagate. We discovered that self-renewal is enabled by inhibition of Polycomb repressive complex 2 (PRC2). Expanded cells show global transcriptome proximity to human naive PSCs and embryo pre-implantation epiblast, with shared expression of a subset of pluripotency transcription factors. Chimpanzee naive PSCs can transition to multilineage competence or can differentiate into trophectoderm and hypoblast, forming tri-lineage blastoids. They thus provide a higher primate comparative model for studying pluripotency and early embryogenesis. Genetic deletions confirm that PRC2 mediates growth arrest. Further, inhibition of PRC2 overcomes a roadblock to feeder-free propagation of human naive PSCs. Therefore, excess deposition of chromatin modification H3K27me3 is an unexpected barrier to naive PSC self-renewal. Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
| Authors | Huang T, Radley A, Yanagida A, Ren Z, Carlisle F, Tahajjodi S, Kim D, O'Neill P, Clarke J, Lancaster MA, Heckhausen Z, Zhuo J, de Sousa JPA, Hajkova P, von Meyenn F, Imai H, Nakauchi H, Guo G, Smith A, Masaki H |
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| Journal | Cell stem cell |
| Publication Date | 2025 Apr 3;32(4):627-639.e8 |
| PubMed | 40015279 |
| PubMed Central | PMC7617839 |
| DOI | 10.1016/j.stem.2025.02.002 |