Inhibition of PRC2 enables self-renewal of blastoid-competent naive pluripotent stem cells from chimpanzee
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.
Authors
- Arthur Radley (ORCID: https://orcid.org/0000-0003-0047-257X)
- Ferdinand von Meyenn (ORCID: https://orcid.org/0000-0001-9920-3075)
- James S. Clarke (ORCID: https://orcid.org/0000-0002-7917-0998)
- Petra Hájková (ORCID: https://orcid.org/0000-0003-4145-1468)
- João Pedro Agostinho de Sousa
- Zoe Heckhausen (ORCID: https://orcid.org/0000-0003-0085-2492)
- Paul M. O’Neill (ORCID: https://orcid.org/0000-0003-4338-0317)
- Hiroo Imai (ORCID: https://orcid.org/0000-0003-0729-0322)
- Somayyeh Sadat Tahajjodi
- Ge Guo
- Austin Smith (ORCID: https://orcid.org/0000-0002-3029-4682)
- Francesca A. Carlisle (ORCID: https://orcid.org/0000-0002-9734-113X)
- Zhili Ren (ORCID: https://orcid.org/0000-0002-6115-050X)
- Ayaka Yanagida (ORCID: https://orcid.org/0000-0002-6350-2185)
- Madeline A. Lancaster (ORCID: https://orcid.org/0000-0003-2324-8853)
- Dong-Wan Kim (ORCID: https://orcid.org/0000-0003-2251-3707)
- Hideki Masaki (ORCID: https://orcid.org/0000-0001-7615-5314)
- Tao Huang (ORCID: https://orcid.org/0000-0003-1743-1942)
- Hiromitsu Nakauchi (ORCID: https://orcid.org/0000-0002-9841-6973)
- Jingran Zhuo
Institutions
- Tokyo Medical University (JP)
- MRC Laboratory of Molecular Biology (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Kyoto University (JP)
- University of Exeter (GB)
- ETH Zurich (CH)
- Stem Cell Institute (PA)
- MRC London Institute of Medical Sciences (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Cell stem cell
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1016/j.stem.2025.02.002
- Citations
- 4
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Wellcome
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science London
- Fondation Leducq
- Kyoto University
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- European Research Council
- H2020 European Research Council