Inhibition of PRC2 enables self-renewal of blastoid-competent naive pluripotent stem cells from chimpanzee PMID: 40015279

ADC Targets in Oncology

2026-04-10

Inhibition of PRC2 enables self-renewal of blastoid-competent naive pluripotent stem cells from chimpanzee

Cell Stem Cell. 2025 Feb 26:S1934-5909(25)00041-4. doi: 10.1016/j.stem.2025.02.002.

Tao Huang ¹ , Arthur Radley ¹ , Ayaka Yanagida ² , Zhili Ren ¹ , Francesca Carlisle ¹ , Somayyeh Tahajjodi ¹ , Dongwan Kim ³ , Paul O'Neill ⁴ , James Clarke ⁵ , Madeline A Lancaster ⁶ , Zoe Heckhausen ⁷ , Jingran Zhuo ⁸ , João Pedro Agostinho de Sousa ⁸ , Petra Hajkova ⁷ , Ferdinand von Meyenn ⁸ , Hiroo Imai ⁹ , Hiromitsu Nakauchi ¹⁰ , Ge Guo ¹ , Austin Smith ¹¹ , Hideki Masaki ¹²

Affiliations

1. Living Systems Institute, University of Exeter, Exeter EX4 4QD, UK.
2. Department of Veterinary Anatomy, The University of Tokyo, Tokyo 113-8657, Japan; Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
3. Stem Cell Therapy Division, Institute of Integrated Research, Institute of Science, Tokyo 113-8510, Japan.
4. University of Exeter Sequencing Facility, University of Exeter, Exeter EX4 4QD, UK.
5. Wellcome-MRC Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK.
6. MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
7. MRC Laboratory of Medical Sciences (LMS), Du Cane Rd, London W12 0HS, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, W12 0NN, UK.
8. Department of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland.
9. Department of Cellular and Molecular Biology, Center for the Evolutionary Origins of Human Behavior, Kyoto University, Inuyama, Aichi 484-8506, Japan.
10. Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Stem Cell Therapy Division, Institute of Integrated Research, Institute of Science, Tokyo 113-8510, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
11. Living Systems Institute, University of Exeter, Exeter EX4 4QD, UK. Electronic address: [email protected].
12. Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Stem Cell Therapy Division, Institute of Integrated Research, Institute of Science, Tokyo 113-8510, Japan. Electronic address: [email protected].

Abstract

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.

Keywords

Polycomb; developmental drift; epiblast; higher primate; mammalian early embryo; naive pluripotency; pluripotent stem cells; self-renewal; single-cell transcriptomics; stem cell-based embryo model.