A fast 2C-induction method reveals a barrier role of SP2 for totipotency

Authors

Hu, S., Zhu, P., Liu, H., Chen, H., Xu, S., Guo, E., Cai, B., Quan, X., Pei, D., Chen, J., Wu, H., Cao, S.

Abstract

The acquisition of totipotency in vitro remains a major challenge, limiting our understanding of early embryogenesis and its clinical and translational applications. Here, we reported a robust and rapid chemical reprogramming system that converts mouse embryonic stem cells (mESCs) into totipotent-like cells (TLCs) within 36 hours, with efficiencies exceeding 70%. The induced cells exhibit transcriptomic, epigenomic, and functional features closely resembling 2-cell (2C) stage embryos, as confirmed by scRNA-seq, ATAC-seq, and chimeric embryo analyses. Single-cell trajectory construction revealed a branching reprogramming process that yields both successful totipotent-like and alternative, non-reprogrammed fates. Mechanistically, we identified the transcription factor SP2 as a barrier to totipotency acquisition, promoting lineage-specific gene expression while repressing totipotency networks. Collectively, our study has established a highly efficient in vitro model for totipotency induction and highlighted molecular barriers shaping cell fate decisions, providing a platform to dissect the mechanisms governing the pluripotency-to-totipotency transition.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 24 Jul 2026.

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