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Modeling post-gastrula development via bidirectional pluripotent stem cells

Cell Research (2025)Cite this article

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Abstract

The absence of stem cells capable of efficiently generating both trophoblast and epiblast lineages has hindered precise recapitulation of embryonic development. Through high-content chemical screening, we established an (AS and LY) AL medium to generate mouse bidirectional pluripotent stem cells (BPSCs) characterized by concurrent expression of OCT4 and CDX2. Mouse BPSCs demonstrated highly plastic differentiation into trophoblast, epiblast and primitive endoderm (PrE) lineages in vitro within 48 h without exogenous inducing factors and efficiently contributed to embryonic and extraembryonic tissues in vivo. Mechanistically, hyperactivation of the Wnt signaling pathway breaks the early lineage differentiation barrier by initiating a Lef1-dependent bypass. Remarkably, integration of BPSCs with PrE induction system enables high-efficiency generation of E8.5-stage embryo models. These advanced models complete gastrulation and recapitulate definitive developmental milestones including brain morphogenesis, neural tube closure, cardiac contraction, somite patterning, and primordial germ cell specification. Moreover, human cells cultured under AL conditions acquire an OCT4 and CDX2 double-positive state and corresponding gene expression profiles, revealing conserved functionality of this culturing platform across species. These findings highlight BPSCs as a powerful tool for investigating early lineage specification and post-gastrulation embryonic development.

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Fig. 1: Chemical induction of BPSCs with co-expression of OCT4 and CDX2.
Fig. 2: BPSCs possess high potential toward embryonic and extraembryonic lineages.
Fig. 3: BPSCs exhibit a unique pluripotency state.
Fig. 4: Wnt signaling pathway expands developmental boundaries of PSCs.
Fig. 5: Construction of embryo model by BPSCs.
Fig. 6: Induction of human double-positive (Oct4+Cdx2+) state cell.

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Data availability

The bulk RNA-seq, ChIP-seq, scRNA-seq and scATAC-seq data generated during this study are available at Genome Sequence Archive of the National Genomics Data Center (https://ngdc.cncb.ac.cn/gsa/): PRJCA027661. All other data used in this study are available from the corresponding authors upon request.

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Acknowledgements

This work was primarily supported by the National Key R&D Program of China (2021YFA1102900) and the National Natural Science Foundation of China (32488101). This work was also supported by the National Key R&D Program of China (2022YFC2702200 and 2024YFA1107000) and the National Natural Science Foundation of China (32330030, 82301921, 32070823, 92168205, 32270909, 82201881, 92168205, 31871448, 31820103009, 82022027, 32300684, 32400677 and 32370842). This work was also supported by the Key Project of the Science and Technology of Shanghai Municipality (19JC1415300 and 21JC1405500), the Natural Science Foundation of Shanghai (21ZR1450700), China Postdoctoral Science Foundation (2023M732660, 2023M732661), the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZB20230523), Shanghai Pilot Program for Basic Research, Shanghai Post-doctoral Excellence Program (2022521, 2022551), Shenzhen Medical Research Fund (B2402013), the Fundamental Research Funds for the Central Universities (22120250374), Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai and Ministry of Education. We thank Rongrong Le (Tongji University), leader of the ethical approval project (2024tjdxsy026), to provide the human cell lines in this study.

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  1. These authors contributed equally: Kuisheng Liu, Zihui Yan, Dandan Bai, Rui Jiang, Yan Bi, Xiangjun Ma.

Authors and Affiliations

  1. Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

    Kuisheng Liu, Zihui Yan, Dandan Bai, Rui Jiang, Yan Bi, Xiangjun Ma, Jiani Xiang, Yifan Sheng, Zhiyuan Ning, Shanru Yi, Yingdong Liu, Xinyi Lei, Yanping Jia, Yan Zhang, Yalin Zhang, Yanhe Li, Tao Wu, Chenxiang Xi, Shanyao Liu, Shuyi Liu, Jiayu Chen, Jiqing Yin, Xiaochen Kou, Yanhong Zhao, Hong Wang, Yixuan Wang, Ke Wei, Shaorong Gao & Wenqiang Liu

  2. Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

    Kuisheng Liu, Zihui Yan, Dandan Bai, Rui Jiang, Yan Bi, Xiangjun Ma, Jiani Xiang, Yifan Sheng, Zhiyuan Ning, Shanru Yi, Yingdong Liu, Xinyi Lei, Yanping Jia, Yan Zhang, Yalin Zhang, Yanhe Li, Tao Wu, Chenxiang Xi, Shanyao Liu, Shuyi Liu, Jiayu Chen, Jiqing Yin, Xiaochen Kou, Yanhong Zhao, Hong Wang, Yixuan Wang, Ke Wei, Shaorong Gao & Wenqiang Liu

  3. College of Life Sciences Technology, Shandong Normal University, Jinan, Shandong, China

    Baoxing Dong

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  1. Kuisheng Liu
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Contributions

S.G., W.L. and Y.W. conceived the project and provided mentoring; K.L., D.B., Y.B. and X.M. designed and performed most of the experiments; Z.Y. provided bioinformatics support; R.J. and K.W. performed compound library screening; K.L., D.B. and Z.Y. wrote the original draft; K.L., D.B., Z.Y., W.L., J.Y. and S.G. reviewed and edited the manuscript; J.X., Y.S., B.D., Z.N., S.Y., Y.D.L., X.L., Y.J., Y.Z., Y.L.Z., Y.H.L., T.W., C.X., Shanyao L., Shuyi L., J.C., J.Y., X.K., Y.H.Z. and H.W. assisted with the experiments.

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Correspondence to Yixuan Wang, Ke Wei, Shaorong Gao or Wenqiang Liu.

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Liu, K., Yan, Z., Bai, D. et al. Modeling post-gastrula development via bidirectional pluripotent stem cells. Cell Res (2025). https://doi.org/10.1038/s41422-025-01172-x

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