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  3. Signaling reprogramming via Stat3 activation unravels high-fidelity human post-implantation embryo modeling

Signaling reprogramming via Stat3 activation unravels high-fidelity human post-implantation embryo modeling

  • Cell Stem Cell. 2025 Oct 2;32(10):1528-1544.e10. doi: 10.1016/j.stem.2025.08.011.
Chuanxin Chen 1,  Jinyi Wu 2,  Xinggu Wang 3,  Litao Chang 2,  Kexin Wang 4,  Kaiyi Wu 4,  Mingyue Guo 5,  Huanhuan Li 2,  Fei Sun 6,  Xinxing Jiang 6,  Yanlin Ma 6,  Guangjin Pan 7,  Zhenyu Xiao 8,  José C R Silva 9
Affiliations

Affiliations

  • 1 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China. Electronic address: chen_chuanxin@gzlab.ac.cn.
  • 2 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China; Guangzhou Medical University, Panyu District, Guangzhou, Guangdong 511495, China.
  • 3 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
  • 4 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China.
  • 5 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China; Guangzhou Medical University, Panyu District, Guangzhou, Guangdong 511495, China; Institute for Regenerative Medicine, University of Pennsylvania, 3400Civic Center Blvd, Philadelphia, PA 19104, USA.
  • 6 Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research & Key Laboratory of Reproductive Health Diseases Research and Translation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan 571101, China.
  • 7 Key Laboratory of Immune Response and Immunotherapy, Center for Development and Regeneration, Guanghzou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 8 School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
  • 9 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China; Guangzhou Medical University, Panyu District, Guangzhou, Guangdong 511495, China. Electronic address: jose_silva@gzlab.ac.cn.
PMID: 40961945 DOI: 10.1016/j.stem.2025.08.011
Abstract

Human embryo models hold great promise for advancing medicine, but current systems lack efficiency and fidelity in replicating post-implantation stages. Here, we investigate whether STAT3 activation can reprogram pluripotent stem cells (PSCs) into early fates that self-organize into embryo models. Using a medium enhancing STAT3 activity (SAM), PSCs reprogram within 60 h into hypoblast, trophectoderm, naive epiblast, and extraembryonic mesoderm. Dissociating SAM-treated PSCs at 60-120 h, followed by 3D culture, results in dynamic development of post-implantation embryo-like structures with up to 52.41% ± 8.92% efficiency. Resulting day 6 examples resemble Carnegie stages 5 (CS5) to 7 (CS7) embryos, exhibiting bilaminar disc structure with epiblast and yolk sac, amniotic cavity, mesenchyme, chorionic cavity, and trophoblast. Notably, CS6/7-like examples exhibit gastrulation, including the formation and correct positioning of primitive streak, epithelial-to-mesenchymal transition, mesoderm, and definitive endoderm. The STAT3-mediated embryo model also closely aligns molecularly with CS6/7 embryo references and represents a state-of-the-art platform for advancing human embryogenesis research.

Keywords

STAT3 signaling; gastrulation; human post-implantation development; integrated embryo model; pluripotency; reprogramming.

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