Cell Stem Cell. 2025 Sep 16. pii: S1934-5909(25)00303-0. [Epub ahead of print]
Chuanxin Chen,
Jinyi Wu,
Xinggu Wang,
Litao Chang,
Kexin Wang,
Kaiyi Wu,
Mingyue Guo,
Huanhuan Li,
Fei Sun,
Xinxing Jiang,
Yanlin Ma,
Guangjin Pan,
Zhenyu Xiao,
José C R Silva.
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