Central to the growth and survival of a healthy embryo are extra-embryonic tissues such as the placenta, yolk sac, and amnion, a robust, fluid-filled membrane traditionally known for its protective role, but now increasingly recognized for its potential involvement in guiding embryonic patterning through signaling cues. In a groundbreaking advancement, researchers at the Francis Crick Institute have developed a highly accurate 3D stem cell-derived model of the human amnion called post-gastrulation amnioids (PGAs), which replicates key structural and functional features of extra-embryonic development up to four weeks post-fertilization.
This model represents the first successful replication of human amniotic sac development beyond two weeks in vitro. It provides critical insight into a stage of human development that has previously remained inaccessible due to ethical constraints and technical limitations. The study, published in Cell, highlights the potential of PGAs to transform our understanding of early embryonic development and to provide an alternative source of amniotic membranes for medical applications.
Gharibi et al. created PGAs by culturing human embryonic stem cells with just two chemical signals over 48 hours. This process led the cells to self-organize into structures that closely resembled the amniotic sac, including the formation of an inner epithelial layer and an outer layer of extra-embryonic mesoderm. By day 10, over 90% of the PGAs developed sac-like structures, which expanded steadily over 90 days without additional input. These structures faithfully mimicked the cellular composition of the natural human amnion, and the fluid within them closely resembled human amniotic fluid.
The model also produced a yolk sac surrounded by extra-embryonic mesoderm, capturing the complexity of extra-embryonic tissue development. This is particularly significant, as the yolk sac plays a crucial role in nutrient delivery, gas exchange, and early blood formation in the embryo.
Using genetic manipulation, the team identified the transcription factor GATA3 as essential for amnion formation. Disabling GATA3 resulted in impaired development of the amniotic tissue, while enhancing its expression was sufficient to induce amnion-like structures without further signaling. These findings suggest that GATA3 is both necessary and sufficient for initiating amnion development and that an autoregulatory feedback loop involving extra-embryonic signals may govern this process.
Beyond structural modeling, the PGAs also provided evidence of active communication between the amnion and the embryo. When mixed with untreated embryonic stem cells, the PGAs influenced those cells to begin forming amnion-like structures. This indicates that the amnion may play a more dynamic role in embryonic development than previously believed, possibly delivering cues that help guide the formation of embryonic tissues.
Zheng et al. in their study used human pluripotent stem cells to model early post-implantation development and showed that amnion-like cells can exert signaling influences on neighboring embryonic tissues.
The medical potential of this model is substantial. Currently, amniotic membranes are used in procedures such as corneal repair, treatment of chronic wounds, and reconstruction of the uterine lining. These membranes are typically sourced from donors, limiting availability. PGAs offer a scalable and ethical alternative that could eventually be generated from a patient’s own cells, reducing the risk of rejection and increasing access.
The research team is now exploring clinical applications of PGAs. This innovative model not only deepens our understanding of human development but also redefines the amnion’s role from a passive protector to an active contributor in shaping the embryo.
References
- Gharibi B, Inge OCK, Rodriguez-Hernandez I, Driscoll PC, Dubois C, Jiang M, et al. Post-gastrulation amnioids as a stem cell-derived model of human extra-embryonic development. Cell [Internet]. 2025 May 15 [cited 2025 May 16];0(0). Available from: https://www.cell.com/cell/abstract/S0092-8674(25)00458-1
- Zheng, Y., Xue, X., Shao, Y. et al. Controlled modelling of human epiblast and amnion development using stem cells. Nature 573, 421–425 (2019). https://doi.org/10.1038/s41586-019-1535-2