Uncovering the hidden origins of the placenta

When an embryo attaches to the uterus around six days after fertilization, it begins forming both the body and the placenta—a process known as implantation. This stage is crucial, as most pregnancies end prematurely. Scientists know little about implantation, and researchers at Caltech have now provided the most detailed picture yet of this process in mouse embryos, revealing an unexpected source for the placenta.

Previously, it was thought that the placenta grew from a single group of cells on the embryo's polar side, which touches the inner cluster of cells that will become the body. However, by filming embryos as they implanted and monitoring gene activity in over 22,000 individual cells during and after implantation, the Caltech team discovered a second source: a few cells from the opposite side of the embryo, called border mural cells, that travel to help build the placenta.

When these cells were removed, the structure responsible for forming the placenta failed to develop. Human embryos likely have similar cells, which could explain why some early pregnancies fail. The findings also highlight a gap in current laboratory models of embryos—those made from stem cells cannot implant or create a functional placenta.

The researchers combined several techniques, including single-cell transcriptomics and live imaging, to capture implantation as it happens. They identified which genes were activated in more than 22,000 single cells from mouse embryos at six closely spaced stages and filmed living embryos as they implanted, testing the effects of removing specific cells. The result is a detailed, cell-by-cell map of implantation, overturning a long-held belief about the placenta's origin.

Before implantation, the mammalian embryo is a hollow ball called a blastocyst. Inside is a cluster of cells that will become the body, while the outer layer, the trophectoderm, will form the placenta. The team found that a small group of mural cells, typically just two to four per embryo, located at the border between the polar and mural sides behave differently.

These border mural cells are among the first to touch the uterine wall, switch on placenta-forming genes, and travel upward to join the ectoplacental cone, which builds the bulk of the placenta.

When most of these mural cells were removed from early embryos grown in the lab, the embryos never formed the initial structure that becomes the placenta. Human embryos showed similar cells and gene signatures, suggesting that a comparable population contributes to the human placenta's formation. The discovery also revealed other changes during implantation, such as a brief state in which body-forming cells transition between two known stages of stem-cell development.

The findings suggest that current lab-grown embryo models, which lack correctly formed mural cells, cannot properly implant or create a functional placenta. The researchers hope to develop methods to create these cells in their models, potentially improving implantation and shedding light on why human embryo implantation occurs so infrequently. The team has made their full dataset freely available through an interactive website, providing researchers worldwide with the opportunity to explore these findings further.