The signals orchestrating the transformation of cells into the highly organized structures of embryos have remained hidden from observation inside the womb. Now, scientists have illuminated early gastrulation of marmoset embryos in utero using spatial transcriptomics and stem cell-based embryo models. In doing so, they have identified the biochemical signals that control the emergence of the body pattern in the primate embryo. This will guide work to understand birth defects and pregnancy loss in humans.

This work is published in Nature in the article, “Spatial profiling of early primate gastrulation in utero.

“This work will provide a definitive laboratory reference for future studies of early embryo development, and the embryonic origins of disease,” said Thorsten Boroviak, PhD, principal investigator in the laboratory for primate embryogenesis in the Centre for Trophoblast Research at the University of Cambridge.

“Elucidating the molecular framework of axis formation in vivo,” the authors wrote, “is fundamental for our understanding of human development and to advance stem-cell-based regenerative approaches.”

The second week of gestation is one of the most mysterious, yet critical, stages of embryo development. Failure of development during this time is one of the major causes of early pregnancy loss and birth defects.

In previous work, Boroviak’s team showed that the first week of development in marmoset monkeys is remarkably similar to that in humans. But with existing methods, they could not explore week two of development, after the embryo implants into the womb.

The latest stage has implanted and established the body axis. SOX2 gene activity in yellow indicates the future head region. [University of Cambridge]

A new laser-assisted technique enabled the team to track down the earliest signals driving the establishment of the body axis—when the symmetrical structure of the embryo starts to change.

The team discovered that asymmetric signals come from the embryo itself and from transient structures that support the embryo during its development—the amnion, yolk sac, and precursors of the placenta.

“Our virtual reconstructions show the developing embryo and its supporting tissues in the days after implantation in incredible detail,” said Boroviak.

More specifically, the 3D-transcriptomes showed “the emergence of the anterior visceral endoderm, which is hallmarked by conserved (HHEX, LEFTY2, LHX1) and primate-specific (POSTN, SDC4, FZD5) factors.” In addition, WNT signaling spatially coordinates primitive streak formation in the embryonic disc and is counteracted by SFRP1/2 to sustain pluripotency in the anterior domain. They also showed that “amnion specification occurs at the boundaries of the embryonic disc through ID1/2/3 in response to BMP-signaling, providing a developmental rationale for amnion differentiation of primate pluripotent stem cells (PSCs).”

The blueprint unlocks new ways of studying human reproduction and development. In the future, the team plans to use their new technique to investigate the origins of pregnancy complications and birth defects using engineered embryo models. Understanding more about human development will help scientists to understand how it can go wrong and take steps toward being able to fix problems.

Image showing gene activity for SOX2, one of the earliest indicators for head formation. [University of Cambridge]

The pre-implantation period, before the developing embryo implants into the mother’s womb, has been studied extensively in human embryos in the lab. On the seventh day, the embryo implants into the womb to survive and develop. Very little was previously known about the development of the human embryo once it implants because it becomes inaccessible for study.

Boroviak’s team used implanted embryos of the marmoset, a small New World monkey, in their study because they are very similar to human embryos at this early stage of development.

The study also provides a reference for fetal tissue generation in the lab. This tissue is in short supply but is needed for drug screening and studies into stem cell-based treatments to regenerate body tissues in diseases such as Parkinson’s disease.

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