Scientists have captured the most detailed images yet of developing human embryos in real time using two common laboratory tools – fluorescent dyes and laser microscopes.
The technique, described in Cell on July 5, 1, allows researchers to study crucial events in the first days of development without genetically altering the embryos, which has previously limited the use of some imaging techniques in human embryos due to ethical concerns.
“This is the first time we can actually image an early human embryo at very early stages of development with cellular resolution,” says Nicolas Plachta, a cell biologist at the University of Pennsylvania in Philadelphia and co-author of the paper. “We can see individual cells and how they interact with each other as they form a pre-implantation human embryo.”
In addition to providing a new tool for researchers, the imaging technique could lead to the development of ways to non-invasively screen embryos conceived through in vitro fertilization (IVF).
Fluorescent dyes: human embryos
Researchers typically have to study human embryos using postmortem samples because many tools for labeling living cells involve genetically engineering them to produce fluorescent proteins.
Plachta and his colleagues developed a solution using fluorescent dyes that can be simply added to a sample to label specific cellular structures.
The embryos used in this study were donated for research through an IVF clinic. They’re in a very early stage of development—each consisting of only 60-100 cells—and don’t yet have any fully formed tissues or organs, Plachta says.
The researchers used SPY650-DNA, a fluorescent dye that labels genomic DNA, and SPY555-actin, which labels a protein called F-actin that makes up the cytoskeleton of cells. They then visualized dozens of live embryos during the first 40 hours of development using powerful laser scanning microscopes.
“We could see these cells dividing and chromosomes segregating, and we could even capture chromosome segregation defects in real time,” says Plachta.
For example the researchers observed that cells in the outer layer of the embryo, known as the trophectoderm, lose some of their DNA during a phase of cell replication called interphase—in which cells replicate their DNA.
Such errors could be associated with chromosomal abnormalities such as aneuploidy, a condition characterized by excess or missing chromosomes in the early embryo and associated with pregnancy loss and implantation failure.
“Knowing when aneuploidy occurs gives us an opportunity to intervene and try to correct the problem,” says Zev Williams, a fertility specialist at Columbia University in New York. The latest images reveal the early days of embryo development “with unprecedented clarity,” he adds.
key events in human embryos and mice
The researchers were also able to compare key events in human embryos and mice – which are often used as models for studying embryonic development. They observed some important differences. For example, a process called compaction, which involves changes in cell shape, begins at the 12-cell stage in human embryos compared to the 8-cell stage in mice; the process is also more asynchronous in human embryos, leading to variations in internal and external cell formation.
“The detection of these small changes is what makes this paper so novel,” says Sade Clayton, a cell biologist at Washington University in St. Louis, Missouri. “These small differences could actually [translate into] quite large differences in terms of in utero development.”
The authors hope to build on this research by imaging human embryos for longer periods of time, using lower-intensity laser microscopes, and incorporating additional dyes that can label different structures, such as cell membranes.
This technique could one day even have clinical applications, Plachta says. “In the future, we could use this type of live imaging approach to non-invasively monitor embryos in the clinic,” he says. This could be part of tests to determine “which human embryo probably has the best potential” before implantation, he adds.
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