The early development of human embryos contains many mysteries at the beginning of life. Technical and ethical constraints make the process feel like a “black box”, and our intuitive understanding of this is extremely limited. In a new paper published online today in the journal Nature, a collaboration between scientists at the University of Cambridge and the Hubrecht Institute in the Netherlands has led to a breakthrough.
Using human embryonic development stem cells, they built a three-dimensional model that simulates early embryos. “This exciting new model system will allow us to reveal and explore the processes of early human embryonic development in the laboratory for the first time,” the study authors said. “
From a single cell to a complex human body, the formation of the primary intestinal embryo is a critical stage in the embryonic development process. In this process, a “uniform” cell folds itself into an orderly tissue that can be divided into three layers of cells. The three cell layers specific to the primary intestinal embryo will then produce all the organs and major systems of the human body.
Many birth defects are caused by alcohol, drugs, chemicals or infections at the primary intestinal stage. The understanding of the original intestinal embryo can also provide clues for infertility, abortion, genetic diseases, etc.
Still, scientists know very little about the formation of the human primary intestinal embryo. One important reason is that law and ethics do not allow human embryos to be cultured in the laboratory for 14 days, and the formation of primary intestinal embryos begins at this point in time. Due to the lack of suitable models, it has been difficult to study the formation of human primary intestinal embryos.
In the study, scientists avoided using natural embryos and used stem cells to build a model of “primary intestinal embryos”, promising to solve the problem.
Pseudo-color scanning electron microscope photo of human-like progenitor (Credit: Naomi Moris)
In previous work, Alfonso Martinez-Arias, a professor of genetics at the University of Cambridge, and colleagues have successfully grown in vitro “primary intestinal embryos” with mouse embryonic stem cells, the trivial-like cell aggregations with similar properties to the original intestinal embryo. Animal models can provide clues to our understanding of the formation of human protoenteros, but as cells differentiate, animal models may behave differently from human embryos, such as reactions to drugs, which are linked to many birth defects.
As a result, the research team has further developed a model of human embryonic development based on past techniques. They cultured a certain number of human embryonic stem cells in small holes, where cells formed a closely connected group. Subsequently, in a special culture environment, the suspended cell groups begin to change after chemical signaling.
The naturally occurring proto-intestinal embryo destroys the symmetry of the original cell group and produces pre- and post-polarity. And from the form point of view, the culture of the primary intestinal embryo will gradually elongate, divided out the front and back. Moreover, like the characteristics of the human primary intestinal embryo, the cell group has a unique three-embryo structure.
Culture24-hour, 48-hour and 72-hour human-like protoentero embryos, blue-labeled DNA, red-labeled nerve cells, and green-labeled germ-layer cells (Credit: Naomi Moris)
To confirm that this three-dimensional model can be used to reproduce key events in early human development, the researchers used spatial transcriptional histology to observe changes in gene expression. In the 72-hour culture of progenitor-like embryos, they found a clear set of gene expression characteristics associated with promoting the development of important body tissues, including thoracic muscles, bones and cartilage structures;
After compared the primary intestinal embryo with the Carnegie staging system human embryo development schedule, the researchers concluded that the cultivation of 72-hour primary intestinal embryos is equivalent to Carneigie 9, that is, about 18 to 21 days old human embryos.
The human-like protointestinal embryo, which appears “before and after”, is the rear of the green, simulates the end of the embryo, and purple is the front, the equivalent of a developing heart cell, gray-labeled DNA (Photo: Naomi Moris)
However, these primary intestinal embryos do not develop formed embryos. They do not contain brain cells and do not have the tissue needed for embryos to be implanted into the uterus. Therefore, they do not go beyond the early stages of development, nor do they violate ethical standards.
“Our model spawned part of the blueprint for human development. Professor Martinez-Arias said, “It’s exciting to be able to witness the development process that no one has seen or studied before.” “
The new model of the “primary intestinal embryo” developed by human embryonic stem cells could also offer great potential to identify the causes of birth defects and improve disease models, Dr. Moris added.