To better understand the earliest stages of human growth, researchers can examine donated embryos or human embryonic stem cells, both of which are in limited supply, or address their questions with animal models. In two studies published in Nature today (March 17), the authors introduce a complementary option: the human blastoid, a blastocyst-like, three-dimensional model system that recapitulates many of the events in the first 10 days of human development—and doesn’t require any starting material from a human embryo.
These papers “are great news,” says Marta Shahbazi, a developmental biologist at the Medical Research Council Laboratory of Molecular Biology in England who was not involved in the work. “Studying human development is quite challenging because . . . it’s very difficult to access human embryos, so developing a stem cell model is a great way to help the field progress.”
A blastocyst is a human embryo around five or six days after fertilization that is growing and preparing to implant into the uterine wall. It’s made of an outer spherical layer called the trophectoderm, composed of cells known as trophoblasts that are the placental precursors, and inside the sphere is a characteristic cavity that contains the so-called inner cell mass. This group of cells contains three embryonic cell types—the ectoderm, mesoderm, and endoderm—that will eventually divide to fill the cavity. These tissues have the potential to give rise to all the cells in the body and are the cells that researchers use to derive human embryonic stem cells.
“The period of early human development near implantation is key to understanding developmental defects and pregnancy loss,” the University of Texas Southwestern Medical Center’s Jun Wu says, but “especially at this stage . . . it is essentially a black box.”
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To generate an alternative to human embryos for research and crack open that black box, Wu and colleagues previously generated blastoids from mouse stem cells and showed that they could form some, but not all, embryonic structures when implanted in a surrogate female. To make a human blastoid, they subjected both human embryonic stem cell lines registered with the National Institutes of Health and induced pluripotent stem cell lines to culture conditions intended to nudge the cells toward making a blastocyst-like structure. About 10–20 percent of the time, their strategy resulted in blastoids, which they found have similar gene expression patterns to blastocysts, are capable of generating stem cells from the inner cell mass–like cells, and, with additional culturing, can form peri-implantation embryo-like structures and attach to plastic dishes.
What was completely surprising is that when you put them together, they self-organize. They seem to talk to each other in some way that we need to investigate.—Jose Polo, Monash University
As they describe in their study, the researchers also treated the blastoids with four different inhibitors for human blastocyst–specific isoforms of the enzyme protein kinase C. The team determined that some of these isoforms were important for generating cavities in the blastoids, indicating that the enzyme may play a specialized role in cavity formation in human blastocysts.
In the other study, a research team led by Jose Polo, a developmental biologist at Monash University in Australia, started with a previously published protocol to reprogram human fibroblasts into trophoblast stem cells. They noticed that by about three weeks in, the cells were differentiating in culture into cells that looked like all three cell types found in a very early human embryo. When they transferred groups of these cells from their flat culture dishes into a three-dimensional culture system, various types of structures formed. Between about 6 percent and 18 percent of these 3-D units had an inner cavity with an adjacent clump of cells that produced several pluripotency markers, as the inner cell mass does in a blastocyst. In contrast, the outer cells surrounding the cavity looked more like trophoblast cells.
“What was completely surprising is that when you put them together, they self-organize,” says Polo. “They seem to talk to each other in some way that we need to investigate.”
Blastoids “clearly do have morphology and gene expression patterns that resemble some of the aspects of the blastocyst,” says Janet Rossant, a stem cell biologist at the University of Toronto and the Hospital for Sick Children who did not participate in the work. There are some limitations to the blastoid strategy, she adds: the primitive endoderm doesn’t seem to form very well, there are other cell types in the mixtures that are not well defined, and the efficiency of making the blastoids is pretty low.
“Neither paper is claiming that they’re perfect,” Rossant says, yet “the potential [is] there to look at how the trophectoderm can—as the embryos develop further—signal the inner cell mass to really promote the rest of development. You have access to blastocyst development, implantation first stages, how the trophoblast works, maybe a little bit of understanding of how the embryo and extra embryonic lineages are required to talk to each other for normal development.” According to Rossant, some of the next steps are to improve the strategy by making it more robust, efficient, and reproducible.
In the future, blastoids could be generated in large quantities to probe questions about infertility, implantation, and the effect of chemicals or pathogens on early development without using actual human embryos, Polo says, because you could start with adult fibroblasts.
All the experts agree that with the strategy’s bright future comes the importance of considering the ethical implications of generating groups of cells that resemble very early embryos. “These blastoid models are an exciting milestone for this emerging field,” Sophie Petropoulos, a developmental biologist at the University of Montréal who did not participate in either study, tells The Scientist. “Policy issues and guidelines for the ethical conduct pertaining to 3-D embryo models [are] at present not well defined,” she adds. “This model raises concerns, and requires a longer conversation.”
X. Liu et al., “Modelling human blastocysts by reprogramming fibroblasts into iBlastoids,” Nature, doi:10.1038/s41586-021-03372-y, 2021.
L. Yu et al., “Blastocyst-like structures generated from human pluripotent stem cells,” Nature, doi:10.1038/s41586-021-03356-y, 2021.