This lab-grown ball of human cells has many similarities to 5-day-old human embryos.
UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER
By Mitch Leslie
A blastocyst-stage human embryo is smaller than the tip of a ballpoint pen and may contain fewer than 100 cells, but this developmental waypoint has long puzzled and annoyed biologists and doctors. For example, many miscarriages occur during this phase and a blastocyst can also split to create twins. Now, multiple research groups have found ways to mimic blastocysts by inducing lab-grown human cells to form clusters that closely resemble the real thing.
The performance, described in two Nature papers this week and two recent preprints, could enable researchers to address important questions about human fertility, such as why in vitro fertilization (IVF) often fails. In addition, the ersatz blastocysts will be “windows into this stage of human development,” said Rice University stem cell biologist Aryeh Warmflash, who was not involved in the work. “They will allow us to study it in ways we couldn’t before.”
We were all blastocysts once. This phase, which starts about 5 days after fertilization in humans and lasts only a few days, is a turning point. “The blastocyst is the first phase in which we have developed specialized cell types,” said developmental biologist Janet Rossant of the Hospital for Sick Children and the University of Toronto. The stage also initiates another momentous event: implantation, in which the blastocyst lodges in the uterine lining and begins to interact with the mother cells to build the placenta.
But it has been difficult to answer questions such as which genes orchestrate blastocyst development and why implantation is so often unsuccessful. The only source for human blastocysts is donated embryos originally generated for IVF treatments, which are scarce and carry heavy ethical baggage. In the United States, for example, researchers cannot use funding from the National Institutes of Health to study these blastocysts. In search of an alternative, several groups of scientists have led mouse stem cells to form blastocyst-like clumps called blastoids, but they don’t perfectly mimic what happens in a human embryo.
To create a human blastoid, cell biologist Jun Wu of the University of Texas Southwestern Medical Center and colleagues initially used embryonic stem cells (ES), which can be isolated from human blastocysts and give rise to all cell types in our body. Under certain culture conditions, the cells can form any of the three cell types in the blastocyst, researchers previously discovered. Wu and his team took it a step further and showed that when they stimulated cultured human ES cells with two molecular mixtures, the cells converged into dead blastocyst ringers.
Since ES cells come from human blastocysts, they share many of the same ethical and practical limitations. But with the right molecular prodding, researchers can convert mature cells, such as skin fibroblasts, into induced pluripotent stem cells (iPS), which have the same tissue-generating properties as ES cells, but do not require the destruction of embryos. Nudging human iPS cells with the same two molecular mixtures also yields blastocyst-like cell clusters, Wu’s team now reports. Nature
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The second group publishes in Nature, led by stem cell biologist Jose Polo of Monash University in Australia, coincidentally came up with a different recipe for making human blastoids while studying how skin cells turn into iPS cells. The group noted that intervening cells, which were not fully converted to iPS cells, were able to turn off all three types of blastocyst cells. The cells failed to show their full potential on standard culture plates. But in wider rooms they converged in spheres that looked very much like blastocysts. In preprints posted last week, two independent groups, led by developmental biologists Magdalena Zernicka-Goetz of the California Institute of Technology and Yang Yu of Beijing’s Third Hospital, also reported making blastocyst-like clusters from “expanded” human stem cells.
Polo’s and Wu’s groups showed that their blastoids recapitulated many features of human blastocysts. For example, they contained roughly the same number of cells and turned on many of the same genes. And at least in the culture dish, blastoids recreate some early implantation steps.
Making the clusters was inefficient, and those that did form showed several important differences from IVF-derived blastocysts. “A lot is happening that we don’t understand,” says reproductive and developmental biologist Susan Fisher of the University of California, San Francisco. Still, she insists, “As a first step, it is extremely exciting and there is a tremendous amount to learn.”
While the new techniques are inefficient, Polo notes that they can still produce blastoids in large numbers. That could allow researchers to use blastoids to test whether certain chemicals interfere with embryonic development, track how mutations lead to birth defects, and refine IVF.
The blastoids are not embryos, Wu warns, but are “a collection of cells going through the early stages of embryogenesis.” A human blastoid cannot develop into a fetus, he adds. A widely accepted research guideline, legally established in some countries, prohibits the cultivation of blastocysts for more than 14 days – and all four groups adhered to that limit with their blastoids. New recommendations from the International Society for Stem Cell Research, due out in May, could provide further guidance on working with embryo-like structures such as blastoids.
But public reaction to these new creations is uncertain, Fisher says. “It is a test case for how scientists and laymen think about a collection of cells.”