This ball of human cells has many similarities to human embryos of 5 days.
UNIVERSITY OF TEXAS SOUTHWEST MEDICAL CENTER
By Mitch Leslie
A human embryo in the blastocyst stage is smaller than the tip of a ball point and may contain less than 100 cells, but this developmental pathway has long amazed biologists and physicians. Many miscarriages occur at this stage, for example, and a blastocyst can also split to create a twin. Now, several research groups have found ways to mimic blastocysts, which attract laboratory-grown human cells to form clusters that closely resemble the real thing.
The performance, described in two Nature This week’s papers and two recent advances may 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 a window 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 have not been able to do before.”
We were all blastocysts once. This phase, which begins in humans about five days after conception, is only a few days. “Blastosis is the first stage in which we develop specialized cell types,” says developmental biologist Janet Rossant of the Hospital for Sick Children and the University of Toronto. The stage also begins another important event: implantation, in which the blastocyst nestles in the uterine membrane and begins to interact with the mother’s cells to build up the placenta.
However, it was difficult to answer questions, such as what development orchestrates blastocyst development and why implantation is so often unsuccessful. The only source for human blastocysts are donations originally generated for IVF treatments, which are scarce and contain large 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 induced mouse stem cells to form blastocyst clusters called blastoids, but they do not perfectly reflect 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 the cell types in our bodies. Under certain culture conditions, the cells can form any of the three cell types in the blastocyst, researchers have previously found. Wu and his team took the discovery a step further and showed that when they stimulated cultured human ES cells with two molecular mixtures, the cells converged into dead rings for blastocysts.
Because ES cells are derived from human blastocysts, they share many of the same ethical and practical limitations. But with the right molecular reproduction, researchers can convert mature cells, such as fibroblasts of the skin, into induced pluripotent stem (iPS) cells, which have the same tissue-generating abilities as ES cells, but which do not require the destruction of embryos. Wu human iPS cells with the same two molecular mixtures also produce blastocyst cell clusters, Wu’s team reports Nature.
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The second group publishes in Nature, led by stem cell biologist Jose Polo of Monash University in Australia, chose a different recipe for making human blastoids while studying how skin cells turn into iPS cells. The group noted that intermediate cells, which had not been fully converted to iPS cells, could grow all three types of blastocyst cells. On standard culture plates, the cells could not display their full potential. But in wider spaces, they merged into spheres that were very similar to blastocysts. In independent groups, led by developmental biologists Magdalena Zernicka-Goetz of the California Institute of Technology and Yang Yu of Beijing University’s Third Hospital, it has been published in pre-print that they also made blastocysts from ‘extended’ human stem cells.
Polos and Wu’s groups showed that their blastoids had many properties of human blastocysts. For example, they contain about the same number of cells and have turned on many of the same genes. And at least in the culture dish, blastoids again create some early steps of implantation.
The making of the bunches was inefficient, and those that formed showed several important differences from blastocysts derived from IVF. “There’s a lot going on that we do not understand,” says reproductive and developmental biologist Susan Fisher of the University of California, San Francisco. Still, she emphasizes, “As a first step, it’s extremely exciting, and a lot can be learned.”
Although the new techniques are ineffective, Polo notes that it can still produce large amounts of blastoids. This could enable researchers to use blastoids to test whether certain chemicals are disrupting the development of the embryo, detect mutations leading to birth defects, and refine IVF.
The blastoids are not embryos, warns Wu, but are a collection of cells undergoing the early stages of embryogenogenesis. “A human blastoid could not develop into a fetus,” he adds. A widely accepted research guideline, codified by law in some countries, prohibits the growth of blastocysts for more than 14 days – and all four groups have met the limit with their blastoids. New recommendations from the International Society for Stem Cell Research, which will be released in May, could provide further guidance on working with embryonic structures such as blastoids.
But the public’s reaction to these new creations is uncertain, Fisher says. “It’s a test case for how scientists and lay people feel about a collection of cells.”