“Embryo Model Completes Gastrulation to Neurulation and Organogenesis”, 2022-08-25 ():
Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro1,2,3,4,5, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells6,7,8,9,10,11.
Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from Pax6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6-knockout embryos.
Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.
[media:] The recipe for mammalian life is simple: take an egg, add sperm and wait. But two new papers demonstrate that there’s another way. Under the right conditions, stem cells can divide and self-organize into an embryo. In studies published in Cell and Nature this month, two groups report that they have grown synthetic mouse embryos for 8.5 days, longer than ever before. The embryos developed distinct organs—a beating heart, a gut tube and even neural folds.
The process is far from perfect. Just a tiny fraction of the cells develop these features, and those that do don’t entirely mimic a natural embryo. But the work still represents a major advance that will help scientists to see organ development in unprecedented detail. “This is very, very exciting”, says Jianping Fu, a bioengineer at the University of Michigan in Ann Arbor. “The next milestone in this field very likely will be a synthetic stem-cell-based human embryo”, he says.
The two research teams achieved the feat using similar techniques. Magdalena Zernicka-Goetz, a developmental and stem-cell biologist with laboratories at the University of Cambridge, UK, and the California Institute of Technology in Pasadena, has been working on this problem for a decade. “We started with only embryonic stem cells”, she says. “They can mimic early stages of development, but we couldn’t take it any further.” Then, a few years ago, her team discovered3 that, when they added stem cells that give rise to the placenta and yolk sac, their embryos developed further. Last year, they demonstrated4; that they could use this technique to culture embryos until day 7. In their latest paper, published in Nature today, Zernicka-Goetz’s team describes how they grew embryos for another 1.5 days…This incubator, which kept the embryos going from day 5 to day 11, takes aspects of a previous technology—in which the embryos reside in glass vials that rotate on a Ferris-wheel-like system—and adds ventilation. The ventilation system controls the pressure and the mixture of oxygen and carbon dioxide entering the vials.
…What about humans? But translating this work into humans won’t be easy. Researchers have coaxed human stem cells to become blastocysts—a hollow, a rapidly dividing ball of cells—and even to mimic some aspects of gastrulation—when the early embryo organizes into distinct layers composed of different cell types. But reaching the stage of organ formation in human cells, which happens about a month after fertilization, presents an important technical challenge. Still, Ali Brivanlou, a developmental biologist at The Rockefeller University in New York City, is optimistic. “The field is not too far away.”