Meanwhile, Hanna’s team in Israel is developing mouse embryo models in a similar way, as they described in a clear paper Cell was published shortly before the paper from Zernicka-Goetz’s group. Hanna’s models are also made solely from embryonic stem cells, some of which have been genetically engineered to become TSC and XEN cells. “Whole embryos filled with fusion organs, including the embryonic outer membrane, can be generated by starting with just naive pluripotent stem cells,” says Hanna.
Hanna’s embryo models, like those of Zernicka-Goetz, have gone through all of the initial stages of development as expected. After 8.5 days, they have a rudimentary body shape, with heads, shoots of extremities, hearts and other organs. Their bodies are attached to a placental prosthesis made of TSC by a column of cells resembling an umbilical cord.
“These embryo models summarize the natural process of embryogenesis very well,” said Zernicka-Goetz. The main difference could be due to the placenta not forming properly, as it cannot make contact with the uterus. Imperfect signals from a faulty placenta can impair the healthy development of certain embryonic tissue structures.
“Without a better alternative to the placenta, it remains to be seen how much further these structures will develop,” she said. That’s why she thinks the next big challenge will be getting embryo models through a stage of development that normally requires the placenta as the interface for the maternal and fetal circulatory systems. No one has yet figured out how to do it in a test tube, but she says her team is working on it.
Hanna admits that he was surprised by how well the embryo models continued to develop after stomach formation. But he adds that after doing this for 12 years, “you get excited and amazed at each milestone, but in a day or two, you get used to it and take it for granted, and you focus on the next goal.”
Army Wu, a stem cell biologist at the University of Texas Southwestern Medical Center in Dallas, is also amazed that embryo models created from embryonic stem cells can go this far. “The fact that they can form embryo-like structures with initial organogenesis clearly suggests that we can obtain tissues that appear to function outside the uterus, based entirely on stem cells,” he said.
On the other hand, it turns out that embryo models are not necessarily developed from literal embryonic stem cells – that is, stem cells harvested from actual embryos. They can also be grown from adult cells taken from you or me and regress to a stem cell-like state. Such “rejuvenating” ability of adult cell types is revolutionary discovery by Japanese biologist Shinya Yamanaka, who won him part of the 2012 nobel prize in Physiology or Medicine. Such reprogrammed cells are called induced pluripotent stem cells, and they are created by injecting adult cells (such as skin cells) with several key genes that function in embryonic stem cells.
So far, induced pluripotent stem cells appear to be able to do almost everything that embryonic stem cells can actually do, including developing into embryo-like structures in vitro. And that success seems to have severed the last essential link between embryo models and real embryos: You don’t need embryos to create them, which makes them largely outside existing regulations.
Growing organs in the laboratory
Even if the embryo models have an unprecedented resemblance to real embryos, they still have many shortcomings. Nicolas RivronA stem cell biologist and embryologist at the Institute of Molecular Biotechnology in Vienna, admits that “embryonic models are rudimentary, imperfect, ineffective and lack the ability to produce a living organism”.
The failure rate for developing embryo models is very high: Less than 1 percent of the original cell clusters make it so far. Subtle abnormalities, mainly related to disproportionate organ sizes, often cause them to be extinguished, says Hanna. Wu believes that more research is needed to understand both the similarities with normal embryos and the differences that might explain why the mouse embryo models failed to develop after 8.5 days.
