A research team headed by Prof. Jacob Hanna at the Weizmann Institute of Science has created complete models of human embryos from stem cells cultured in the lab - and managed to grow them outside the womb up to day 14. As reported in Nature, these stem-cell embryo models had all the structures and compartments characteristic of this stage, including the placenta, yolk sac, chorionic sac and other external tissues that ensure the models' dynamic and adequate growth. KU Leuven helped to characterize the new human embryo model.
Cellular aggregates derived from human stem cells in previous studies could not be considered genuinely accurate human embryo models, because they lacked several of the defining hallmarks of a post-implantation embryo. In particular, they failed to contain several cell types that are essential to the embryo's development, such as those that form the placenta and the chorionic sac. In addition, they did not have the structural organization characteristic of the embryo and revealed no dynamic ability to progress to the next developmental stage.
Collaboration with KU Leuven
"Last year, our team showed that stem cells could form an important building block of the human embryo, extraembryonic mesoderm cells. We predicted that combining these cells with other cell types could form complex post implantation human embryo models. This is exactly what has been achieved in the new work" explains Prof. Vincent Pasque from KU Leuven, whose team helped to characterize the new human embryo model.
Given their authentic complexity, the human embryo models obtained by Hanna's group may provide an unprecedented opportunity to shed new light on the embryo's mysterious beginnings. Little is known about the early embryo because it is so difficult to study, for both ethical and technical reasons, yet its initial stages are crucial to its future development. During these stages, the clump of cells that implants itself in the womb on the seventh day of its existence becomes, within three to four weeks, a well-structured embryo that already contains all the body organs.
Letting the embryo model say "Go!"
Hanna's team built on their previous experience in creating synthetic stem cell-based models of mouse embryos. As in that research, the scientists made no use of fertilized eggs or a womb. Rather, they started out with human cells known as pluripotent stem cells, which have the potential to differentiate into many, though not all, cell types. Some were derived from adult skin cells that had been reverted to "stemness." Others were the progeny of human stem cell lines that had been cultured for years in the lab.
The researchers then used Hanna's recently developed method to reprogram pluripotent stem cells so as to turn the clock further back: to revert these cells to an even earlier state - known as the naïve state - in which they are capable of becoming anything, that is, specializing into any type of cell. This stage corresponds to day 7 of the natural human embryo, around the time it implants itself in the womb.
"We confirmed that the cells made by the Hanna team represent the key cell types of the early human post implantation embryo" adds Prof. Vincent Pasque, who guided PhD student Thi Xuan Ai Pham.
Soon after being mixed together under optimized, specifically developed conditions, the cells formed clumps, about 1 percent of which self-organized into complete embryo-like structures.
The stem cell-based embryo-like structures (termed SEMs) developed outside the womb for 8 days, reaching a developmental stage equivalent to day 14 in human embryonic development. That's the point at which natural embryos acquire the internal structures that enable them to proceed to the next stage: developing the progenitors of body organs.
New direction of research into early pregnancy failure
"Our models can be used to reveal the biochemical and mechanical signals that ensure proper development at this early stage, and the ways in which that development can go wrong," professor Jacob Hanna from the Weizmann Institute of Science says.
In fact, the study has already produced a finding that may open a new direction of research into early pregnancy failure. The researchers discovered that if the embryo is not enveloped by placenta-forming cells in the right manner at day 3 of the protocol (corresponding to day 10 in natural embryonic development), its internal structures, such as the yolk sac, fail to properly develop.
"An embryo is not static. It must have the right cells in the right organization, and it must be able to progress - it's about being and becoming," Hanna says. "Our complete embryo models will help researchers address the most basic questions about what determines its proper growth."
This ethical approach to unlocking the mysteries of the very first stages of embryonic development could open numerous research paths. It might help reveal the causes of many birth defects and types of infertility. It could also lead to new technologies for growing transplant tissues and organs. And it could offer a way around experiments that cannot be performed on live embryos - for example, determining the effects of exposure to drugs or other substances on fetal development.
