Human EPS cells (green) can be detected in both the embryonic part (left) and extra-embryonic parts (placenta and yolk sac, right) of a mouse embryo. Credit: Salk Institute
What totipotent stem cells can do that pluripotent ones can’t do, however, is develop into tissues that support the embryo, like the placenta. These are called extra-embryonic tissues, and are vital in development and healthy growth. Now, scientists at the Salk Institute, in collaboration with researchers from Peking University, in China, are reporting their discovery of a chemical cocktail that enables cultured mouse and human stem cells to do just that: generate both embryonic and extra-embryonic tissues. Their technique could yield new insights into mammalian development that lead to better disease modeling, drug discovery and even tissue regeneration. This new technique is expected to be particularly useful for modeling early developmental processes and diseases affecting embryo implantation and placental function, possibly paving the way for improved in vitro fertilization techniques.
“During embryonic development, both the fertilized egg and its initial cells are considered totipotent, as they can give rise to all embryonic and extra-embryonic lineages. However, the capture of stem cells with such developmental potential in vitro has been a major challenge in stem cell biology,” says Salk Professor Juan Carlos Izpisua Bemonte. Once a mammalian egg is fertilized and begins dividing, the new cells segregate into two groups: those that will develop into the embryo and those that will develop into supportive tissues like the placenta and amniotic sac. Because this division of labor happens relatively early, researchers often can’t maintain cultured cell lines stably until cells have already passed the point where they could still become either type. The newly discovered cocktail gives stem cells the ability to stably become either type, leading the Salk team to dub them extended pluripotent stem (EPS) cells.
Highlights
•A chemical cocktail enables derivation of EPS cells from both humans and mice
•A single mouse EPS cell generates both embryonic and extraembryonic lineages in vivo
•Mouse EPS cells show robust and superior chimeric ability at the single cell level
•Human EPS cells show interspecies chimeric competency in mouse conceptuses
“The discovery of EPS cells provides a potential opportunity for developing a universal method to establish stem cells that have extended developmental potency in mammals,” says Jun Wu, a senior scientist at Salk. “Importantly, the superior interspecies chimeric competency of EPS cells makes them especially valuable for studying development, evolution and human organ generation using a host animal species.” To develop their cocktail, they first screened for chemical compounds that support pluripotency. A simple combination of 4 chemicals and a growth factor could stabilize the human pluripotent stem cells at a developmentally less mature state, thereby allowing them to more efficiently contribute to chimera formation in a developing mouse embryo. They also applied the same factors to mouse cells and found, surprisingly, that the newly derived mouse stem cells could not only give rise to embryonic tissue types but also differentiate into cells from the extra-embryonic lineages. Moreover, the team found that the new mouse stem cells have a superior ability to form chimeras and a single cell could give rise to an entire adult mouse, which is unprecedented in the field, according to the team.
“The superior chimeric competency of both human and mouse EPS cells is advantageous in applications such as the generation of transgenic animal models and the production of replacement organs,” adds Wu. “We are now testing to see whether human EPS cells are more efficient in chimeric contribution to pigs, whose organ size and physiology are closer to humans.” Human EPS cells, combined with the interspecies blastocyst complementation platform hold great potential for the generation of human organs in pigs to meet the rising demand for donor organs.
http://www.cell.com/cell/fulltext/S0092-8674(17)30183-6
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