Achieving pluripotent human embryonic stem cells directly from the embryo
For the first time, researchers have managed to derive a naïve type of stem cell from human embryos. Previously, the closest version to a naïve human stem cell that could be obtained in the lab were cells that were already classed as ‘primed’ towards differentiation. In contrast, naïve embryonic stem cells offer a developmental ‘ground state’.
The ability to source naïve pluripotent stem cells offers hope for regenerative medicine in creating replacement tissues that cannot currently be compensated for if damaged, for example, nerve cells.
Identifying and being able to propagate human stem cells akin to those found in the very early embryo has been a holy grail for stem cell research. As described in the journal Stem Cell Reports, researchers from the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute were able to isolate and culture cells derived from human embryos (donated to research after being produced by IVF) that showed the characteristics of naïve rather than primed stem cells.
Researchers from the Cambridge Stem Cell Institute and the Babraham Institute worked together using lab-based, epigenetics and computer-based approaches to perform a full analysis of the cells to verify that they behaved as ground state embryonic stem cells.
“Until now it hasn’t been possible to isolate these naïve stem cells, even though we’ve had the technology to do it in mice for thirty years – leading some people to doubt it would be possible,” explains Ge Guo, the study’s first author and researcher from the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, “but we’ve managed to extract the cells and grow them individually in culture. Naïve stem cells have many potential applications, from regenerative medicine to modelling human disorders.”
The analysis of the isolated stem cells involved a careful look at their epigenetic status, work performed by researchers at the Babraham Institute. “One of the distinguishing features of naïve human embryonic stem cells is the overall lack of DNA methylation in the genome. This could be likened to a blank page where anything is possible,” describes Ferdinand von Meyenn, a postdoctoral research fellow at the Institute who undertook the epigenetic analysis of the cells. “As cells differentiate into particular cell types, DNA methylation occurs in specific locations in the genome. This is responsible for specifying the cell’s identity and making sure that this identity is fixed.”
In terms of DNA methylation, naïve stem cells, including the ones derived by Guo et al. show very low levels of DNA methylation in their genome (25-40%) which corresponds to their unlimited developmental potential. In contrast, 70% of the genome of primed stem cells showed methylation marks.
Professor Wolf Reik, author on the paper and Head of Epigenetics at the Babraham Institute, said: “This research is very exciting. The fact that the epigenetic status of the isolated human naïve embryonic stem cells matches that of the cells from which they were derived is a robust indicator that these cells are truly naïve.”
The research was supported by the Medical Research Council, Biotechnology and Biological Sciences Research Council, Swiss National Science Foundation and the Wellcome Trust.
Triptych of an image of an early mouse embryo represented in 3-D. The left- and right-hand images are stylised versions of the middle image. The middle image shows the segmentation of a mouse embryo into the external cells which will form the placenta and the inner ball of cells which will go on to form the embryo and all its tissue types. This inner ball of cells in the human embryos was used to obtain human naïve embryonic stem cells.
Guo, G et al. (2016) Naïve pluripotent stem cells derived directly from isolated cells of the human inner cell mass. Stem Cell Reports
Institute affiliated authors (in author order):
Ferdinand von Meyenn, postdoctoral research fellow (Reik lab)
Fatima Santos, senior research scientist (Reik lab)
Wolf Reik, Head of Epigenetics programme and group leader at the Babraham Institute, and associated faculty at the Wellcome Trust Sanger Institute