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Naïve, primed or somewhere in between?

Key points:

• Use of stem cells in future regenerative medicine depends on the exact identification of a cell’s ‘inner state’.
• Research used single-cell analysis to identify the gene expression profiles relating to different stem cell states, creating a sliding scale from naïve to primed.
• Stem cells can be placed on this spectrum by their specific expression profile.
• Research also identified a new intermediate cell population showing characteristics of naïve and primed human embryonic stem cells which might be present in the early human embryo.

 
As part of a team of Cambridge researchers, ����������̳ scientists have undertaken a cell-by-cell comparison of nearly 1,000 human embryonic stem cells to learn more about the development stages of the cells that establish a new being. The details of the research are published in the journal Cell Reports today.
 
Before embryos exhibit defined tissue types, the cells that form them have the amazing ability to self-renew and give rise to all the different cell types of the body as the embryo develops. The cells that possess this amazing potential are called pluripotent stem cells. Being able to create stem cells and to direct their development into desired cell types are current research goals towards achieving the therapeutic use of stem cells in regenerative medicine, for example to repair spinal cord injuries, or tissue damage. Bone marrow transplants are the most widely used stem-cell therapy at the moment but use of a person’s own cells for treatment reduces the need for donor matches and avoids reaction with the immune system.
 
“We don’t actually know much about the cells that provide the source of all the different cell types in the later human embryo and what drives the decisions on cell fate,” says Dr Ferdinand von Meyenn, co-first author on the research paper and UKRI Rutherford Fund Fellow at King’s College London at the time of this research. “There’s known variability in mouse embryonic stem cells that is associated with stem cell state but we know a lot less about how the different cell types of the embryo are established in humans. This single-cell analysis gives a window into that timepoint.”
 
The researchers compared individual cells derived from very early human embryos to pinpoint the differences between stem cells of a ‘naïve’ state and stem cells in a ‘primed’ state – considered to be a step closer towards assuming a distinct cell identify – using a technique called single-cell RNA sequencing.
 
The technique gave a view of the bits of the genome that were being read in the cells and allowed the researchers to create a genetic profile of naïve and primed stem cells, each state showing characteristic differences in the genes that were being read. Importantly, the research identified markers for precisely identifying the naïve or primed state of embryonic stem cells.
 
The researchers expected to see some variation within these gene expression profiles but surprisingly the cells of each state all appeared very similar amongst themselves. One unexpected result was that the researchers identified an intermediate population of naïve cells with a primed-like expression profile.
 
“We were expecting to see some differences within each stem cell state that would allow us to identify sub-populations within them, perhaps giving an indication of the development states the cells progress through so we were surprised by how similar the cells in each state were,” explains Dr von Meyenn. “Finding the intermediate population of cells was unexpected. It could be that cells within this population only exist at a precise developmental timepoint. Our analysis mapped these cells to day 5 of human embryonic development, indicating that this cell population may be present in developing embryos and relevant to understanding human embryonic development.”
 
The researchers used the single-cell data to create a naïve-to-primed spectrum, where single-cell profiling allows the cell to be mapped to a point on the spectrum, either as naïve, primed or somewhere in between. Profiling and categorising stem cells by this method can confirm stem cell state and detect any variability or deviation in cells that may be used for therapeutic purposes.
 
“It's interesting to resolve the developmental stages of stem cells by single-cell sequencing especially in human where this hasn't been done before,” says Professor Wolf Reik, Head of the Epigenetics research programme at the ����������̳ and associate faculty member at the Wellcome Sanger Institute. “We can then compare this knowledge with other species and hopefully derive more general insights which can help with approaches moving towards using pluripotent stem cells for regenerative medicine in humans.”
 
Notes for Editors
 
Publication reference
Messmer & von Meyenn et al. Transcriptional heterogeneity in naive and primed human pluripotent stem cells at single-cell resolution. Cell Reports, 22 January 2019, DOI: 10.1016/j.celrep.2018.12.099

Research funding
This research was supported by funding from Cancer Research UK and EMBL to John Marioni at the Cancer Research UK Cambridge Institute, a UKRI Rutherford Fund Fellowship to Ferdinand von Meyenn, BBSRC and Wellcome Trust funding to Wolf Reik.
 
Press contact
Dr Louisa Wood, Institute Communications Manager, louisa.wood@babraham.ac.uk, 01223 496230
 
Affiliated authors (in author order):
Ferdinand von Meyenn, previously a research fellow in the Reik group, Epigenetics programme
Aurora Savino, Reik group, Epigenetics programme
Fátima Santos, Reik group, Epigenetics programme
Hisham Mohammed, Reik group, Epigenetics programme
Wolf Reik, Head of the Epigenetics research programme
 
About the ����������̳
The ����������̳ undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. ����������̳ focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC) through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.