'Rebooted' stem cells may lead to new treatments

"Scientists have managed to 'reset' human stem cells," the Mail Online reports. It is hoped studying these cells will provide more information about the mechanics of early human development.

This headline comes from a laboratory study that reports to have found a way to turn the clock back on human stem cells so they exhibit characteristics more similar to seven- to nine-day-old embryonic cells.

These more primitive cells are, in theory, capable of making all and any type of cell or tissue in the human body, and are very valuable for researching human development and disease.

Previous research efforts have successfully engineered early-stage stem cells capable of making several cell and tissue types, called pluripotent stem cells.

However, pluripotent stem cells engineered in the laboratory are not perfect and display subtle differences to natural stem cells.

This study involved using biochemical techniques to return pluripotent human stems cells to a more primitive "ground-state" stem cell.

If this technique is confirmed as reliable and can be replicated in other studies, it could ultimately lead to new treatments, although this possibility is uncertain.

While the immediate impact is probably minimal, it's hoped this research may lead to advances in the years to come.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge, the University of London and the Babraham Institute.

It was funded by the UK Medical Research Council, the Japan Science and Technology Agency, the Genome Biology Unit of the European Molecular Biology Laboratory, European Commission projects PluriMes, BetaCellTherapy, EpiGeneSys and Blueprint, and the Wellcome Trust.

The study was published in the peer-reviewed journal Cell as an open access article, so it's available to read online for free.

The Mail Online's coverage was accurate and reflected many of the facts summarised in the press release issued by the Medical Research Council. Interviews with the research's authors and other scientists in the field added useful extra insight to interpret and contextualise the findings.

What kind of research was this?

This was a laboratory study to develop and test a new technique to return pluripotent human stem cells to an earlier, more pristine developmental state.

Pluripotent stem cells are early developmental cells capable of becoming several different cell types. Some stem cells are said to be totipotent (capable of becoming all types of cell), such as early embryonic stem cells shortly after fertilisation.

These types of cells are very valuable in developmental science research as they allow the study of developmental processes in the laboratory that aren't possible to study in a foetus shortly after conception.

As the MRC press release explains: "Capturing embryonic stem cells is like stopping the developmental clock at the precise moment before they begin to turn into distinct cells and tissues.

"Scientists have perfected a reliable way of doing this with mouse cells, but human cells have proved more difficult to arrest and show subtle differences between the individual cells. It's as if the developmental clock has not stopped at the same time and some cells are a few minutes ahead of others."

The aim of this study was therefore to devise and test a way of turning back the clock in human pluripotent stem cells so they exhibit more totipotent characteristics. This was also termed as returning the pluripotent cells to a "ground-state" pluripotency.

What did the research involve?

This research took existing human pluripotent stem cells and subjected them to a battery of laboratory-based experiments in an effort to produce stable stem cells showing a more ground-state pluripotency.

This chiefly involved culturing the human stem cells in a range of biological growth factors and other chemical stimuli designed to coax them into earlier phases of development. Extensive monitoring of the cell characteristics, such as self-replication, gene and protein activity (expression), occurred along the way.

What were the basic results?

The main findings include:

• Short-term expression of proteins NANOG and KLF2 was able to put into action a biological pathway leading to the "reset" of pluripotent stems cells to an earlier state. The MRC press release indicated this was equivalent to resetting the cells to those found in an embryo before it implants in the womb at around seven to nine days old.
• Inhibiting well-established biochemical signalling pathways involving extracellular signal-regulated kinases (ERK) and protein Kinase C (both of which are proteins involved in cell regulation) sustained the "rewired state", allowing cells to stay in the arrested development state.
• The reset cells could self-renew – a key feature of stem cells – without biochemical ERK signalling, and their observable characteristics and genetics remained stable.
• DNA methylation – a naturally occurring way of regulating gene expression associated with cellular differentiation – was also dramatically reduced, suggesting a more primitive state.

These features, the authors commented, distinguished these reset cells from other types of embryo-derived or induced pluripotent stem cell, and aligns them closer to the ground-state embryonic stem cell (totipotent) in mice.

How did the researchers interpret the results?

The researchers indicate their findings demonstrate the "feasibility of installing and propagating functional control circuitry for ground-state pluripotency in human cells". They added the reset can be achieved without permanent genetic modification.

The research group explained the theory that a "self-renewing ground state similar to rodent ESC [embryonic stem cells] may pertain to primates is contentious", but "our findings indicate that anticipated ground state properties may be instated in human cells following short-term expression of NANOG and KLF2 transgenes. The resulting cells can be perpetuated in defined medium lacking serum products or growth factors."

Conclusion

This laboratory study showed human pluripotent stem cells could be coaxed into a seemingly more primitive developmental state, exhibiting some of the key features of an equivalently primitive embryonic stem cell in mice. Namely, this is the ability to stably self-renew and be able to develop into a range of other types of cell.

If replicated and confirmed by other research groups, this finding may be useful to developmental biologists in their efforts to better understand human development and what happens when it goes wrong and causes disease. But this is the hope and expectation for the future, rather than an achievement that has been realised using this new technique.

Sounding a note of caution, Yasuhiro Takashima of the Japan Science and Technology Agency and one of the authors of the study, commented on the Mail Online website: "We don't yet know whether these will be a better starting point than existing stem cells for therapies, but being able to start entirely from scratch could prove beneficial."

This is the start rather than the end of the journey for this new technique and the cells derived from it. The technique will need to be replicated by other research groups in other conditions to ensure its reliability and validity.

The cells themselves will also need to be studied further to see if they do really have the stability and versatility of true primitive stem cells expected under different conditions and time horizons. This will include looking for any subtle or unusual behaviour further down the development line, as has been found to be the case with other types of stem cell thought to be primitive.

Overall, this study is important to biologists and medical researchers as it potentially gives them new tools to investigate human development and associated diseases. For the average person the immediate impact is minimal, but may be felt in the future if new treatments arise.