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On 2 July Nature retracted the papers and the associated news and views about this research. For further information see their editorial www.nature.com/news/1.15488 and links at the bottom of this article.

Stressed out cells revert to stem cells

08 Apr, 2014

Pluripotent stem cells – cells that can differentiate into one of many cell types – have traditionally been derived from ethically questionable embryonic sources or by the relatively time-consuming and expensive process of manipulating genes inside a cell’s nucleus (induced pluripotent stem (iPS) cells). But now, new research from Japan and the US has uncovered a shortcut to creating pluripotent stem cells by stressing out mature cells.

Medical scientists believe that pluripotent stem cells hold the key to treating an increasing number of diseases. These stem cells are capable of differentiating into many cell types and could be used to effectively replace diseased or damaged parts of the body – a field known as regenerative medicine.

Stressing cells with acid

The new research, published in two papers in the 30 January issue of Nature, discovered that, if mature somatic cells from mice are temporarily exposed to sub-lethal stimuli such as a dose of acid that lowers the pH to 5.7 for 30 minutes, they revert back to an embryonic state – a phenomenon the researchers have called stimulus-triggered acquisition of pluripotency (STAP).

After the researchers had cultivated the mature blood cells to be tested, they tried stressing the cells almost to the point of death by exposing them to various stressful environments including trauma, low oxygen environments and acidic environments. They found that, within a period of only a few days, the cells that had survived recovered from the stressful stimulus by naturally reverting to stem cells. These stem cells began growing in spherical clusters, and when implanted into developing mice embryos, they were able to redifferentiate and mature into any type of cell and grow into any type of tissue, depending on the environment into which they were placed, confirming that the cells were indeed pluripotent.

The researchers went on to reprogramme a dozen cell types, including those from the brain, skin, lung and liver, suggesting that the STAP method will work with most, if not all, cell types – at least in mice.

The team of researchers, led by Dr Haruko Obokata, a stem-cell researcher at the RIKEN Center for Developmental Biology in Kobe, Japan, conclude that the next step is to explore this process in more sophisticated mammals and ultimately in humans.

This type of reprogramming in response to environmental stress has been observed many times in plants whereby mature cells can become immature cells capable of forming a whole new plant structure, including roots and stalks. This is the first time that it has been shown that animals might have a similar defence mechanism.

Using the patient’s own cells – a game changer

Professor Chris Mason, Chair of Regenerative Medicine Bioprocessing, University College London, said that Dr Obakata’s approach in the mouse is the most simple, lowest cost and quickest method to generate pluripotent cells from mature cells. “If it works in man, this could be the game changer that ultimately makes a wide range of cell therapies available using the patient’s own cells as starting material – the age of personalised medicine would have finally arrived.”

“Who would have thought that to reprogram adult cells to an embryonic stem cell-like (pluripotent) state just required a small amount of acid for less than half an hour – an incredible discovery.

“For potential medical use, stimulus-triggered acquisition of pluripotency (STAP) cells will not immediately replace human induced pluripotent stem (iPS) cells discovered in 2007, just as iPS cells have not replaced human embryonic stem (ES) cells discovered in 1998. Every breakthrough has to catch up with the years of accumulated scientific and clinical knowledge that the earlier discovery has generated. However, this knowledge pool accelerates the development of later discoveries enabling game-changing technologies to progress faster to the clinic. For example, it took human ES cells 12 years before their first use in man but only 6 years for human iPS cells. Given the substantial overlap between all three technologies, it is likely that this will shorten the development pathway for STAP cells, however, it will still be many years before the technology could potentially be in everyday clinical practice.”

References

Haruko Obokata et al. (2014). Bidirectional developmental potential in reprogrammed cells with acquired pluripotency. Nature, 505: 676–680. doi:10.1038/nature12969 (http://dx.doi.org/10.1038/nature12969)

Haruko Obokata et al. (2014). Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature, 505: 641–647. doi:10.1038/nature12968 (http://dx.doi.org/10.1038/nature12968)

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