In findings that, in addition to their practical relevance, upend current ideas of the relative importance of genetics and environment for the determination of cell fate, researchers have generated pluripotent stem cells from differentiated cells of young mice without using any sort of genetic manipulation to do so. The only thing that was necessary was to expose the cells to stress, such as low pH or mechanical force.

Stem cell experts in the UK who are working to translate basic research through to therapeutic reality, said the simple, low-cost and quick method of generating pluripotent cells from mature cells could be a “game changer.”

“If it works in man, this could ultimately make a wide range of cell therapies available using a patient’s own cells as starting material – the age of personalized medicine would have finally arrived,” said Chris Mason, chair of regenerative medicine bioprocessing at University College London.

Researchers have long hoped that it might be possible to generate cells with the versatility of embryonic stem cells, but without their ethical and regulatory baggage.

Six years ago, researchers first generated such cells – induced pluripotent stem (iPS) cells – by treating skin cells with different cocktails of nuclear reprogramming factors. (See BioWorld Today, Nov. 21, 2007.)

But iPS cells – which ultimately won one of their developers, Kyoto University’s Shinya Yamanaka, a Nobel Prize – had its own issues in terms of clinical development. Originally, such cells had to be genetically transformed with several oncogenes.

Those obstacles to clinical development have since been overcome, and iPS cells have entered clinical trials.

Still, the new cells – which their makers have called stimulus-triggered acquisition of pluripotency (STAP) cells – are simpler than even the newest generation of iPS cells, as well as being faster to generate.

Corresponding author Haruko Obokata of the Riken Center for Developmental Biology described her team’s results to reporters at a press conference on Tuesday. They were then published in two papers in the Jan. 30, 2014, issue of Nature.

Obokata was careful not to oversell her teams’ results, noting that the paper only describes work with mouse cells – though she said that her team has as-yet unpublished results showing that human cells, too, can be reprogrammed with environmental stimuli.

But, she told reporters, the cells “do have all the hallmarks of pluripotency.”

“Once again Japanese scientists have unexpectedly rewritten the rules on making pluripotent cells from adult cells,” Mason said. “The method requires only transient exposure of adult cells to an acidic solution: How much easier can it possibly get?”

Fiona Watt, director of the Centre for Stem Cells and Regenerative Medicine at Kings College London, agreed the finding that blood cells can be converted to pluripotent cells by exposing them to low pH conditions is “remarkable.”

However, she noted that resulting pluripotent cells differ from embryonic stem cells in several respects, notably because they have a limited ability to self-renew.

“The studies have been carried out with mouse cells, and it will be very interesting to know whether the observations hold true for human cells,” Watt said.

Obokata herself agreed that currently, the pluripotent potential of STAP cells is “much lower than ES or iPS cells. . . . They can be passaged only four to five times, and we can culture them for only two weeks or so.”

In addition, although the technique does work for both newborn cells and older ones, it worked better on the younger cells, while any clinical applications of STAP cells, for obvious reasons, are much more likely to be in older individuals than younger ones.

But Obokata was optimistic that “in the future, I think we will be able to modify the conversion conditions or culture conditions. I think that it will work for older animals.”

iPS cells, too, were first generated from neonatal foreskin cells, and proof that they could be generated from the cells of the sort of older, sicker individuals most likely to need them came only later. (See BioWorld Today, Aug. 1, 2008.)

And if STAP cells are less pluripotent than ES and iPS cells in some respects, they are more so in at least one way. In their second paper, Obokata and her colleagues showed that STAP cells were able to generate cells of both the embryo and the placenta, showing that they may be in “an even more immature state” than ES or iPS cells – though she said that in her opinion, the ability of STAP cells to generate placental as well as embryonic cells was “not important for medical applications . . . but mainly for biological understanding of differentiation.”

For Dusko Ilic, reader in stem cell science at Kings College London, the two papers describe a major scientific discovery, opening a new era in stem cell biology. “The authors have demonstrated that environmental clues are sufficient to change cell fate, not only in plants but also in mammals, he said.”

Like Watt, Ilic said it remains to be seen if human cells would respond in a similar way. “I am sure that the group is working on this and I would not be surprised if they succeed even within this calendar year.”

The scientists also questioned what impact the discovery will have on current attempts to translate stem cells through to therapies. “For potential medical use, stimulus-triggered acquisition of pluripotency (STAP) cells will not immediately replace human induced pluripotent stem cells, just as iPS cells have not replaced human embryonic stem cells,” Mason noted.

However, it will accelerate translation in future. It took 12 years before human ES cell were first used in humans, but only six years for iPS cells. “Given the substantial overlap between all three technologies, it is likely that this will shorten the development pathway for STAP cells,” Mason said. But, he added, “It will still be many years before the technology could potentially be in everyday clinical practice.”

Ilic agreed with this. “The approach is indeed revolutionary. It will make fundamental changes in the way scientists perceive the interplay of the environment and the genome, but it will not change how stem cells are translated to the clinic. It does not bring stem cell-based therapy closer. We will need to use the same precautions for the cells generated in this way as for the cells isolated from embryos or [cells] reprogrammed by the existing method.”