Stem cells, or immature cells with the potential to differentiate into many types of cell, have enormous potential for treating many diseases including cancer.

However, natural sources of stem cells are extremely limited: the use of the most malleable stem cells, derived from embryos, is ethically charged and such adult stem cells as can be harvested have limited differentiation potential.

It is generally considered that the fate of normally differentiating somatic cells in mammals is progressively and completely determined, so under normal conditions it is extremely difficult if not impossible to return them to a less differentiated state.

In 2006, Shinya Yamanaka from the University of Tokyo, Japan, reported that he had been able to re-program mouse fibroblasts into a state closely reminiscent of embryonic stem cells by exposing them to a cocktail of embryonic regulatory factors.

Yamanaka was awarded a share in the 2012 Nobel Prize for Medicine for the creation of these cells, which have been termed induced pluripotent stem cells (iPSCs).

Now another group of Japanese researchers, led by Haruko Obokata of the RIKEN Center for Developmental Biology, Kobe, have discovered a much simpler way of re-programming differentiated cells into an embryonic-like state.

Obokata and her co-workers were inspired by natural phenomena in which a physical stimulus can control the fate of cells or organisms, such as temperature-dependent sex determination in crocodile embryos [1].

They sought to determine whether there were any external physical triggers that could be used to re-program somatic cells towards a stem-like state.

Leukocytes expressing the antigen CD45, which do not express any protein markers of pluripotency, were extracted from the spleens of week-old transgenic mice [2].

These mice had been engineered so that their cells would express green fluorescent protein (GFP), and therefore fluoresce, if Oct4, a gene that is expressed in pluripotent cells, is turned on. 

The leukocytes were exposed to a variety of strong, transient physical and chemical stimuli and then examined for Oct4 activation.

Substantial numbers of cells expressing Oct4 were observed seven days after they had been incubated transiently in a low pH medium.

These Oct4-expressing cells also expressed other genes that are known to be expressed in embryonic stem cells.

A similar expression pattern reminiscent of embryonic stem cells could also be induced by physically squeezing the cells and by penetrating the cell membranes with a bacterial toxin.

Cells treated in these ways also shared some of the physical features of stem cells, such as small size.

Obokata and her colleagues named this technique ‘stimulus-triggered acquisition of pluripotency’ or STAP and cells that had been treated in this way STAP cells.

The researchers injected STAP cells generated from CD45 cells from neonatal mice into mouse blastocysts, and observed GFP-expressing cells – that is, cells derived from STAP cells – throughout the resulting embryos, indicating that these were chimeras derived from both host embryonic tissue and STAP cells.

However, STAP cells, unlike embryonic stem cells and iPSCs, have a limited capability to survive and renew themselves in culture.

The researchers then transferred the cells into a medium that has been used to grow populations of pluripotent stem cells, and found that they began to proliferate and to acquire further markers that are characteristic of embryonic stem cells.

These self-renewing STAP cells were termed STAP stem cells.

Obokata and her co-workers continued their investigation of the unexpected and intriguing properties of STAP cells, focusing on their potential for differentiation during embryonic development [3].

Examination of the chimaeras produced when blastocysts were injected with STAP cells showed that in about 60% of cases cells derived from STAP cells were located in the placenta and fetal membranes as well as in the embryo itself.

This colonisation of extra-embryonic tissue is rarely seen when embryonic stem cells or iPSCs are injected into blastocysts, indicating that the range of cell types that STAP cells can differentiate into is unusually broad, even for pluripotent stem cells.

Interestingly, similarly injected STAP stem cells could not be found in placental tissue, suggesting that the transformation of STAP cells into STAP stem cells includes the loss of ability to differentiate down this lineage.

The researchers then cultured STAP cells in a medium including the growth factor Fgf4, which has previously been used to obtain stem cells like those found naturally in the trophoblast, a layer of cells that develops into the placenta.

The resulting STAP stem cells expressed markers of trophoblast stem cells, and when they were injected into blastocysts cells derived from these cells were observed in the developing placentas.

Taken together, these results establish the principle that a simple physical stimulus may be all that is necessary to induce pluripotency in mammalian cells.

Although these experiments are very preliminary and apply to an immature mouse model only, they may still represent a step forward for personalised medicine that has important implications for cancer research and treatment.

References

[1] Smith, A. (2014). Potency unchained. Nature 505: 622-3.

[2] Obokata, H., Wakayama, T., Sasai, Y., Kojima, K., Vacanti, M.P., Niwa, H., Yamato, M. and Vacanti, C.A. (2014). Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature 505: 641-7. doi:10.1038/nature12968

[3] Obokata, H., Sasai, Y., Niwa, H. and 8 others (2014). Bidirectional developmental potential in reprogrammed cells with acquired pluripotency. Nature 505: 676-9. doi:10.1038/nature12969