Cells Take an Acid Trip to Pluripotency


By Sally Burn

The stem cell field has reacted with both excitement and surprise to the publication of a novel method for reprogramming somatic cells to a pluripotent state [1,2]. The last decade has seen major advances in this area, most notably the generation of induced pluripotent stem cells (iPSCs) [3], but the available techniques were far from perfect. Embryonic stem (ES) cells are a valuable resource for regenerative medicine as they have the capacity to differentiate into all the mature cell types derived from the three embryonic germ layers (pluripotency). However, as the name suggests, ES cells are derived from embryos, raising ethical issues about their collection and use. iPSCs are a more ethically sound option, created by reprogramming differentiated somatic cells back to a pluripotent state with a cocktail of transcription factors. Takahashi and colleagues showed that mouse iPSCs could then differentiate into an entire embryo [3]. One limitation, however, is that iPSCs cannot differentiate into placental tissue. An advantage of the new technique, published last week in Nature across two papers by Haruko Obokata, is that both embryonic and placental tissue can be generated from somatic cells. However, that’s not the finding that’s got the field in such a fluster. The mind-blowing twist is that Obokata’s team didn’t use an elaborate mix of transcription factors to reprogram the somatic cells, but instead used… acid.

Dr Obokata isolated white blood cells from newborn mice then de-differentiated them back to a pluripotent state using brief exposure to low pH (acidic) media [1]. The authors term this process stimulus-triggered acquisition of pluripotency (STAP). The blood cells lost their identity and formed clusters of so-called STAP cells in which a fluorescent pluripotency reporter became activated. STAP cells were then induced to proliferate using pluripotency-promoting media, resulting in a supply of self-renewing STAP stem cells. Upon injection into a mouse blastocyst, STAP stem cells contributed to every part of the resulting chimeric embryo. Moreover, they could contribute to extraembryonic tissues, including the trophoblast (from which the placenta develops)[2] – a feature not inherent to ES cells or iPSCs. The technique also works with cells taken from a range of other neonatal tissues, including the brain, liver, muscle, and skin.

A number of eminent scientists reacted with surprise bordering on skepticism – a reaction that Dr Obokata is now used to dealing with [4]. One concern they raised is that the starter cells were from newborn mice and the technique has not yet been proven with adult cells. However, the more common question being bounced around was: could it really be that simple? Could something as inelegant as acid undo the complex genomic changes required for cell specialization? The answer appears to be ‘yes’ as the data looks sound and STAP is not without precedent. There are a number of examples of physical stimuli inducing changes in cell identity, both in nature (e.g. temperature-dependent control of sex determination in turtles) and in the laboratory (e.g. acid-induced conversion of skin to neural tissue in newts [5]). Indeed, the rationale for the study was to mimic the physical stress an adult cell is put through when tissue damage occurs, leading to initiation of tissue regeneration, according to last author Dr Charles Vacanti [6]. In effect the cells were pushed to near-death, tricking them to invoke latent reprogramming mechanisms in order to revert to a pluripotent state and then differentiate into new tissue.

Whether STAP-like cells exist in nature is unknown. Another uncertainty is whether human cells can be reprogrammed in a similar manner. If they could, the implications for personalized regenerative medicine are very exciting. A more ethically-dubious application could be the creation of clones. Theoretically a single adult cell could be used to generate a cluster of STAP stem cells which could then be implanted in the uterus, where it would differentiate into both an embryo and its supporting tissues, resulting in a cloned fetus. Dr Vacanti told New Scientist that this may have already been achieved in mice, although Dr Obokata denies this [6]. Such experiments would obviously pose major ethical issues.


Footnote: On a completely personal note, Dr Obokata is now my role model scientist. Only thirty years old, and running her own group, she is described as follows by Wikipedia: “When Obokata became a unit leader of the Riken Center for Developmental Biology, she changed the color of her laboratory’s wall to pink and yellow and decorated the room with Moomin items and stickers. She also keeps her turtle as a pet in her laboratory. During experiments, she wears a sleeved Japanese cooking apron called kappogi instead of a laboratory coat” [7]. Moomin and kappogi facts can be verified by watching her BBC interview [8]; the turtle fact is corroborated by this comment she made in the Japan Times: “Since this guy came here, we got our research on the right track, so he brings good luck” [4]. On this basis, the NIH should start providing all labs with a turtle forthwith…