KOBE, Japan—A recent study published in Nature may raise more questions than it answers. If scientists can create pluripotent stem cells by exposing T cells to acid, it would be, as some people say, a “game changer.” Still, according to others, it may be too good to be true.
A Japanese team claims that it has come up with a surprisingly easy method—exposure to stress, including a low pH—that can make cells that are even more malleable than induced pluripotent stem (iPS) cells and do it faster and more efficiently. Haruko Obokata, a young stem-cell biologist at the RIKEN Center for Developmental Biology in Kobe, Japan, and a co-author of the latest studies, has spent five years developing the method.
It began when Dr. Charles Vacanti, a Brigham and Women’s Hospital anesthesiologist, wanted to find a better cell type to use on tissue engineering projects. He and his brother, Martin, a pathologist, discovered a new kind of stem cell that they isolated with a technique in which they ground up mature tissue and passed it through ever-smaller pipettes to sift out a new type of cell.
When Obokata arrived in Vacanti’s laboratory as a graduate student, he asked her to revisit the project. Ultimately, the team found that the environmental stress was producing the stem cells. Stress, such as bathing the cells in an acidic solution, transformed a portion of the cells into STAP (stimulus-triggered acquisition of pluripotency) cells. If researchers put the STAP cells in lab dishes with the appropriate growth medium, the STAP stem cells became just like embryonic stem cells.
Obokata noticed that stressing cells might make them pluripotent and decided to try applying different kinds of stress, including exposure to low pH, which could make the cells appear to be pluripotent. To demonstrate that the cells could turn into all cell types, she injected fluorescently tagged cells into a mouse embryo. If the introduced cells are pluripotent, the glowing cells show up in every tissue of the resultant mouse. Using fully differentiated cells from newborn mice instead of those from adult mice worked to produce a fully glowing mouse embryo.
Then Okobata made pluripotent cells by stressing T cells, a type of white blood cell whose maturity is clear from a rearrangement that its genes undergo during development. She caught the conversion of T cells to pluripotent cells on video.
STAP cells can also form placental tissue, something that neither iPS cells nor embryonic stem cells can do. That could make cloning dramatically easier. Currently, cloning requires extraction of unfertilized eggs, transfer of a donor nucleus into the egg, in-vitro cultivation of an embryo and transfer of the embryo to a surrogate. If STAP cells can create their own placenta, they could be transferred directly to the surrogate.
Obokata has already reprogrammed a dozen cell types, including those from the brain, skin, lung and liver, hinting that the method will work with most, if not all, cell types. The cells survive the stress and convert to pluripotent cells at a higher rate than iPS cells, which take several weeks to become pluripotent. She now wants to use these results to examine how reprogramming in the body is related to the activity of stem cells and to make the method work with cells from adult mice and humans.
However, according to Dr. Jun Seita of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine, it is “well known that stressed and/or damaged cells harbor significant autofluorescence.” This is particularly pertinent to the case of STAP cells, “because the various stresses applied to cells may themselves induce cellular autofluorescence.” He claims that “Neither flow cytometry nor a fluorescent microscope can distinguish the origin of an observed fluorescent signal.”
The discovery could eliminate complicated genetic manipulation, according to the global head of neuroscience at Novartis Institutes for Biomedical Research, Ricardo Dolmetsch, who noted that, “From a practical point of view, if all it takes is a change in pH and a change in cell culture conditions, then this will make the process of making stem cells a lot simpler.” Stem cell biologist Rudolf Jaenisch, from the Whitehead Institute, advised that further research must be done as “quite a lot of questions were unresolved.”
As of the time this issue went to press, some concerns had also been raised that some images included in Obokata papers on the stem cell process seem to have been altered, while others bear a strong resemblance to each other, and the journal Nature, in which the papers were published, said it was investigating the issue.
