STAP Paper Author Urges that the STAP Paper Be Withdrawn


Japanese scientist, Teruhiko Wakayama, a professor at Japan’s University of Yamanashi, who was part of the research team that described the production and characterization of STAP cells, has called for his own headline-grabbing study on stem cells to be withdrawn from publication. Wakayama says that the main findings of this paper have been thrown into doubt.

When the STAP cells came out in January it was hailed as a game-changer that could herald a new era of medical biology. The paper was published in the prestigious journal Nature and was also widely covered in Japan and across the world.

Since that time, however, there have been reports that several other scientists have been unable to replicate the Japanese team’s results. Also there seem to be some disparities with some of the paper’s data and images.

“It is no longer clear what is right,” Wakayama told public broadcaster NHK.

STAP or stress-triggered acquisition of pluripotency cells seemed to represent a simple way to reprogram mature animal cells back into an embryonic-like state that would allow them to generate many types of tissue.

From these STAP cell papers, various editorials dreamed big and suggested that just about any cell in your body could be simply and cheaply reprogrammed back into embryonic cell-like cells, and be used to replace damaged cells or grow new organs for sick and injured people.

Wakayama even said, “When conducting the experiment, I believed it was absolutely right.” However, now he is not so sure. He continued: “But now that many mistakes have emerged, I think it is best to withdraw the research paper once and, using correct data and correct pictures, to prove once again the paper is right. If it turns out to be wrong, we would need to make it clear why a thing like this happened.”

A spokesperson from the journal Nature has said that they were aware of, “issues relating to this paper,” and that an investigation was underway. However, at this point, the journal had no further comment to make.

Robin Lovell-Badge, a stem cell expert at Britain’s National Institute for Medical Research, cautioned against premature assumptions on whether the research was flawed. “I have an open mind on this,” he told Reuters. “I’m waiting to hear from several serious stem cell labs around the world on whether they have been able to reproduce the methods.”

Wakayama’s co-researcher Haruko Obokata, the first author on the STAP paper, became an instant celebrity in Japan after she spoke during a Nature media briefing to science reporters all over the world about her findings.

The Japanese team was joined by other researchers from Brigham and Women’s Hospital and Harvard Medical School in the United States in this research. They took skin and blood cells from mice, grew them, and then subjected them to stresses that brought the cells “almost to the point of death.” They exposed the cells to a variety of stresses, including trauma, low oxygen levels, and acidic environments.

One of these “stressful” situations used by these researchers was to bathe their cells in a weak acid solution for around 30 minutes. Within days, the scientists said they had found that the cells had not only survived but had also recovered by naturally reverting into a state similar to that of an embryonic stem cell.

Unfortunately, other research teams have yet been able to replicate the findings, and the RIKEN Center for Developmental Biology in Japan, where Obokata works, said last week it had “launched an independent inquiry into the content of the paper.

That inquiry will be conducted by a panel of experts from within and outside RIKEN, it said, and would be published as soon as it was concluded.

A spokesperson from the RIKEN Institute declined to comment on Wakayama’s call for the paper to be withdrawn.

Human Fat Contains Multilineage Differentiating Stress Enduring Cells With Great Potential for Regenerative Medicine


A collaboration between American and Japanese scientists has discovered and characterized a new stem cell population from human fat that do not cause tumors and can differentiate into derivatives from ectoderm, mesoderm, and endoderm.

Multilineage Differentiating Stress-Enduring or Muse cells are found in bone marrow and the lower layers of the skin (dermis). Muse cells are a subpopulation of mesenchymal stem cells, and even express a few mesenchymal stem cell-specific genes (e.g., CD105, a cell-surface protein specific to mesenchymal stem cells). However, Muse cells also express cell surface proteins normally found in embryonic stem cells (e.g., stage-specific embryonic antigen-3, SSEA-3). Additionally, Muse cells have the ability to self-renew, and differentiate into cell types from all three embryonic germ layers, ectoderm (which forms skin and brain), mesoderm, (which forms muscle, bone, kidneys, gonads, heart, blood vessels, adrenal glands, and connective tissue), and endoderm (which forms the gastrointestinal tract and its associated tissues). Finally, Muse cells can home to damaged sites and spontaneously differentiate into tissue-specific cells as dictated by the microenvironment in which the cells find themselves.

A new publication by Fumitaka Ogura and others from Tohoku University Graduate School of Medicine in Sendai, Japan and Saleh Heneidi from the Medical College of Georgia (Augusta, Georgia), and Gregorio Chazenbalk from the David Geffen School of Medicine at UCLA has shown that Muse cells also exist in human fat.

The source of cells came from two places: commercially available fat tissue and freshly collected fat from human subjects, collected by means of liposuction. After growing these cells in culture, the mesenchymal stem cells and Muse cells grew steadily over the 3 weeks. Then the Dezawa research group used fluorescence-activated cell sorting (FACS) to isolate from all these cells those cells that express SSEA-3 on their cell surfaces.

FACS uses antibodies conjugated to dyes that can bind to specific cell proteins. Once the antibodies bind to cells, the cells are sluiced through a small orifice while they are illuminated by the laser. The laser activates the dyes if the cell fluoresces, one door opens and the other closes. The cell goes to one test tube. If the cell does not fluoresce, then the door stay shut and another door opens and the cell goes into a different test tube.  In this way, cells with a particular cell-surface protein are isolated from other cells that do not have that cell-surface protein.

Fluorescent-Activated Cell Sorting
Fluorescent-Activated Cell Sorting

In addition to expression SSEA-3, the fat-based Muse cells expressed other mesenchymal stem cell-specific cell-surface proteins (CD29, CD90), but they did not express proteins usually thought to be diagnostic for fat-based mesenchymal stem cells (MSCs) such as CD34 and CD146.  Muse cells also expressed pluripotency genes (Nanog, Oct3/4, PAR4, Sox2, and Tra-1-81).  The Muse cells grew in small clusters and some cell expressed ectodermal-specific genes (neurofilament, MAP2), others expressed mesodermal-specific genes (smooth muscle actin, NKX2) and endodermal-specific genes (alpha-fetoprotein, GATA6).  These data suggested that the cultured Muse cells were poised to form either ectoderm, mesodermal, or endodermal derivatives.

When transplanted into mice with non-functional immune systems, the Muse cells never formed any tumors or disrupted the normal structure of the nearly tissues.  When placed in differentiating media, fat-derived Muse cells differentiated into cells with neuron-like morphology that expressed neuron-specific genes (Tuj-1), liver cells, and fat.  When compared with Muse cells from bone marrow or skin, the fat-derived Muse cells were better at making bone, fat, and muscle, but not as good as bone marrow Muse cells at making neuronal cell types, but not as good at making glial cells.  Many of these assays were based on gene expression experiments and not more rigorous tests.  Therefore, the results of these experiments might be doubtful until they are corroborated by more rigorous experiments.

These cells are expandable and apparently rather safe to use.  More work needs to be done in order to fully understand the full regenerative capacity of these cells and protocols for handling them must also be developed.  However, hopefully pre-clinical experiments in rodents will give way to larger animal experiments.  If these are successful, then maybe human trials come next.  Here’s to hoping.