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Problems with stem-cell papers noted at a RIKEN conference in March 2014 have now been further analysed.

The latest investigation into a debunked method of generating stem cells has left researchers grappling with questions about what went wrong in a laboratory at the RIKEN research institute in Japan.

The final report from the independent investigation, released on 26 December, bolstered suspicions that the stem cells which were supposedly generated by applying stress to ordinary adult cells in an acid bath were actually embryonic stem cells that had been introduced to the samples. But investigators were unable to determine how the contamination occurred or whether it was accidental.

The investigation also has not explained one of the most notable features of the cells their ability to form a placenta something that embryonic stem cells do not generally do. That is still one question that to me is still a mystery, says Manuel Serrano, a cancer biologist who has worked with stem cells at the Spanish National Cancer Research Centre in Madrid.

Serrano, like many of his colleagues, was intrigued by the papers, published in Nature in January 2014, reporting that adult cells could behave like stem cells after experiencing severe stress1, 2. To him, the premise made sense there was ample evidence in the literature that stressed cells were prone to taking on new identities. Cells respond to damage by trying to acquire the plasticity to repair the tissue, he says. But it was surprising that this stress was sufficient to fully reprogram the cell.

Serrano tasked two researchers in his lab with making stem cells using the authors method called stimulus-triggered acquisition of pluripotency (STAP). He initially urged them to keep trying when their attempts failed. But within about two months, Serrano advised them to abandon their efforts. Reports were pouring in from other labs that could not reproduce the method, and questions arose about the validity of data in the papers.

In response to the controversy, RIKEN launched two investigations into the work, much of which was carried out at the RIKEN Center for Developmental Biology in Kobe. An internal review reported in March that lead investigator Haruko Obokata had manipulated images in the two Nature publications. The papers were retracted in July3.

The second investigation, carried out by a team of scientists not employed by RIKEN, delved deeper, analysing cell lines and tissue samples from the laboratories to determine their provenance. In addition to unearthing two more fabrications in figures from the January publications, the team found that three STAP cell lines contained embryonic stem cells.

The results confirmed suspicions in the field, says George Daley, a stem-cell researcher at Childrens Hospital Boston in Massachusetts. The fact that the reported STAP cells had different properties from embryonic stem cells was what piqued many peoples interest, he says. But there was always the concern that some part of the data could have come from the use of standard embryonic stem-cell lines.

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Questions linger over stress-induced stem cells

IMAGE:Induced pluripotent stem cells (iPSCs) derived from patients with frontotemporal dementia were genetically corrected and converted to cortical neurons. The green staining indicates the cortical marker CTIP2, the red stain... view more

Credit: Susanna Raitano/Stem Cell Reports 2014

Belgian researchers have identified a new strategy for treating an inherited form of dementia after attempting to turn stem cells derived from patients into the neurons most affected by the disease. In patient-derived stem cells carrying a mutation predisposing them to frontotemporal dementia, which accounts for about half of dementia cases before the age of 60, the scientists found a targetable defect that prevents normal neurodevelopment. These stem cells partially return to normal when the defect is corrected.

The study appears in the December 31st issue of Stem Cell Reports, the official journal of the International Society of Stem Cell Research published by Cell Press.

"Use of induced pluripotent stem cell (iPSC) technology"--which involves taking skin cells from patients and reprogramming them into embryonic-like stem cells capable of turning into other specific cell types relevant for studying a particular disease--"makes it possible to model dementias that affect people later in life," says senior study author Catherine Verfaillie of KU Leuven.

Frontotemporal disorders are the result of damage to neurons in parts of the brain called the frontal and temporal lobes, gradually leading to behavioral symptoms or language and emotional disorders. Mutations in a gene called progranulin (GRN) are commonly associated with frontotemporal dementia, but GRN mutations in mice do not mimic all the features of the human disorder, which has limited progress in the development of effective treatments.

"iPSC models can now be used to better understand dementia, and in particular frontotemporal dementia, and might lead to the development of drugs that can curtail or slow down the degeneration of cortical neurons," Verfaillie says.

Verfaillie and Philip Van Damme of the Leuven Research Institute for Neuroscience and Disease explore this approach in the Stem Cell Reports study by creating iPSCs from three patients carrying a GRN mutation. These immature cells were impaired at turning into mature, specialized cells called cortical neurons--the most affected cell type in frontotemporal dementia.

One of the top defective pathways in the iPSCs was the Wnt signaling pathway, which plays an important role in neuronal development. However, genetic correction or treatment with a compound that inhibits the Wnt signaling pathway restored the ability of the iPSCs to turn into cortical neurons. Taken together, the findings demonstrate that the GRN mutation causes the defect in cortical neuron formation by altering the Wnt signaling pathway.

"Our findings suggest that signaling events required for neurodevelopment may also play major roles in neurodegeneration," Van Damme says. "Targeting such pathways, as for instance the Wnt pathway presented in this study, may result in the creation of novel therapeutic approaches for frontotemporal dementia."

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Patient stem cells used to make dementia-in-a-dish; help identify new treatment strategy

The research involved creating human cells in a laboratory dish instead of relying on tests on mice. Photograph: corfield / Alamy/Alamy

Cells used to study dementia in a dish have led scientists to a potential new treatment strategy for an inherited form of the brain disease.

Defective stem cells grown in the lab revealed a signalling pathway linked to frontotemporal dementia (FTD), which accounts for about half of dementia cases before the age of 60.

Treatment with a drug that suppressed the pathway, known as Wnt, restored the ability of neurons affected by the disease to develop normally.

Prof Philip Van Damme, from the Leuven Research Institute for Neuroscience and Disease in Belgium, said: Our findings suggest that signalling events required for neurodevelopment may also play major roles in neurodegeneration.

Targeting such pathways, as for instance the Wnt pathway presented in this study, may result in the creation of novel therapeutic approaches for frontotemporal dementia.

Mutations in the progranulin (GRN) gene are commonly associated with FTD, which results in damage to the frontal and temporal lobes of the brain.

The fact that GRN mutations produced in mice do not display all the features of the human disorder has limited progress towards effective treatments for FTD.

Instead of relying on animal tests, the new research involved creating human cells in a laboratory dish.

The scientists reprogrammed skin cells from three dementia patients into induced pluripotent stem cells (iPSCs), immature cells that mimic stem cells taken from early-stage embryos.

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Stem cell study leads to potential new dementia treatment