Reprogrammed stem cells work as well as those from embryos

Pregnant with possibilities. Cells reprogrammed in living mice (green) can contribute to both the placenta and body tissues of a developing mouse.

Sagrario Ortega/Spanish National Cancer Research Center (CNIO), Madrid

Researchers who hope to use stem cells—the unspecialized cells that produce all of our tissues—to treat diseases face a dilemma. Stem cells from embryos (ES cells) could provide a wealth of new cells but spark ethical objections. Stem cells produced from adult cells (so-called induced pluripotent stem [iPS] cells) avoid the ethical difficulties, but some scientists have questioned whether they are as powerful as ES cells. A new study suggests that the two types of stem cells are equivalent and may help soothe worries about the capabilities of iPS cells. 

“I think it was a very well done study, and it will ease some of the concerns about ES cells versus iPS cells,” says stem cell biologist Joseph Wu of the Stanford University School of Medicine in Palo Alto, California, who wasn’t connected to the study. Stem cell biologist William Lowry of the University of California, Los Angeles, agrees. “It’s probably going to be a lot easier to go forward with iPS cells because of studies like this.”

ES cells can specialize into any type of cell in the body, but they are controversial because obtaining them destroys embryos. In 2006, researchers found a possible workaround. Adding four genes to a specialized adult cell—such as a skin cell from a patient—can convert it into an iPS cell. These cells seem to have similar abilities as ES cells in the lab, and iPS cells don’t rouse the ethical objections of ES cells. Such reprogrammed cells are now widely used by stem cell labs around the world, and the scientist who figured out how to make them, Shinya Yamanaka of Kyoto University in Japan, won the Nobel Prize in Physiology or Medicine in 2012 for the discovery.

Problem solved, right? Not quite. Some researchers have questioned whether iPS cells measure up to ES cells. Different genes are switched on in iPS cells, some studies have found, raising the possibility that the two types of stem cells aren’t equally capable. “There is still controversy out there about how similar they are,” says stem cell researcher Konrad Hochedlinger of Massachusetts General Hospital in Boston. Determining whether ES and iPS cells are comparable is important because clinical trials of both kinds of cells are underway.

Hochedlinger and his colleagues note that several factors could explain why iPS cells and ES cells show different patterns of gene activity. One is the source of the cells. The embryo used to derive an ES cell is not genetically identical to the donor of the cell that is transformed into an iPS cell, so researchers expect some discrepancies in gene activity. The sex of the stem cells could also be significant, because activity of some genes varies between males and females.

To try to rule out these factors, the scientists obtained two lines of ES cells that were male. They allowed cells from each line to mature and then coaxed these cells to transform into iPS cells. Thus, the iPS cells genetically matched their ES cell parents. When the researchers measured gene activity, they found that the iPS cells were more similar to the ES cells they descended from than to each other, suggesting that the source of the cells explains many of the disparities researchers had noted between the two stem cell types.

The iPS cells the researchers created weren’t identical to their ES cell parents, however. Hochedlinger and colleagues pinpointed 49 genes whose activity consistently differed between iPS and ES cells. To gauge whether these differences altered the cells’ capabilities, the scientists analyzed two of the genes. One helps cells imbibe glucose, whereas the other helps cells break it down. Even though both genes were less active in iPS cells, the cells were just as efficient as ES cells at absorbing and digesting glucose. At least when it comes to these two genes, the researchers conclude, the two types of cells are functionally equivalent.

The ultimate test of a stem cell is its ability to produce different cell types. ES cells and iPS cells were equally good at specializing into a variety of nervous system cells, the researchers report online today in Nature Biotechnology. They also ran a standard test that measures the cells’ ability to produce the three major cell lineages in the body and found no differences. “The two cell types appear functionally indistinguishable based on the assays we used,” Hochedlinger says.

The paper won’t silence all doubts about iPS cells, says stem cell biologist Andras Nagy of the Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital in Toronto, Canada. The fact that the researchers made their iPS cells from cells that matured in the lab from ES cells, instead of from the cells of a patient or donor, means that they still might carry traces of the ES cells’ gene activity patterns. “It’s a nice paper, but still there is a little bit of reservation about how broad the conclusion can be,” he says.