Curious differences in gene expression between reprogrammed adult stem cells, called induced pluripotent stem cells (iPS cells), and the embryonic stem cells that the former are designed to mimic might now be explained by a new discovery about just how much information a "reprogrammed" adult stem cell retains.

Two new studies describe the extent to which iPS cells retain genetic markers from their past lives as skin, blood or other types of progenitor cells via the reprogramming process. This process has aimed to make the cells as flexible as embryonic stem cells—which have the capability of becoming any type of specialized body cell—but the new findings throw its effectiveness into question.

One of the studies found that iPS cells taken from adult mice kept much more of their original genetic information than cells reprogrammed via somatic cell nuclear transfer (SCNT, in which an adult cell's nucleus is put into an unfertilized egg cell). These SCNT cells behaved much more like the flexible embryonic stem cells, the researchers reported in a paper published online July 19 in Nature (Scientific American is part of Nature Publishing Group).

The process of nuclear transfer is more cumbersome than standard iPS cell processing. But the resulting cells are "on average, closer to bona fide embryonic stem cells than are iPS cells," George Daley, director of the Stem Cell Transplantation at Children's Hospital Boston and coauthor of the study, said in a prepared statement. This research showed that regular "iPS cells retain a 'memory' of their tissue of origin," Daley explained. "IPS cells made from blood are easier to turn back into blood than, say, iPS cells made from skin cells or brain cells."

This so-called memory comes in the form of epigenetic signs that alter the way genes are expressed in the cell. "The residual epigenetic marks in the iPS cells helped to explain the lineage restriction," Andrew Feinberg, director of the Center for Epigenetics at Johns Hopkins University and coauthor of the Nature paper, said in a prepared statement. "This paper opens our eyes to the restricted lineage of iPS cells," he said, calling the restriction "both a blessing and a curse."

These differences can elucidate some of the results that have perplexed some stem cell researchers. In another study, published online July 19 in Nature Biotechnology, a team of researchers examined different patterns of gene expression in iPS cells from skin, muscle and two varieties of immune progenitor cells in mice. The group found that the differences among the various iPS cells mirrored differences among the tissues from which they came. This cellular memory could affect the way some studies are conducted and interpreted, the researchers noted. In particular, having an iPS cell that retains epigenetic marks of a certain type of tissue might help in coaxing that cell back into that breed, for instance using blood iPS cells to make blood cells for a patient.

"Even rigorously selected iPSCs can retain epigenetic marks characteristic of the donor cell that influence differentiation propensity," Daley and his colleagues wrote in their paper in Nature.

The hurdle to creating more flexible, embryonic-like stem cells from adult cells, however, might not be insurmountable. Daley and his group found that treating cells with chromatin-modifying drugs can help wipe clean marks from cells' previous iteration. Konrad Hochedlinger, of the Massachusetts General Hospital's Center for Regenerative Medicine and coauthor of the Nature Biotechnology paper, and his group also found that if iPS cells are put through additional rounds of cell division, "they lose that memory" of their tissue of origin, Hochedlinger said in a prepared statement. "Completely reprogramming cells appears to be a gradual process that continues beyond the iPSC stage, which may explain many of the reported differences between iPSCs and embryonic stem cells," he said.

A better understanding of different stem cells will help refine research methods in the future. "Everyone working with these cells has to think about the tissues of origin and how that affects reprogramming," Daley said. "These findings cut across all clinical applications people are pursuing and whatever disease they are modeling."

Image courtesy of Wikimedia Commons/Nissim Benvenisty