Stem cells made by reprogramming don't completely let go of their past

London(ANI): Adult cells that have been reprogrammed into induced pluripotent stem cells (iPS cells) do not completely let go of their past, perhaps limiting their ability to function as a less controversial alternative to embryonic stem cells for basic research and cell replacement therapies, according to new research.

The study, by researchers at Children's Hospital Boston, John Hopkins University and their colleagues, appears online in Nature.

It highlight a major challenge in developing clinical and scientific applications for the powerful new technique of making iPS cells, which, like embryonic stem cells, have the capacity to differentiate into any type of cell in the body.

"iPS cells retain a 'memory' of their tissue of origin. iPS cells made from blood are easier to turn back into blood than, say, iPS cells made from skin cells or brain cells," said senior author George Daley, a Howard Hughes Medical Institute investigator and Director of the Stem Cell Transplantation Program at Children's.

In contrast, another technique known as nuclear transfer creates pluripotent stem cells without apparent memory and equally adept at transforming into several tissue types, the paper reports. In iPS cells, the memory of the original donor tissue can be more fully erased with additional steps or drugs, the researchers found, which made those iPS cells as good as the nuclear-transfer stem cells at generating different types of early tissue cells in lab dishes.

The residual cellular memory comes in part from lingering genome-wide epigenetic modifications to the DNA that gives each cell a distinctive identity, such as skin or blood, despite otherwise identical genomes. In the study, the persistent bits of a certain type of epigenetic modification called methylation were so distinctive in iPS cells that their tissues of origin could be identified by their methylation signatures alone.

"We found the iPS cells were not as completely reprogrammed as the nuclear transfer stem cells. Namely, DNA methylation was incompletely reset in iPS cells compared to nuclear transfer stem cells. Further, the residual epigenetic marks in the iPS cells helped to explain the lineage restriction, by leaving an epigenetic memory of the tissue of origin after reprogramming," said co-senior author Andrew Feinberg, director of the Center for Epigenetics at Johns Hopkins, whose group did systematic epigenomic analyses of the cells.

Epigenetic memory may be helpful for some applications, such as generating blood cells from iPS cells originally derived from a person's own blood, the researchers said. But the memory may interfere with efforts to engineer other tissues for treatment in diseases such as Parkinson's or diabetes or to use the cells to study the same disease processes in laboratory dishes and test drugs for potential treatments and toxicities.

Daley said: "These findings cut across all clinical applications people are pursuing and whatever disease they are modelling. Our data provide a deeper understanding of the iPS platform. Everyone working with these cells has to think about the tissues of origin and how that affects reprogramming."

Feinberg added: "This paper opens our eyes to the restricted lineage of iPS cells. The lineage restriction by tissue of origin is both a blessing and a curse. You might want lineage restriction in some cases, but you may also have to do more work to make the iPS cells more totally pluripotent."

Similar findings were published simultaneously online in Nature Biotechnology by other Boston researchers.

"Our paper comes to a similar conclusion that a retention of memory reflects the cell of origin and affects the capacity of the iPS cell to differentiate into other cell types," said senior author Konrad Hochedlinger, PhD, a stem cell biologist at the Massachusetts General Hospital Center for Regenerative Medicine and, like Daley, a member of the Harvard Stem Cell Institute, who demonstrated another method to more fully reprogram iPS cells. "When we let the cells go through a lot of cell divisions, they lose the memory," he said.