Reprogrammed adult stem cells retain a memory of their tissue of origin that could limit their ability to function as an alternative to embryonic stem cells for basic research and cell replacement therapies, according to researchers from Harvard University and John Hopkins University.

Results from the research of two separate groups were published online in the journal Nature and simultaneously in the journal Nature Biotechnology. Their findings could have major implications in the growing field of regenerative medicine where scientists have been developing stem cell therapies to repair or replace damaged tissues or organs.

Reprogrammed adult stem cells, or induced pluripotent stem cells (iPS cells), which have the capacity to differentiate into any type of cell in the body, have been viewed as attractive, in part, because they avoid the ethical issues surrounding the use of human embryonic stem cells, which are derived through the destruction of a human embryo.

“These findings cut across all clinical applications people are pursuing and whatever disease they are modeling,” says George Daley, researcher at the Harvard Stem Cell Institute and Children’s Hospital and lead author of the Nature study. “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.”

The residual cellular memory comes in part from lingering genome-wide epigenetic modifications to the DNA, called methylation, giving each cell a distinctive identity despite otherwise identical genomes. The researchers found that the DNA methylation was incompletely reset in iPS cells compared to nuclear transfer stem cells, leaving an epigenetic memory of the tissue of origin after reprogramming.

The memory of the original donor tissue in iPS cells can be more fully erased with additional steps or drugs, making the iPS cells as good as the nuclear transfer stem cells at generating different types of early tissue cells in lab dishes. Nuclear transfer stem cells, the technique used in cloning, creates pluripotent stem cells without apparent memory and equally adept at transforming into several tissue types.

While epigenetic memory may be helpful for some applications, such as generating blood cells from iPS cells originally derived from a person’s own blood, it 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.

iPS cells became a focal point of stem cell biology four years ago when a Japanese team led by Shinya Yamanaka created the functional equivalent of embryonic stem cells from adult mouse skin cells with a cocktail of four molecular factors. A year later, Yamanaka's team, Daley’s team and a University of Wisconsin group all independently reported creating human iPS cells from adult skin cells, raising hopes for future clinical and research applications. Earlier this month, Daley’s team and two other groups reported making human iPS cells from adult blood cells, a faster and easier source. In that study, iPS cells from blood were also better at differentiating back into blood cells than into other tissue types.

In the current study, researchers tested mice iPS cells head-to-head with pluripotent cells made through somatic cell nuclear transfer. “Stem cells generated by somatic cell nuclear transfer are, on average, closer to bona fide embryonic stem cells than are iPS cells,” says Daley. “This has an important political message—we still need to study the mechanisms by which nuclear transfer reprograms cells, because the process seems to work more efficiently and faithfully. Learning the secrets of nuclear transfer may help us make better iPS cells.”

The researchers worked with older mice to emulate the future human clinical scenario, which is likely to involve older people. Older cells are also set in their ways and harder to reprogram.

Originally the team wanted to compare the transplantation success of blood cells made from three different pluripotent sources: iPS cells, embryonic stem cells (the gold standard), and nuclear transfer stem cells. But they didn’t get that far. “Even in vitro we observed strikingly different blood-forming potential,” the co-authors wrote in the paper. “We focused instead on understanding this phenomenon.”

The iPS cells had to be reset by differentiating them first into blood cells and then reprogramming them again, or by treating them with drugs that change their epigenetic profile. In contrast, nuclear transfer stem cells from the same sources—blood cells and skin—were equally able to differentiate into blood and bone, the researcher found. Like iPS cells, the nuclear transfer technique also creates patient-specific cells; however, it has not yet proven successful with human cells.

The study published online in Nature Biotechnology reported similar results. “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,” says senior author Konrad Hochedlinger, a stem cell biologist at the Massachusetts General Hospital Center for Regenerative Medicine and 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.”