Two HSCI groups find residual genetic ‘memory’ in iPS cells

Two groups of Harvard Stem Cell Institute researchers led by Konrad Hochedlinger, PhD, at Massachusetts General Hospital and George Daley, MD, PhD, at Children’s Hospital Boston have each found that iPS (induced pluripotent stem) cells retain some of the genetic characteristics—an epigenetic “memory”—of the cells from which they are derived.

Kitai Kim, PhD, a postdoctoral fellow in Daley’s lab and first author of a paper published online in Nature that reported this finding, compared mouse iPS cells with an older type of pluripotent cell created through somatic cell nuclear transfer. Nuclear transfer reprograms an adult cell by transferring its nucleus into an unfertilized egg cell, or oocyte, that has had its nucleus removed. The process of transferring the nucleus immediately reprograms it epigenetically, replicating the same process that happens to sperm upon fertilization, Kim said.

“Stem cells generated by somatic cell nuclear transfer are, on average, closer to bona fide embryonic stem cells than iPS cells,” Daley said. “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 residual epigenetic marks in the iPS cells help explain why the cells were limited in what types of cells they could become—a property called lineage restriction. “The lineage restriction by tissue of origin is both a blessing and a curse,” said Andrew Feinberg, MD, MPH, director of the Center for Epigenetics at Johns Hopkins University School of Medicine, and the paper’s co-senior author. “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.”

Hochedlinger reported that his group, like Daley's, found epigenetic memory in iPS cells. However, the team also found that when the iPS cells are cultured multiple times, eventually the memory of their origin fades. After about 10 passages—the process of splitting the cell culture into smaller populations, allowing those populations to grow, and then repeating the process—the cells’ epigenetic memory is erased.

“How faithfully iPS cells can be reprogrammed into a truly embryonic state has been a longstanding question, and we have found that the cell of origin does affect the capacity of iPS cells to differentiate in vitro into particular cell types," Hochedlinger said. “Completely reprogramming cells appears to be a gradual process that continues beyond the iPS cell stage, which may explain many of the reported differences between iPS cells and embryonic stem cells.”

Epigenetic memory may prove helpful in some clinical applications, such as generating blood cells from iPS cells originally derived from a person’s own blood. However, the memory may interfere with efforts to engineer other tissues for treatment of diseases such as Parkinson’s or diabetes. It may also interfere with using the cells to study the same disease processes in laboratory dishes and to test drugs for potential treatments and toxicities.

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