Some stem cells are unwilling to let go of their past. They cling to traces of a previous life, even after researchers have wiped their slates clean.
In the search for an inexpensive and less controversial alternative to embryonic stem cells, scientists have created induced pluripotent stem (iPS) cells, adult cells that have been reprogrammed for experimental use.
New research has found, however, that iPS cells from adult mice seem to remember what they were before being reset—and therefore remain best suited to carrying out tasks linked to that previous role.
“iPS cells retain a ‘memory’ of their tissue of origin,” said George Daley, senior author of the study, an HMS professor of biological chemistry and molecular pharmacology at Children’s Hospital Boston and director of the hospital’s Stem Cell Transplantation Program. “iPS cells made from blood are easier to turn back into blood than, say, iPS cells made from skin or brain cells.”
The findings, published online July 19 in Nature, have significant implications for the use of adult stem cells in research or in cell-replacement therapies.The results are especially noteworthy in light of an August ruling by a federal district court judge that temporarily blocked government funding of research on human embryonic stem cells.
The residual memory comes from epigenetic modification, a means of changing a cell’s makeup that does not alter the cell’s underlying genetic structure. In the study, residues left behind by a certain type of epigenetic modification called methylation were so distinctive in iPS cells that they could be used to identify where the cells came from.
Daley’s team also found that an alternative technique, known as somatic cell nuclear transfer, creates pluripotent stem cells, which are just as good as iPS cells at turning into several different types of tissue—without the residual memory. Somatic nuclear transfer reprograms an adult cell by transferring its nucleus into an unfertilized egg cell, the method famously used to clone Dolly the sheep.
Although nuclear transfer has yet to be successfully used in human cells (the current study used cells from adult mice), Daley believes the findings warrant investigation. “Stem cells generated by somatic cell nuclear transfer are, on average, closer to bona fide embryonic stem cells than are iPS cells,” he said.
“This has an important political message,” Daley said. “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.”
Andrew Feinberg, director of the Epigenetics Center at John Hopkins, who worked with Daley on the study, described residual cell memory as “both a blessing and a curse,” adding: “You might want lineage restriction in some cases, but you may also have to do more work to make the iPS more totally pluripotent.”
Another study published online simultaneously in the journal Nature Biotechnology supports Daley’s findings. Its senior author, Konrad Hochedlinger, HMS assistant professor of medicine at Massachusetts General Hospital, said, “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.”
For more information, students may contact George Daley at george.daley@childrens.harvard.edu.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The Howard Hughes Medical Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute (American Recovery and Reinvestment Act); the Thomas and Stacey Siebel Foundation; Special Fellow Career Development award/Leukemia and Lymphoma Society; fellowship/California Institute for Regenerative Medicine; and Cooley’s Anemia Foundation; the authors are solely responsible for the content of the work.
