Stem cells made from mature cells and rewound to an embryonic-like state retain a distinct “memory” of their past that might limit their potential for therapeutic use, scientists reported Wednesday in the journal Nature.
In a side-by-side comparison of these induced pluripotent stem cells and embryonic stem cells, researchers from the Salk Institute in San Diego found a consistent pattern of reprogramming errors — places where the iPS cells did not revert completely to an embryonic state.
“This study definitively demonstrates that there are differences between the two cell types,” said Joseph Wu, a stem cell biologist at the Stanford University School of Medicine who was not involved in the research.
Knowing exactly what those differences are is a key step in developing ways to use iPS cells to treat diseases, experts said. Most researchers still consider embryonic stem cells to be the gold standard for regenerative medicine because they can grow into any type of cell in the body. But many scientists and policymakers would like to see treatments based on iPS cells because they can be made without destroying embryos. In addition, iPS cells can be custom-made for patients, ensuring a perfect genetic match.
To catalog the differences between the two cell types, the Salk team, led by molecular biologist Joseph Ecker, studied the epigenomes — chemical markers attached to DNA that regulate the way genes dial on and off — of 11 different cell lines.
They looked at 1.2 billion places in each genome where such chemical markers exist. The analysis was unusually rigorous — and therefore unusually revealing, Ecker said. Earlier studies examined representative regions in the genome, rather than the whole thing.
“Up to this point, people were looking through a keyhole,” he said. “We’re opening up the door.”
For the most part, the contents of Ecker’s metaphorical rooms looked alike. But when they zoomed in, inconsistencies emerged.
Large regions of the iPS epigenomes hadn’t reverted to the embryonic state, but instead held on to the epigenetic memory of their tissue of origin. When the researchers used the iPS cells to create mature cells in the lab, this memory persisted.
The regions were clustered near telomeres and centromeres, structures that help direct how chromosomes divide.
“There is something about these regions that makes it harder to modulate the epigenome,” Ecker said.
In some ways the iPS cells were different from one another, suggesting the reprogramming process itself might contribute to aberrations, he added.
That does not mean iPS cells can’t be used in medicine, experts said. Improvements in technology could one day erase their epigenetic memory.
In addition, Wu said, scientists might find ways to harness that epigenetic memory to help treat disease. For example, if heart cells generated from iPS cells retain some of their cardiac characteristics, he suggested, they might be useful in therapies to treat heart disease.
“We need to do more research to see what exactly this means,” he said.