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Reprogrammed Stem Cells Remember Their Past

Engineered stem cells carry markers of their former identities–a trait that could hinder research into diseases.

While reprogrammed stem cells–those derived from fully differentiated adult cells–can be transformed into any type of tissue, scientists have now discovered that they preserve a memory of where they came from. That memory appears to influence the cells’ development; reprogrammed stem cells are more easily converted back to their original identity, according to a study released online today in Nature. The findings could affect research into the two main uses for reprogrammed stem cells; growing efforts to study disease in cells derived from patients with those diseases, and the development of replacement cell therapies.

Making bone: Stem cells derived from skin are better at forming bone cells (right) than stem cells derived from blood (left) are, because skin is more closely related to bone. Colonies of bone cells are shown in red.

A few years ago, researchers developed a way to reprogram adult cells into stem cells using a simple combination of genetic or chemical factors, no embryo required. Like embryonic stem cells, these induced pluripotent stem (iPS) cells can both reproduce themselves and differentiate into just about any type of tissue in the body. The technology spread rapidly around the globe, providing a way to study stem cells and their potential therapeutic benefits without the technical and ethical hurdles of using cells derived from embryos. But three years later, complications continue to crop up.

While iPS cells have passed all the traditional tests of so-called pluripotency–the ability to differentiate into any type of tissue–and appear genetically identical to embryonic stem cells, they do have limitations. George Daley and his colleagues have found, by studying stem cells from mice, that cells derived from blood are better able to differentiate back into blood cells than into bone; those derived from bone make poor blood cells and even poorer neurons.

Daley’s team also compared mouse iPS cells to those that had undergone nuclear transfer, the technique used to clone Dolly the sheep. The two methods trigger different mechanisms to push a cell back to a stem-cell state, and the chemical methods of iPS cell reprogramming appear to be less thorough. The iPS cells maintain chemical modifications on their DNA indicative of their previous identity, while nuclear transfer wipes the slate clean. (It wasn’t possible to do similar experiments with human cells, because no one has yet cloned human cells.)

The findings create a snag for the use of iPS cells for basic disease research. Many scientists have been collecting skin samples from patients with various diseases, reprogramming them back to iPS cells, and then prompting them to differentiate into tissues affected by the disease. This allows them to examine how the disease unfolds at a molecular level. But if the disease is a neurologic one, such as Parkinson’s, or anything not related to skin tissue, the variation that occurs due to the originating tissue could mask effects of the disease.

In terms of developing replacement cell therapies from iPS cells, the finding may be a boon. “It’s a double-edged sword,” says Daley. “It’s been very challenging to make and direct differentiation of iPS cells into specific tissues.” Starting off with the tissue of interest may make that easier, he says. To grow new bone cells, for example, scientists would be better off taking a bone biopsy from the patient as starting material, rather than beginning with blood or skin cells.

A second study released online today in Nature Biotechnology shows that these cellular memories fade after the cells have been grown for successive generations. “When the cells undergo hundreds of thousands of cell divisions, this memory seems to disappear,” says Harvard stem cell biologist Konrad Hochedlinger, who led the second study. “The cells become indistinguishable from each other, and the differences we observe early on seem to vanish.” But because extensive culturing can also introduce genetic mutations in the cells, this may not be a viable solution to wiping cellular memory.

Collectively, the studies make clear that researchers still have a lot to understand about iPS cells. “If for no other reason, we should still be studying nuclear transfer in order to study how nature does its own programming,” says Evan Snyder, who directs the stem cell and regenerative biology program at the Sanford-Burnham Medical Research Institute in La Jolla, CA. Snyder was not involved with the research. Nuclear transfer is a tricky process, never successfully performed in human cells and not a likely candidate for therapeutic use. But even as a research tool, it’s largely disappeared, and few labs continue to study it now that they can create their own iPS cells.

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