August 2, 2010

Some Stem Cells Find it Hard to Forget

Microscope image of numerous round cells Induced pluripotent stem cells derived from blood cells.Kim et al., Nature.

Scientists have discovered why induced pluripotent stem cells—which many hope will replace the need for embryonic stem cells one day—don’t always function as well as the embryonic variety. The researchers also developed ways to get around the problem.

Embryonic stem cells have the ability to form virtually any cell type in the body and can grow indefinitely in the laboratory. Many scientists hope to learn how to harness the potential of these cells to repair tissues and organs. However, the cells have been controversial because isolating them entails destroying an early human embryo.

In recent years, researchers have developed 2 different ways of reprogramming adult cells to give them the properties of embryonic stem cells. One technique involves adding just 4 genes that convert adult cells into multipurpose stem cells called induced pluripotent stem (iPS) cells. The other technique entails transferring the nucleus—the compartment that contains the DNA—from an adult cell into an egg from which the original nucleus has been removed. The egg then reprograms the adult nucleus, enabling the isolation of pluripotent stem cells with the genetic makeup of the adult cell.

Learning how to guide any of these cells to different fates is a significant challenge for scientists. Reprogramming iPS cells into cells other than the type they were originally derived from is particularly inefficient. Two research teams—one led by Dr. George Q. Daley at Children's Hospital Boston, the other by Dr. Konrad Hochedlinger at Harvard University—worked independently to explore why iPS cells seem to retain a "memory" of their former states. Both teams were supported by NIH, the Howard Hughes Medical Institute and others. They coordinated joint publications on July 19, 2010, in the advance online editions of Nature (Daley) and Nature Biotechnology (Hochedlinger).

The teams looked for differences in methylation—a chemical modification to DNA that can affect gene expression. They discovered that genetically reprogrammed mouse iPS cells still have some residual DNA methylation reflecting their tissue of origin. The methylation patterns affect gene expression and restrict the ultimate fates of the cells.

Daley's team also discovered that, compared to genetically reprogrammed iPS cells, stem cells derived through nuclear transfer were more similar to embryonic stem cells in their methylation patterns and their ability to differentiate. Methylation, they concluded, is more effectively erased and reset by nuclear transfer.

The encouraging news is that the researchers discovered the memories of iPS cells could be reset—at least in part—either by growing the cell lines for long periods or by treating them with drugs that affect DNA methylation.

"The backdrop to this research is that a lot of people have the impression that iPS cells are the equivalent of embryonic stem cells," Daley says. "That has been used as an argument that we do not need to keep studying embryonic stem cells. But iPS cells often don’t function as well as embryonic cells, and our new research offers an explanation as to why that is the case."

The finding has other implications as well. Patient-specific iPS cells are a potentially valuable tool for studying diseases and developing therapies. "Any subtle differences you see in your patient-derived iPS cells could in fact be the result of not only the disease abnormality, but also the memory retained in the iPS cells," Hochedlinger explains. Researchers will need to learn how iPS cells derived from different cell types vary on a molecular level before they draw conclusions about the molecular mechanisms of disease.

—by Harrison Wein, Ph.D.

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