HU discovery could lead to stem-cell treatment of disease

While the highly praised discovery will not make tissue repairs with stem cells possible in the immediate future, it is an important step in understanding the mechanism.

By JUDY SIEGEL-ITZKOVICH
stem cell 88 GENERIC thumbnail (photo credit: )
stem cell 88 GENERIC thumbnail
(photo credit: )
Two veteran Hebrew University-Hadassah Medical School researchers have accomplished the equivalent of turning omelets back into eggs by discovering the mechanism of differentiation, in which embryonic cells lose their flexibility and turn into more mature cells. The mechanism could be used to develop specific tissues and eventually to repair diseased organs. While the highly praised discovery, just published in Nature Structural & Molecular Biology, will not make tissue repairs with stem cells possible in the immediate future, it is an important step in understanding the mechanism, said Prof. Howard Cedar, who performed the research with Prof. Yehudit Bergman. "It is another brick in the wall of discovery" that is expected someday to allow embryonic stem cells to be used for repair of diseased tissue and organs such as the brain, heart, pancreas, muscle or liver, Cedar told The Jerusalem Post on Sunday. Such uses would revolutionize the treatment of chronic disorders, especially those of middle and old age. At a very early stage of human development, all embryonic cells are identical, but unlike adult cells, they carry within them the potential to become any tissue type, said Cedar (whose achievements in science have been matched in the film world by his son, director and screenwriter Joseph Cedar, winner of the 2007 Silver Bear Award at the Berlin International Film Festival and an Oscar nominee for his movie Beaufort). The kippa-wearing professor explained that the cell differentiation process begins at about the time that the embryo settles into the uterus. As a control mechanism, the genes that keep the embryo in their fully potent state are turned off, and at the same time, tissue-specific genes are turned on. By activating a certain set of genes, the embryo can make muscle cells. By turning on a different set, these same immature cells can become liver cells. Cedar, a molecular biologist, and Bergman, a professor of cancer research and experimental medicine, found that G9a was capable of directing a gamut of changes that involve turning off a large set of genes so that they remain locked for the lifetime of the organism. Then these genes are unable to activate any further cell flexibility. Their studies shed light on this central process, and may eventually lead to new medical treatments. Among these could be the generation of new tissues to replace damaged cells from a variety of diseases, such as Parkinson's or Alzheimer's disease or diabetes. Scientists around the world have tried to "reprogram" readily available adult cells but have discovered it's almost impossible, mainly because normal tissues have lost their ability to revert to fully potent and flexible embryonic cells. Now, with the new HU discovery, the molecular program responsible for turning off cell flexibility has been identified. This, they suggest, may clear the way toward developing approaches to program cells in a controlled and specific manner. "The field is moving very quickly," Cedar said. "Every month there is more information about factors. We think our discovery is important because we found one of the things this special master gene does to make embryonic stem cells pluripotent. If you take a heart cell, lymphocyte or fibroblast cell and inhibit this molecule, it helps it go revert to a stem cell. So a small molecular drug added to the cells inhibits an enzyme, making the cell go back to being a stem cell." "Until now, genes have been injected into cells, and this is much harder. Researchers have been taking blood cells and inserting in them a combination of genes, but this works very slowly at reverting to stem cells. It is inefficient because something in the cell is doing something to prevent it, like a brake, from acting. By releasing the brake, it would be much easier to revert. "We can't say if our discovery will turn into something very practical, but it is a novel finding that produced much amazement when Yehudit presented it at scientific meetings at Harvard and in Australia. Our article in Nature offered genetic proof of the power of G9a," he said. The team have not yet tried it on humans, "even though the gene probably plays a role. It can be done on human cells in the lab; there are no restrictions on this." He added that it was too early to know whether G9a had a role in cancer; a tumor cell is one that has reverted to some extent to become pluripotent. I imagine that researchers will work on this, too."