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A Marrow Victory for Stem Cells?

Biologists attempt to illuminate the true potential of stem cells derived from adults rather than embryos.

New research on the potential of adult stem cells may give opponents of embryonic stem cell research new ammunition, but it provides no clear answer on the key question of whether adult stem cells can indeed develop into many kinds of tissue.

In a study published last Friday in the journal Science, researchers in the lab of Yale University stem cell biologist Diane Krause attempted to confirm claims that transplanted bone marrow cells could do more than just regenerate the blood system, forming cells in other tissues such as the lung, liver, and skin.

Embryonic stem cells have the ability to become any type of cell in the body. But several different kinds of adult stem cells exist, each of which was thought to develop only into a limited number of cell types. Stem cells in the bone marrow, for instance, were originally thought to develop only into blood cells. In the past few years, however, biologists have claimed that adult stem cells are more plasticthat is, capable of forming a wider variety of cell typesthan previously believed. Bone marrow stem cells, for instance, have reportedly become liver, muscle, skin, and even nerve cells in the lab.

In addition, researchers have found tantalizing evidence in human bone marrow transplant recipients: male donor cells have been seen in the livers of female recipients, for example; the telltale XY chromosome pattern of these liver cells indicates they had to have developed from the donated marrow. And in Wednesdays issue of the Journal of the American Medical Association, Diana Bianchi and colleagues at the Tufts-New England Medical Center report evidence of cells apparently derived from fetal stem cells in the livers, thyroids, and spleens of women who have been pregnant with male children.

It remains unclear, however, whether the cells found in such studies are actually derived from donor stem cells. One possibility frequently cited by critics is that the cells may represent donor and recipient cells that have fused together. To try to confirm that bone marrow-derived stem cells can indeed form tissues other than blood without fusing with a host cell, Robert Harris, a postdoc in Krauses lab, used two strains of genetically engineered mice, designed so that their cells would produce a glowing green jellyfish protein if fusion occurred. Harris and his colleagues used male donors and female recipients to further mark the cells origin.

After irradiating the female mice to kill their bone marrow cells, the researchers transplanted bone marrow from the male mice. Two to three months after transplantation, the lungs, livers, and skin of the recipients were examined for the presence of epithelial cells derived from the donor cells. (Epithelial cells are those that form the internal and external surfaces of the body and its organs.) They found differentiated cells from the donors in all three tissues, none of which glowed green, indicating that the cells had formed without fusing with host cells. We wouldnt argue that fusion never occurs, Harris says. But, he adds, the new findings definitively show that fusion is not absolutely required for bone marrow cells to turn into nonblood cells.

The researchers have been careful to say that their results do not confirm that blood-forming stem cells transdifferentiate into other cell types. However, Harris does think that the study implies there is likely to be a far more flexible stem cell in the bone marrow than has been previously identifieda possibility that adds fuel to the adult versus embryonic stem cell debate.

Some experts say the new marrow research is much more meticulous than previous studies looking at adult stem cell plasticity. Theyve been particularly rigorousand more so than other studies that have been published with similar technologyin establishing that no fusion events were detectable, says Neil D. Theise, a stem cell researcher at Beth Israel Medical Center in New York. Theise believes the study helps to counter what he sees as largely political arguments that cell fusion is the only way adult stem cells can turn into a variety of different cell types. It restores some balance to the field, he says.

But other experts are skeptical. This is an incomplete study, says George Daley, a stem cell biologist at Harvard Medical School. His objection: the team used whole bone marrow rather than only blood-producing stem cells. It really begs the issue: is it the stem cell, or is it something else thats going on? None of this means that marrow stem cell plasticity doesnt happen naturally, Daley says, or that it cant happen with lab intervention. I believe that plasticity can be engineered, he says. And that, he says, could still be useful clinicallybut youve got to prove it.

Daley and Theise agree, however, that the Yale paper will be seized upon as one more political football in the embryonic versus adult stem cell debate. And that, they say, would be inappropriate. The two lines of research are synergistic, says Theise. It isnt a matter of one or the other; if we exclude one line of research, we slow down progress for both. And despite the strength of the evidence that bone marrow cells can produce tissue other than blood, the true capabilities of adult stem cells still have to be sorted out. Says Daley: It just seems foolhardy to advocate shutting down all of embryonic stem cell research for what might ultimately turn out to be alchemy or might turn out to be real. We just dont know.

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