Adult stem cells have none of the ethical issues associated with them that make embryonic stem cells so contentious. For that reason, they often are cited by opponents as an alternative that makes embryonic stem cell research unnecessary.

That suggestion is based on ethical concerns, not scientific evidence. Few scientists, regardless of what type of stem cells they personally work on, would subscribe to the view that enough is currently known about adult stem cells to confidently dismiss embryonic stem cell research as unnecessary.

And in work published in the May 17, 2005, issue of the Journal of Experimental Medicine, researchers from Stanford University presented new data that support a less-than-sanguine view of the capacities of the most frequently used adult stem cell, the hematopoietic, or blood-forming stem cell.

While harvesting bone marrow is certainly no picnic for the donor, blood stem cells are nevertheless relatively easy to both find and obtain compared to other adult stem cell types, which would make them highly desirable candidates for clinical development.

If only they were more versatile.

"A lot of the studies suggesting that hematopoietic stem cells could transdifferentiate have been explained by other mechanisms," said Amy Wagers, now assistant professor at Harvard Medical School and a co-author on the paper. As a result, transdifferentiation, or the possibility that under the right conditions, blood stem cells can generate cell types that are not part of their normal progeny, "is not the mainstream view anymore."

The Journal of Experimental Medicine paper is an extension of previous research, which had demonstrated that in the normal brain, transplanted blood stem cells do not form neurons or astrocytes in appreciable numbers. One of the goals of the current research was to see whether the situation might be different in an injured brain, opening up what Wagers termed "a niche for hematopoietic stem cells" to generate those cell types in clinically relevant scenarios. For that reason, the scientists investigated whether they could find neurons or astrocytes derived from blood stem cells in either brain-injured or normal mice. But the take-home message in both cases appears to be: no such luck.

The scientists used several different models to test the plastic capacities of hematopoietic stem cells. They transplanted both purified stem cells and unpurified bone marrow cells into irradiated mice, which is a standard way of testing the cell fates of blood stem cells.

Additionally, they used a less frequently employed method to identify possible contributions of other circulating cells to possible brain cells: Parabiosis, which is essentially the surgical creation of mouse Siamese twins that share a common vasculature. Wagers told BioWorld Today that parabiosis has two advantages compared to bone marrow transplant: The irradiation that is used to kill the recipient's bone marrow inhibits later stem cell proliferation, and the method can detect not just the cells that the experimenter thinks are important to transplant. The approach "assays any cells that are circulating in the blood" for their ability to settle down and procreate in the recipient's brain.

The researchers did see copious amounts of blood cells derived from the blood stem cells, confirming that the transplants themselves had been successful. They also found low levels of microglia, a type of support cell, in the recipient brains, regardless of whether they transplanted bone marrow, single blood stem cells.

But of more than 10,000 cells analyzed using both confocal microscopy and marker studies, they saw only a single case of a possible neuron or astrocyte from a blood stem cell - and even that one cell could not be definitively confirmed. While the details varied, the general result held true in mice that were treated with purified blood stem cell, bone marrow, or surgically hooked onto a donor mouse's blood supply.

Now You See It, Now You Don't - But Why?

Negative results pose a scientific challenge, since it can be difficult to say whether an effect was not observed because it does not exist or because of details of experimental design or execution. That is especially true when positive results previously have been reported, as is the case for the generation of neurons from blood stem cells.

Negative results also often are difficult to publish, partly because of those concerns and partly because not finding something often is considered inherently less interesting than finding something.

Asked about possible other mechanisms for the brain cells observed after previous blood stem cell treatments, Wagers listed several, including the possible fusion of donor stem cells with recipient brain cells after transplantation, and the existence of other stem cell types in the bone marrow, though she pointed out that her group's bone marrow transplantation data would argue against the latter possibility.

Asked the reason for her confidence in the negative results, Wagers explained: "We know that we isolated hematopoietic stem cells, because we do that routinely. And we know that we had good engraftment in the blood lineage" from the experimental results. Beyond that, the sheer thoroughness of her team's approach makes her confident in their conclusions.

"We analyzed thousands of cells," she said. "We cannot absolutely say that this never ever happens. But we can say that it happens at such a vanishing low frequency that it is unlikely to contribute [to regeneration after injury] in a meaningful manner."