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How 'plastic' are adult stem cells?

Not nearly as much - or useful - as their embryonic counterparts, says research by Norihiro Awaya, fellow in Torok-Storb laboratory
Kate Rupert looks through a microscope at adult stem cells.
With the image of what she is seeing reflected in a protective shield, Kate Rupert looks through a microscope at adult stem cells. The lab's found that adult stem cells have no potential to form stromal cells, the support cells in marrow that nourish of blood and immune cells. Photo by Todd McNaught

Adult stem cells have been hailed as a potential alternative to ethically controver- sial embryonic stem cells as a means to regenerate tissue for treating disease.

But new research from the Clinical Research Division suggests that adult stem cells from the bone marrow (known as hematopoietic stem cells) that normally give rise to the blood and immune system, may have more limited potential than other studies have indicated.

Dr. Norihiro Awaya, a research fellow in Dr. Beverly Torok-Storb's lab, studied the bone marrow from long-term survivors of stem-cell transplantation, a treatment for leukemia and other blood disorders, to evaluate the regenerative potential of their transplanted stem cells.

Awaya found that the transplant survivors' stromal cells, the support cells in the marrow that nourish the development of the blood and immune cells, originate solely from recipient tissue, suggesting that hematopoietic stem cells do not have the potential to form this cell type. Even 27 years after transplant, transplant recipients' stromal cells were entirely of recipient origin.

The findings raise caution about the promise of adult stem cells for therapeutic use, Torok-Storb said.

"Studies on the plasticity (potential to form a wide range of cell types) of adult marrow-derived stem cells needs to be evaluated rigorously," she said.

"Before we throw away the idea of embryonic stem cells in favor of adult stem cells, we need substantial proof that adult stem cells have similar potential. Otherwise, there is a danger of wasting a lot of time and resources and giving false hope to patients with illnesses for which stem-cell therapy is being explored."

The study appears in the August issue of Experimental Hematology, a special edition focused on stem cell plasticity. Co-authors of the paper are Kathleen Rupert and Dr. Eileen Bryant of the Cytogenetics laboratory at the Seattle Cancer Care Alliance.

Unique, long-lived cells

Stem cells are unique cells that are long-lived, have considerable growth potential and have not yet made commitments to become specialized.

Embryonic stem cells - the few cells from which an entire organism develops - are flexible enough to become virtually any kind of cell when stimulated by the appropriate growth factors. For that reason, many scientists argue that they are the best hope for regenerating tissues to treat incurable ailments such as Parkinson's disease and spinal cord injures.

But because they are derived from human embryos, their use has been subject to much ethical debate. The Bush administration recently approved use of only a limited number of already established embryonic stem cell lines for biomedical research.

Adult stem cells give rise to tissues, such as blood or skin, which are continually renewed over the course of a lifetime.

While such cells retain enough flexibility to spawn multiple cell types of a given tissue - both red and white blood cells arise from a single marrow stem cell - they traditionally have not been thought to possess an unlimited array of developmental capabilities.

Recent research, though, suggests that some adult stem cells may have the capacity to differentiate into tissues outside their normal repertoire of activities. Studies have shown that blood-forming stem cells apparently can contribute at low frequency to many other tissue types, although researchers debate the validity of these results.

Many of these studies were conducted in mice, and parallels cannot always be drawn between these small, short-lived mammals and humans. In addition, blood cells known as macrophages can travel to many parts of the body, where their presence is sometimes mistaken for other cell types and may account for these rare sightings of donor cells.

Awaya and colleagues hypothesized that if marrow cells were "plastic," they would not only generate blood and immune cells but would also contribute to non-blood cells in the marrow, such as stromal cells.

Opposite-gender donors

To evaluate this, the investigators analyzed the bone marrow from transplant survivors who had received bone marrow from a donor of the opposite gender, because in that circumstance it is possible to distinguish donor cells from recipient cells by microscopic analysis of the sex chromosomes.

Marrow stromal cells were grown in culture and then analyzed for sex chromosomes by fluorescence in situ hybridization (FISH), a technique that uses fluorescent dyes to visualize chromosomes, to determine if they were donor or recipient.

The researchers found that although all of the patients' blood and immune cells could be traced to the donor, the non-blood forming stromal cells cultured from their bone marrow were generated by their own cells.

For example, in one female patient who had received bone marrow from her brother, the hematopoietic cells in her bone marrow contained the male Y chromosome but her stromal cells did not. Even 27 years after transplant, stromal cells were entirely of recipient origin.

Experts have argued that one explanation for the limited capacity of marrow stem cells to form unrelated cell types is their inability to migrate to sites distant from their normal bodily location, where they would then differentiate into new cell types.

For that reason, Torok-Storb said it is especially surprising that the stem cells were unable to contribute to the formation of the stroma, since hematopoietic stem cells and stromal cells reside in close physical proximity in the marrow.

"If the blood-forming stem cells aren't capable of making a different cell type in the same physical compartment - the bone marrow - we really have to limit our definition of the plasticity of these cells."


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