The cells that make bone marrow, peripheral blood, and umbilical cord blood transplants effective — so-called stem cells — are a central focus of research at the University of Minnesota.

That's because once researchers understand the biology of stem cells, they will be able to get the stem cells to do even more healing work. Two major areas of interest are survival of stem cells and gene therapy.

On this page:

• Survival of Stem Cells
• Gene Therapy
• Homing and Engraftment
• Genetic Markers

Survival of Stem Cells

How well do stem cells survive manipulation — specifically "expansion," in which stem cells are grown outside the body in a lab? How well do they survive the manipulations of gene therapy and gene marketing? "We don't exactly know what a stem cell looks like," says one of the researchers working on stem cell manipulation. "We define a stem cell by ability, not by shape or size. Stem cells in the body are defined by their property of self-renewal, and by their ability to contribute to the making of blood after transplantation." Whether stem cells survive, and whether they can still be transplanted after manipulation will have to be tested in experimental models.

Gene Therapy

In this manipulation, stem cells are activated so that they are able to accept new genes that can change their behavior. One way this might be used is to insert a gene that enables stem cells to better survive chemotherapy. This is potentially useful because there are cases in which a cancer patient would benefit from additional chemotherapy after stem cell transplantation. Normally, this would kill the newly transplanted stem cells. However, "fortified" stem cells treated by gene therapy could survive, thus giving physicians another treatment tool. Also, new genes may be used to correct an inherited defect, for example, Fanconi Anemia, Wiskott-Aldrich Syndrome, or Sickle Cell Anemia.

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Homing and Engraftment

Homing refers to the stem cells' innate ability to travel to the right place in the body — the bone marrow — suited for making blood. The term "engraftment" means that the stem cells have begun their work; they are functioning properly within the marrow by producing various kinds of blood cells. Experimental evidence suggests that manipulated stem cells may lose some of their homing and engraftment abilities. If this evidence is true for humans as well, a troubling paradox may arise: The very success of an umbilical cord blood transplant could be undermined by the manipulations performed on stem cells — manipulations intended to increase their healing properties, not decrease or eliminate them. Research needs to clarify this. Work of this kind, at the University of Minnesota, is crucial to the success of stem cell expansion.

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Genetic Markers

As in gene therapy, stem cells that are being genetically marked are activated to accept new genes. But instead of receiving genes that change their behavior, they receive genes that serve as "flags'' or markers, that are reproduced and expressed in every generation of subsequent cells. The markers can then be used by researchers to keep track of stem cell activity in the body after transplantation.

For example, genetically marked stem cells are being used in a new experimental protocol at the University. In this experiment, one-third of the stem cells the patient receives has been expanded and genetically marked outside the body in a lab.

The remaining two-thirds of the stem cell dose is taken straight from the umbilical cord and frozen. This two-thirds fraction of the dose is sufficient for successful transplantation, so even if the one-third expanded fraction of stem cells fails to function properly, the transplant can still work.

After transplantation, researchers test the patients's blood to look for the genetic markers of expanded stem cells. If they continue to see the markers months and years after a transplant, it's good news.

It means that the stem cells have retained the essential trait of self-renewal, even after being expanded in the lab, and that expansion is a reliable way of increasing the number of stem cells available for treatments.

In all these areas of inquiry there are both promises and pitfalls. Before the potential gains of cell expansion, gene therapy or genetically marked stem cells can be embraced and used widely on patients, the risks must be fully understood.

Above all, preserving a stem cell's vital properties of self-renewal, homing and engraftment is "Challenge Number One."

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