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Primitive Powerhouses
Stem Cells 101

by Alicia P. Gregory

"Stem cells are the ultimate resource for development, maintenance, regeneration, and repair in an organism," says Van Zant, but, he emphasizes, there's a clear distinction between embryonic stem cells and the "adult," fully developed, stem cells he uses in his research.

"The press and scientists have not done a good job in describing to the public the difference between embryonic stem cells and adult stem cells. Embryonic stem cells are controversial," he says, "and they are unique because they can grow into any kind of cell. They are necessary for fundamental research into understanding how stem cells are specified." But, he stresses, adult stem cells can yield their own important answers, and they’re readily available.

"Adult stem cells are a resource that exists in all of us." His excitement builds as he explains that birth itself yields an "untouched reservoir" of stem cells. "We can get stem cells from the blood that exists at the time of birth in the placenta and in the umbilical cord of the fetus. And this resource is usually just discarded in the delivery room," says Van Zant. Stem cell treatment using blood from umbilical cords does not involve human embryos. For more see Umbilical Cord Blood & the Cord Blood Bank.

Adult stem cells have three general properties: they are capable of dividing and renewing themselves for long periods of time, they are unspecialized, and they give rise to specialized cell types.

A stem cell is unspecialized—it does not have any tissue-specific structures that allow it to perform specialized functions. A stem cell cannot carry oxygen through the bloodstream (like a red blood cell), and it cannot fire electrochemical signals to make the body speak or move (like a nerve cell). But stem cells spawn specialized cells like blood cells and nerve cells.

Unlike blood or nerve cells, which do not normally duplicate themselves, stem cells replicate many times over—a process called proliferation. They can create exact copies of themselves or they can breed specialized cells—a process called differentiation.

Photo of Alison Miller, Debbie Bell and Amanda WaterstratGrad student Alison Miller (left) and postdoc Debbie Bell (center, background) have worked in Van Zant's research lab for two years. Grad student Amanda Waterstrat (right) has spent one year as part of a lab team that's been focusing on stem cell "homing" and population size.

The triggers for cell differentiation are internal (signals from the cell's genes, which carry blueprints on how to build cell structures) and external (other cells in the immediate environment).

Inside our bones, Van Zant explains, stem cells have neighbors called stromal cells, which provide a sort of "pocket" for the stem cells. "Stromal cells provide a poorly understood series of biochemical and physical interactions that somehow keep stem cells from differentiating willy-nilly and prevent them from proliferating in an uncontrolled manner," he says, noting that uncontrolled cell division is the calling card of cancer.

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Bone Marrow Transplant 101

Bone marrow is home to HSCs. "Hematopoietic tissue is nice because it's almost a liquid organ," says Van Zant. "You punch a hole in one end of the bone, stick a needle in the other end, squirt, and the whole plug of marrow comes out the other end. You can harvest and collect marrow very quickly."

But the process is painful. "In a bone marrow harvest, a patient goes to the OR, is anesthetized, punches are made across the back around the rim of the hipbone, and large amounts of marrow are pulled. It involves anesthesia—there's a certain risk there—and a recovery time," Van Zant says, but quickly points out that 10 years ago scientists found a better way to collect HSCs.

"We can inject a patient with a drug that causes the stem cells to leave the marrow and enter the circulation—we call this mobilization. This is the most common way of harvesting stem cells today."

The blood sample is passed through a machine (in a process called leukapheresis) that separates out the white blood cells, which contain the stem cells, and returns the other blood cells to the patient.

So what happens in a bone marrow transplant? There are two types: autologous transplants, in which patients receive their own stem cells; and allogeneic transplants, in which patients receive stem cells from a brother or sister or unrelated matched donor.

Van Zant sets up a hypothetical scenario for an autologous transplant. "You have cancer. You’re early in your disease, so you’re going to be responsive to drugs. We give you drugs, and you go into remission. We collect stem cells from your peripheral blood. We freeze those in liquid nitrogen down in the stem cell lab and put them away for later.

"We turn around and give you, essentially, a lethal dose of radiation or chemotherapy, and, we hope, this huge dose will kill all of your tumor cells, and maybe even some of the mutated, cancer-causing stem cells." He notes that this is the rationale for high-dose chemotherapy.

"You would die if we didn't have those bone marrow stem cells frozen. A day or two after your chemo, we inject into your blood a small number of stem cells. Those stem cells are going to have to replenish your entire hematopoietic system, and that's going to take some time. Meanwhile you're extremely vulnerable to infection, and the longer it takes for you to recover your white blood cell count, the more at risk you are from complications post-transplant."

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Umbilical Cord Blood & UK's Cord Blood Bank

"Umbilical cord blood is a tremendous source of stem cells that's virtually untapped, because it's usually just thrown away in the delivery room,' says Van Zant, who emphasizes that these are "adult," fully developed, stem cells.

"Go to any OB-GYN waiting room, and you'll see brochures for national commercial companies that will make sure your child's cord blood is harvested and stored indefinitely. Many parents are now getting savvy and paying to freeze their child's cord blood just in case the child develops leukemia or other diseases that can be treated with stem cells.

"At UK we're not in the business of storing blood for families," says Van Zant, who directs the year-and-a-half-old UK Cord Blood Bank. He adds that there are certain regulatory and liability issues to do so that the institution hasn't delved into. "We're interested in experimental and investigational use.

"So how do we obtain our blood? It's a partnership between the Cord Blood Bank and the people in OB-GYN, who get consent, as part of the regular paperwork mothers fill out, to donate their child's cord blood to research. A very large number of mothers agree to this.

"It takes a lot of cooperation from the OB-GYN residents who are actually in the delivery room, because, obviously, this is an afterthought to the big event," Van Zant says with a smile.

"At best you can get 50 to 100 milliliters of blood from the placenta and umbilical cord of a newborn. Although this blood is rich in stem cells, until recently it was simply not thought to contain enough stem cells to transplant and repopulate the entire hematopoietic system of an adult. So it was used only in children who weighed 50 pounds or less."

But in December 2004, at the annual American Society for Hematology conference, two findings came out that may have a huge impact on umbilical cord blood transplantation.

"The first big finding, from a group at the University of Minnesota, was that it is feasible to pool cord blood from different—even completely unrelated—births to get enough stem cells for transplantation." Van Zant points out that scientists had been wary of combining sources because this could trigger undesirable immune responses. "The cord blood stem cells are very young, and they have diminished immune sensitivities, and it looks like you can, under some controlled conditions, combine them to get the numbers you need."

The second finding, the result of collaborative studies between Duke University, the University of Minnesota and the New York Blood Center, showed that perhaps the number of stem cells needed for an adult transplant is lower than scientists originally thought. Van Zant says, "They found that the number of stem cells actually needed, for most people, is within reach with the standard cord blood harvest. Now, that's only one study, and it needs to be followed up and duplicated, but it's very encouraging.

"Together these findings have really enhanced the possibility of expanding cord blood use for a wider number of transplants."

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