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In Vivo

Stem Cell Research

CUMC Researchers Explore 
Stem Cells on Many Fronts

In the popular press, it often seems as if groundbreaking stem cell therapies are just around the corner. In reality the challenges involved in turning stem cells into viable therapies are formidable.

"The entire stem cell field is still in its infancy," says Tom Jessell, Ph.D., professor of biochemistry and molecular biology and a member of the Neural Stem Cell Scientific Oversight Committee. "Typical of a new field, a lot of findings that have come out have not been reproducible."

Serge Przedborski
At CUMC, the goal of stem cell research is not to make short-term sensational headlines, but to rationally explore the potential of both embryonic and adult stem cells to treat and cure many diseases for which there currently are no viable therapies. A Stem Cell Consortium has been created here that enables all researchers to pool their expertise and provide funding for young researchers entering the field.

Though many questions still need to be answered, Gerald Fischbach, M.D., executive vice president and dean, says "there's enough information now from animal studies and from transplantation of small pieces of tissue to indicate that therapies using stem cells, adult or embryonic, are possible in humans and have a good chance of success. It's one of the more revolutionary approaches to therapeutics that I've seen in my time in medicine."

The stem cell researchers' work is being funded by government grants, individuals such as Bernard Spitzer, a civil engineer and real estate developer, who established the Bernard and Anne Spitzer Fund for Cell and Genetic Therapy at Columbia; the Jean I. and Charles H. Brunie Foundation; and, the Russell Berrie Foundation.

Just a few of the many stem cell projects pursued by Columbia faculty are presented below.

Mending Broken Hearts

In stem cell research, perhaps no field is moving faster toward the clinic than cardiology. With several trials under way or already completed in Europe, and a few set to begin in the United States, cardiologists are anxious to find a way to stop the almost inevitable demise of the heart after an attack.

Weeks, months and even years after a heart attack, the heart continues to change as nearby healthy muscle must compensate to keep blood moving. The harder working heart muscle needs more oxygen but the blood vessels that deliver it have not grown in response to the increased demand. The overworked tissue thus eventually starts to die, placing even more stress on the remaining muscle.

"It's an ongoing process that just keeps spiraling outward until the person develops heart failure. There's really nothing to stop it," says Silviu Itescu, M.D., director of transplantation immunology for the Departments of Surgery and Medicine.


In rats with heart failure, certain bone marrow stem cells, Stro-1+ cells, create new arterioles, stimulate repair, and create a nearly normal heart. Photos courtesy of Timothy Martens.

Researchers worldwide have been trying to figure out ways to coax new heart muscle cells from embryonic and adult stem cells, but Dr. Itescu approaches the problem from a different angle. If the heart cells die because they cannot get enough oxygen, why not give them more oxygen?

"In embryos, we know that certain cells are responsible for creating blood vessels throughout the body," Dr. Itescu says. "So we thought there may be cells in adults that could also create vessels from scratch to supply more oxygen to the heart."

Dr. Itescu's lab has now identified specific cells from bone marrow – Stro-1+ cells – that are capable of repairing most of the damage caused by a heart attack.

"When we give these cells to rats who have had a massive heart attack, we see full blown arterioles and you can get most of the heart's normal function back." says Timothy Martens, M.D., a postdoctoral research fellow at CUMC who performed the experiments.

"The Stro-1+ cells are not turning into heart muscle," adds Dr. Itescu. "They're secreting all sorts of factors that are responsible for the improvement. In rats, we've essentially prevented heart failure."

The effect is much stronger than that seen from other bone marrow cells called angioblasts. The researchers are now trying to get approval to try the stronger-acting Stro-1+ cells in patients for the first time.

The ultimate goal is to use the cells to prevent heart failure in patients who have just suffered a heart attack.

"One day," Dr. Martens says, "we hope that a patient coming into the ER with an acute myocardial infarction would get current medical therapy (anticoagulants/ antiplatelets, beta-blockers and oxygen to protect the remaining viable muscle) plus cell-based therapies to grow a new vascular network and possibly regenerate cardiac muscle."

Replacing Lost Neurons

When implanted into a spinal cord, motor neurons developed from mouse embryonic stem cells connect with nearby cells but have yet to extend to muscle, which they must in order to be functional. Photo courtesy of Makiko Nagai.

Two years ago, two Columbia researchers, Dr. Jessell and Hynek Wichterle, Ph.D., assistant professor of pathology, took stem cells from mouse embryos, covered them with several different growth factors and transformed the cells into the same neurons that are lost in amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease).

When the researchers took these cells from the petri dish and put them into young chicken embryos, they grew into normal looking neurons, reaching down into the limbs of the chicken and making connections with distant muscles.

Researchers hope a similar process could work in adults to replace the lost motor neurons in ALS, the lost dopamine neurons in Parkinson's disease, and the cells damaged as a result of spinal cord injuries. Many questions still remain, however, before the cells reach the clinic.

Serge Przedborski, M.D., Ph.D., the William Black Professor of Neurology, is now trying to answer one of the most important questions about stem cell therapy: how the cells will behave in an adult animal where the cellular environment differs dramatically from the embryonic milieu.

"Before birth there's still a lot of development in the brain and the spinal cord. A newcomer may be able to find a way using cues that are already there," Dr. Przedborski says. "After development ends, though, we know the cues disappear. How will the cell find its way?"

So far, the experiments with rats suggest the new cells can't find their way in healthy adults, or even in diseased adults where some of the cues may be present. The injected cells seem healthy and even send out axons toward other cells. Some of these grafted cells appear to connect with other neurons present in the immediate vicinity, but they do not appear to send axons out of the grey matter of the spinal cord, which they ultimately must do to connect with muscle.

But replacing lost neurons may not be the best strategy. "We are recognizing more and more that inflammation plays a large role in neurodegeneration," Dr. Przedborski says. "Introducing stem cells may have some success not in repairing the system but in making substances that soothe inflammation. It may be an easier goal and more achievable than restoring neurons."

Surrogate Cells for Diabetes

Adult or embryonic stem cells may replace the insulin-producing beta cells (shown above) that are destroyed in Type 1 diabetes. Photo courtesy of the Journal of Clinical Investigation.

Unlike neural stem cell researchers, who are still unsure whether neurons or glia have more therapeutic potential, diabetes researchers are certain they have identified the proper cells – the insulin-producing islet cells that are destroyed in type I diabetes. The problem is, they still do not know how to make beta cells.

"Diabetes researchers lag behind on the basic science of how to turn stem cells into islet cells," says Dr. Jessell. "But once they succeed, they are further along because they know how to transplant cells into people."

That transplantation knowledge comes from a 1999 Canadian breakthrough. Until then, all transplant attempts using frozen islets, a cluster of cells that contain beta cells, were not particularly successful. The Canadian researchers finally succeeded when they tried the procedure with fresh islet cells and new immunosuppressive drugs to prevent rejection of the cells. Now called the "Edmonton protocol," a limited number of U.S. universities, including CUMC, are performing islet transplantation with FDA approval. In some cases, the transplant has kept the recipient off injected insulin for as long as four years.

Today, one of the procedure's biggest problems is the shortage of donor organs. "More than one pancreas is usually necessary to harvest enough islets for a single transplant," says Rudolph Leibel, M.D., co-director of the Naomi Berrie Diabetes Center at Columbia. "One of our goals then, is to grow an unlimited supply of insulin-producing cells that can act as surrogate beta cells from either embryonic stem cells or adult stem cells from the pancreas."

"Our philosophy is ‘Don't put all of your eggs in one basket,'" says Argiris Efstratiadis, Ph.D., Higgins Professor of Genetics and Development in the Institute for Cancer Genetics. "Adult stem cells may have some advantages, since they're already closer to the target, but they have a disadvantage in that they're very few in number and very difficult to identify."

Dr. Efstratiadis is now looking for the cells in mice and hopes to use what he learns to find the same cells in humans. "In several tissues, we know that the cells are there, but you can't just look in an organ and pick out the stem cells. We're chasing markers and genes that are unique to adult stem cells and so far we have some interesting clues. With the pancreas, the situation is even more difficult, considering that the very existence of adult stem cells in this organ is disputed."

The Berrie Foundation funds also support collaborations with stem cell researchers at other universities, including Doug Melton, Ph.D., at Harvard, who has been trying to coax human embryonic stem cells into insulin-producing cells.

Though several labs claim they have made insulin-producing cells from embryonic stem cells, Dr. Melton has found all these reports mistakenly attribute increases in insulin inside the cells as a sign of insulin production. Instead, Dr. Melton says, these cells took in insulin from the surrounding culture media and are not true insulin-producing cells.

"I think we will succeed eventually," Dr. Efstratiadis says. "But it will be a painstaking process and require a community effort that will take several years."

Scientists at CUMC are committed to the effort and collaboration involved in stem cell research and are optimistic that one day stem cells will indeed prove to be useful in the treatment of certain chronic, intractable diseases. "I would not be surprised if, in five years time, we had an approach to recovery from neurodegenerative diseases and spinal cord injury in animal models," Dr. Jessell says. "The insurmountable barriers are not so insurmountable anymore."

—Susan Conova