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From Mice to Man 

A Diabetes Stem Cell Research Breakthrough at Tulane

Sometimes even the experts can be mistaken, but that doesn't always mean catastrophic results. Just ask Dr. Darwin Prockop, a leading authority in the field of adult stem cell study and the director of the Tulane Center of Gene Therapy. Prockop laughs when he recalls giving his opinion about a proposed experiment The center had been using human adult stem cells to treat mice that had either a spinal cord injury or heart disease. The research had yielded some success when Dr. Ryang Hwa Lee, a postdoctoral researcher, suggested employing the adult stem cells to treat mice with diabetes. Prockop agreed to let Lee conduct the tests, but he was pretty blunt about what he thought the outcome would be.

"I told her it wouldn't work," Prockop says.

He was wrong. The human adult stem cells were injected into diabetic mice, and, as stated in Prockop and Lee's recent article in Proceedings of the National Academies of Sciences, the results were "remarkable." Not only did the adult stem cells help to reduce the diabetic mice's elevated blood sugar levels, the cells also seemed to home in on the damaged organs, the pancreas and the kidneys. Prockop was ecstatic about the outcomes and didn't mind being proven off the mark.

"That's how I learn," Prockop says.

That research could be the beginning of adult stem cell therapy for diabetics. According to the Centers for Disease Control, there are 20.8 million diabetics in the United States. The potential new therapy has Tulane endocrinologist Dr. Vivian Fonseca cautiously excited.

"Until we test it, we don't know, but it certainly has promise," Fonseca says. "We have to test it on humans."

In order to start testing on human subjects, the Tulane Center of Gene Therapy will have to receive Food and Drug Administration (FDA) approval to become a lab authorized to produce adult stem cells that can be used on human patients. Prockop reports that the center has been able to grow large numbers of the cells, which is critical for continuing research. The Tulane center takes adult stem cells from human bone marrow, then cultivates them in the lab.

"There are similar stem cells in most tissue you look at, but we find the easiest place to get them is from bone marrow," Prockop explains. "Other people are getting them from fat tissue, which seem to be similar cells, although it's very hard to know if you have the exact same cell or a slightly different one."

Whether these adult stem cells, taken from fat tissue or bone marrow, are the same or different could factor into what the stem cells are capable of doing therapeutically. Scientists have been struggling to find common genes and proteins — also called "markers" — for adult stem cells. Unfortunately, Prockop says, no such "signature" has been discovered yet.

In addition to getting approval for producing the stem cells for human testing, the center needs FDA consent before it can conduct the diabetes-specific therapy experiment. Tulane is also in the process of developing FDA applications for human testing with adult stem cell therapy to treat spinal injury and heart disease. The center held a preliminary meeting with the FDA in August, and was told further animal testing would be necessary before Tulane can be approved to use the adult stem cells on human subjects. Prockop expects this will take at least six months. However, he says, since the diabetes experiment employed human cells and not mice cells, this puts the center way ahead of the game in terms of getting approval for clinical trials with humans.

Although six months doesn't seem like a long time, a lot can happen during that period in the exploding field of stem cell research. Papers are being published constantly, and Prockop says it's hard to keep up with the 15 to 20 new articles every week. Some of the research might not be groundbreaking, but, as is the case with the Tulane center's work, sometimes the results can begin to change the way researchers think about adult stem cells.

Until recently, Prockop explains, it was assumed that adult stem cell therapy worked because of a stem cell's ability to replicate itself and to "differentiate" or become another type of cell. Normally, adult stem cells are found throughout the body but aren't specialized like blood cells, nerve cells or muscle cells. The stem cells remain dormant and non-dividing until they're activated by an injury or disease. Researchers, including Prockop, believed that following an injury or illness, the adult stem cells would begin dividing or replicating themselves — something specialized cells cannot do — and that the replicated cells then differentiate into the specialized cells where the injury or disease occurred.

Prockop says that scientists thought that differentiation was the main feature of all stem cells, both embryonic and adult. When Dr. Lee conducted her tests by injecting the adult stem cells into the diabetic mice, Prockop assumed the adult stem cells might eventually differentiate, but something else happened.

"We kept looking for them to differentiate, but that's not what they're doing," Prockop explains. "They're rescuing the diabetic state by rescuing the cells that are damaged."

A few of the injected adult stem cells did actually differentiate into specialized mouse cells, but for the majority, their main function was to produce nutrients and hormones so that the mouse's own cells could regenerate. Even though the mice's insulin levels increased, alleviating the diabetic state, and other healing took place, Lee and Prockop found little evidence of the adult stem cells in the mice weeks after the injections. Prockop says this follows what has been seen in adult stem cell therapy models for heart disease.

"The hearts began beating better, but you couldn't find many cells. That's one of the things that got us thinking that they may be there for only a short time, but they're repairing the tissue or triggering repair."

Prockop says researchers have known for a couple of years that stem cell therapy can improve heart disease, but this latest experiment is the first to demonstrate that these injected human stem cells can act as repair cells for the test subject's (in this case the mouse's) own stem cells.

"I think we can claim to be the first to show that these cells actually regenerate stem cells in different tissues and repair them," he says.

The other key finding in the center's diabetes research was how the stem cells went directly to the organs injured by diabetes. The cells originally were injected into the heart, and small traces of the stem cells later were detected there during tissue evaluation. But the majority of the stem cells were found in the kidneys and pancreas. When Lee initiated the experiment, she anticipated that the stem cells would go to the pancreas so the organ would regenerate and begin insulin production, which is limited or halted in diabetes. What she didn't expect was the discovery of the injected cells in the kidneys.

"Surprisingly, we found stem cells in the kidneys, too," Lee says. "Diabetic patients also have kidney damage besides the pancreatic damage."

Further tests revealed that diabetic lesions on the kidneys had begun to heal. The transplanted human adult stem cells weren't detected in any of the mice's other organs, strengthening the argument that the cells knew where to go. Prockop also says the stem cells did not travel to the kidneys and pancreases of the experiment's control group of mice without diabetes.

The Tulane center works exclusively with adult stem cells, not controversial embryonic stem cells. Although Prockop fully supports embryonic stem cell research and its potential to help scientists understand how the body works, he thinks there are several advantages to adult stem cell therapy. Embryonic stem cells, which have not yet been used on humans, are known to cause tumors, whereas adult stem cells do not. And when adult stem cells are used in therapy, the cells come from the patient's own body — unlike embryonic stem cells, which come from fertilized human eggs during the first two months of gestation. Since the adult stem cells are from the patient's body, there isn't a risk of rejection.

Prockop says that while the FDA has not officially accepted adult stem cell therapy, the agency has approved numerous clinical trials using the cells.

"Thousands are being treated with one kind or another of adult stem cells, particularly in the area of heart disease. I don't know of anyone using embryonic stem cells on patients," Prockop says.

Dr. Fonseca, who will partner with Prockop's team for the human clinical trials, says that until Lee and Prockop's work, it had been difficult to demonstrate the efficacy of adult stem cells in treating diabetes. Experts and research foundations, including the Juvenile Diabetes Research Foundation, posit that the best option would be the use of embryonic stem cell therapy.

Fonseca hopes these experts are wrong and that adult stem cell therapy can be used for diabetes.

"It (adult stem cell therapy) is the wave of the future. There's been a lot of controversy regarding embryonic stem cells, so what's exciting about this is that you're taking a person's own cells," Fonseca says. "Yes, we may someday for some people and some diseases need embryonic stem cells, but here we have the opportunity to do it without that."

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