Originally created 02/05/01

MCG researches stroke repair



It was once the stuff of science fiction or bad horror movies. But with the discovery of master cells within the brain that can be converted into new brain cells, the idea of regenerating the brain has suddenly become an attractive goal.

Researchers at Medical College of Georgia and across the country are racing to understand and harness that power in hopes of restoring lost function, such as that which occurs after a stroke.

At the same time, some stem cell research has generated controversy because the cells have been taken or developed from discarded embryos and fetal tissue. The Bush administration might ban the cells' use. But researchers at MCG are sidestepping the controversy by working with stem cells and supporting cells developed from adult bone marrow.

Stem cells often are considered mother cells or factory cells because they are capable of reproducing not only themselves but also cells that turn into red blood cells, muscle cells or other specialized cells.

The discovery of neural stem cells in the hippocampus of the adult brain a few years ago seemed to fly in the face of conventional thinking, said Dr. David Hess, the interim chairman of the Department of Neurology at MCG and executive of the Neurosciences Service Line at the Department of Veterans Affairs Medical Centers in Augusta. Dr. Fred Gage at the Salk Institute in California showed that humans as old as 50 and 60 make new neurons in the hippocampus, Dr. Hess said.

"It used to be thought that you were born with the number of neurons you have and you never make any more," Dr. Hess said. "That (research) kind of overturned the party line: no new neurons. That got a lot of things going."

A small pool of neural stem cells also were found in the dentate gyrus, deep in the hippocampus; because the hippocampus is involved in memory, these cells might have something to do with the creation of memories, Dr. Hess said.

The neural stem cells also provided a surprise - when neural stem cells of mice were injected into mice whose bone marrow had been wiped out by radiation, the cells turned around and made blood products like bone marrow stem cells would, Dr. Hess said. And if it works one way, it should work the other, he said.

"This is really important because it would imply that not only can your brain turn into your blood but your blood can turn into your brain," Dr. Hess said.

That might be what happens normally, said Eva Mezey, an investigator at the National Institute for Neurological Disorders and Stroke. Dr. Mezey's work, published in the Dec. 1 issue of the journal Science, focused on transplanting bone marrow from male mice into females that had no white blood cells. Over time, Dr. Mezey was able to trace cells still containing the Y chromosome from the male cells and found the Y trait in different neuronal cells in various areas across the brain. She is now looking to confirm her work in human brains.

"What I think is happening is these neural stem cells are being replenished from time to time from the bone marrow and then from there, they become neural stem cells," Dr. Mezey said. "And then maybe they can be recruited to become neurons or glial cells (support cells) or anything that's needed."

Regeneration might be happening to a small extent all the time, replacing some cells, Dr. Mezey said.

"It's a very different question of what happens when there is a lesion (from a stroke) in the brain," she said.

There are a number of theories about why there isn't regeneration after a stroke. Dr. Mezey said the area of damage might be too large for the normal repair process to handle.

Although he also says that there is ongoing repair, Robert K. Yu, the director of MCG's Institute of Molecular Medicine and Genetics, said the brain's response to the injury might interfere with neuron repair.

Brain cells called astrocytes - whose job is to clear out debris - flock to the site of the injury and form a scar or plaque there, Dr. Yu said.

"They form plaques, and normal neurons cannot grow into them," he said.

The problem might be that there is an inhibiting factor or that the proper signals aren't reaching the affected area, Dr. Hess said. Or neurons might be forming but not connecting with the neural network.

The MCG team collaborating on stem cell research is focusing a majority of its first efforts on strokes. Using mice whose DNA have been altered to express a green fluorescent protein, Dr. Hess and colleague Dr. William David Hill are transplanting the bone marrow from those mice into mice whose marrow has been wiped out by radiation. The mice without marrow will then be induced to have a stroke. The fluorescent protein, which shows up under a microscope, will allow the researchers to determine whether brain cells develop from those bone marrow stem cells, and whether those cells respond to the damage from the stroke.

Dr. Fung-Chow Alex Chiu at the Institute of Molecular Medicine is doing similar work with the green protein mice but is injecting the marrow directly into the brains of the mice who have had strokes. He already has some preliminary results that show the marrow stem cells flocking to the area of the stroke and integrating into the surrounding tissue and surviving. Dr. Chiu is also trying to convert the blood stem cells into neurons.

Dr. Hess will take leftover human bone marrow drawn for other tests and also try to convert it into neurons. The MCG team is focusing on the blood-derived cells for good reason, Dr. Chiu said.

"With this political uncertainty, it actually drives our efforts to focus on (bone) marrow stromal cells," Dr. Chiu said, "and umbilical cord blood cells," which often are discarded after birth.

The MCG team also is benefiting from having basic researchers trying to unlock how the cells work and clinicians focusing on applications, Dr. Chiu said.

"The really advantageous situation we have is the close collaboration with the clinicians," he said.

Stroke is a good area for the MCG team to focus on because of Georgia's position in the "Stroke Belt," and the massive toll it takes across the country, Dr. Hess said.

Stroke is the leading cause of disability, and there are more than 4 million stroke survivors in the United States, Dr. Hess said.

"So look at the population that could be helped," he said.

There are others besides stroke victims who might be helped. Some of Dr. Yu's work is funded by the Children's Medical Research Fund, founded by the parents of a child who suffers from Sanfilippo syndrome. The child's body doesn't make certain enzymes to break down byproducts of carbohydrates, and the resulting clutter kills off brain cells and can cause developmental problems. But transplanting the correct astrocytes might be a cure, Dr. Yu said.

"If you transplant normal astrocytes, there's a very good chance that they will do the job," Dr. Yu said. He keeps the child's picture sitting on top of the cabinets above his desk, always staring down at him as he works. It is an inspiration, he said.

"We're just going to have to work harder, quicker," he said.

Reach Tom Corwin at (706) 823-3213.