Promise of stem cells amplified

October 24, 2004

SAN DIEGO, Oct. 24 -- Continuing to counter the dogma that once brain cells give out, they're gone forever, new evidence shows that newly created neurons may provide hope for treating a wide variety of disorders.

Embryonic stem cells have been shown to restore movement after paralysis. And with genetic engineering, stem cells can act as sophisticated protein delivery systems. Scientists have used them to deliver GDNF, a factor to aid in the survival of neurons targeted by Parkinson's and Huntington's diseases. Another team has used them to seek and destroy brain tumor cells. And a Norwegian group has proved that even in adults, neural stem cells have the power to become functioning neurons.

Scientists at the University of California , Irvine , have reversed spinal cord damage in paralyzed adult rats, allowing them to walk again. The researchers, led by Hans Keirstead, PhD, used human embryonic stem cells, which have the potential to become any cell type in the entire body--and turned them into oligodendrocytes--a type of cell in the brain. Oligodendrocytes form the fatty substance myelin that insulates the long wirelike extensions of nerve cells, called axons. Oligodendrocytes wrap themselves around these axons, allowing electrical signals to be rapidly transmitted to other cells in the brain and body.

Spinal cord injury results in a cut through the axons, breaking the information circuit and resulting in paralysis. Even if the neurons are able to regrow new axons, they require oligodendrocytes to form new myelin. "By transplanting new oligodendrocytes, we repaired the lost insulation," Keirstead says.

The researchers manipulated human embryonic stem cells to become oligodendrocyte progenitor cells (OPCs), an intermediate step before becoming oligodendrocytes. Once implanted to the nervous system of rats, the cells completed their maturation.

When the OPCs were transplanted into rats just seven days after a spinal cord injury, the rats regained the ability to walk nine weeks later. Rats that had to wait until ten weeks after injury, however, did not improve with the transplant. Keirstead says that scar-forming cells may block the re-insulation of axons by the oligodendrocytes. "Older, scarred spinal cord injuries pose another hurdle that we have yet to conquer," he says. "Future studies may find a way around this barrier."

The broader accomplishment of this work, says Keirstead, is the generation of a highly pure population of oligodendrocytes from human embryonic stem cells. Previous efforts to collect oligodendrocytes from human fetuses resulted in samples contaminated with other cell types and oligodendrocytes at different stages of development. This pure population will allow researchers to explore the value of using oligodendrocytes in other applications.

In other work, scientists at the University of Wisconsin at Madison have rescued the cells that are attacked by Parkinson's disease and Huntington's disease. Both diseases are movement disorders that specifically kill off neurons that use the neurotransmitter dopamine. "Replacement of dopamine neurons using embryonic stem cells has long been the holy grail," says Clive N. Svendsen, PhD. "But stem cell transplantation can introduce serious problems, including tumors and dyskinesia, or impaired, sporadic muscle movements."

So instead of replacing the dopamine cells, she and her colleagues found a way to provide support to neurons under attack. Dopamine neurons require glial-derived neurotrophic factor (GDNF) to survive. So even if stem cells could be successfully introduced to an adult brain, chances are they would require GDNF. Yet in an earlier study, Berhstock's group showed that GDNF alone could restore function to the neurons affected by Parkinson's.

In this earlier study, the researchers delivered GDNF to the brains of patients using a pump and a small catheter implanted in the putamen, a brain area severely stricken by Parkinson's disease. But because the delivery system was so localized, the GDNF did not travel very far. Nevertheless, the patients' symptoms and dopamine neurons improved.

"We thought real cells might better deliver GDNF to the brain," Svendsen says. The group considered using embryonic stem cells, but realized they might lead to tumors and dyskinesia, so they tried neural stem cells. These cells don't have quite the enormous potential of embryonic stem cells, but they can become astrocytes, a type of glial cell found in the brain. Best of all, they do not induce tumors.

"We wanted to use genetically modified stem cells as organic GDNF 'mini-pumps,'" says Svendsen. In order to get the astrocytes to produce and deliver GDNF, they gave them a gene for the growth factor and another gene that acts as an "on/off switch" for GDNF production. The researchers were able to control the release of GDNF with the antibiotic doxycycline. They lowered GDNF production simply by administering the drug to the animals, and then resumed GDNF production by withdrawing it.

They then transplanted the genetically modified astrocytes into the brains of rats that served as animal models of either Parkinson's disease or Huntington's disease. The GDNF produced by these astrocytes caused the dopamine neurons to sprout new fibers and to transport the GDNF back to the neuron cell bodies, signs of improved neuronal health and function. "The study provides evidence that this delivery method might be used as a clinical tool for Parkinson's and Huntington's diseases," says Svendsen.

Another group of scientists has used the remarkable ability of human neural stem cells to home in on harmful brain tumors. Evan Snyder, MD, PhD, of the Burnham Institute in San Diego, and his colleagues at Yonsei University in South Korea implanted neural stem cells to adult mice and watched as they attacked the brain tumors.

Cancerous tumors move quickly throughout the brain. "Brain tumors are entirely untreatable because they are so migratory," says Snyder. "They are inevitably lethal because they can evade even the most extensive surgical excision and therapies. Neural stem cells are uniquely poised to treat tumors because the cells are attracted to areas of abnormality."

The researchers used genetic engineering to turn the cells into delivery vehicles for therapeutic agents. They inserted the gene for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This substance, secreted by the implanted stem cells, is like kryptonite to the hazardous tumor cells.

The scientists studied the most lethal type of brain cancer: intracranial glioblastomas. Adult mice with the tumors received transplants of the stem cells that could deliver TRAIL. The stem cells traveled throughout the main tumor site and even to the cancer's satellite locations, called metastases. The stem cells attacked the cancer and reduced tumor size dramatically.

"Treating brain tumors is perhaps the most promising use of stem cells," Synder says. "It's truly the 'low-hanging fruit' in the field."

In other research, scientists at Oslo 's University Hospital have now shown that even adults harbor stem cells that can become real neurons. Throughout our lives, neural stem cells are born in the ventricular zone, the areas inside hollowed-out spaces in the brain that contain cerebrospinal fluid. Several groups of researchers have watched these cells mature into what look like neurons. But the true test of a neuron's function--electrical conductivity--had not yet been seen.

Iver Langmoen, MD, and his colleagues harvested the adult neural stem cells from the ventricular zone of patients undergoing brain surgery. In the laboratory, the stem cells formed aggregates called neurospheres, which must be dissociated before subsequent divisions can occur. After several generations, the researchers treated the cells with a mix of nutrients to help them differentiate into neurons.

They used a tiny electrode designed to measure the electrical activity of individual neurons. This technique, called patch-clamp electrophysiology, revealed that the cells indeed fired action potentials, a neuron's electrical signature. The cells also release glutamate, one of the brain's most important neurotransmitters. In addition, the neurons expressed glutamate receptors, indicating that they could sense glutamatergic messages in addition to sending them.

Final evidence that the cells were able to communicate as neurons came from experiments in which the researchers recorded electrical activity from pairs of neighboring neuronlike cells simultaneously. This cemented the notion that the cells used a classical neuronal mechanism of transmission.

"Stem cells from the adult human brain can develop into functional neurons and establish networks," says Langmoen. The researchers hope to explore the possibility of autotransplantation, in which neural stem cells gathered from the brain of a patient could be multiplied in the lab and then returned to that person's brain. "Such a scenario would avoid the ethical and immunological complications associated with embryonic stem cell therapy," Langmoen says.
The new research was presented at the 34th Society for Neuroscience annual meeting in San Diego.

Society for Neuroscience

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