STUDIES PAVE THE WAY FOR USING STEM CELLS AS TREATMENTS FOR BRAIN CANCER, PARKINSON'S DISEASE, STROKE AND MORE
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STUDIES PAVE THE WAY FOR USING STEM CELLS AS TREATMENTS FOR BRAIN CANCER, PARKINSON'S DISEASE, STROKE AND MORE
WASHINGTON, DC, November 15, 2005 — In the latest research, scientists are harnessing new knowledge about the brain’s own neural stem cells to develop potential treatments for conditions as diverse as brain tumors, Parkinson’s disease, and genetic diseases involving myelin deficiency. They are also using the knowledge to aid recovery after stroke and to find ways to help reverse the cognitive decline seen with aging.
“This is a tremendously exciting time as scientists translate stem cell biology into new therapeutics for brain repair,” says Dennis Steindler, PhD, executive director of the McKnight Brain Institute of the University of Florida. “Since we discovered brain tumor stem cells several years ago, tremendous strides have been made in many different areas of cancer stem cell biology, all the way up to important discoveries in controlling how both abnormal and normal neural stem cells behave so we can better adjust their action in the brain.”
Neural stem cells normally found in the adult brain can make copies of themselves and give rise to new brain cells. Scientists have recently found that some cells in brain tumors closely resemble these neural stem cells with one important difference—some can divide faster, making them “cancer stem cells.” Cancer stem cells may arise from mutations in normal neural stem cells.
The idea of cancer stem cells is a new way of understanding cancer, says Harley Kornblum, MD, PhD, of the departments of psychiatry, pharmacology, and pediatrics and director of the Neural Stem Cell Research Center at the University of California, Los Angeles. The common view of cancer is that most cells within a tumor can make a cancer spread, and that all these cells must be eliminated to fully rid a cancer. In contrast, the cancer stem cell theory suggests that only a few cells within a tumor cause it to grow and spread, suggesting that targeting these cells may be a more effective way of treating cancer.
“Commonly used treatments do not attack cancer stem cells, but kill only their offspring, so they do not eradicate the ‘heart’ of the cancer,” says Kornblum, who chairs a symposium on “Stem Cells and Brain Tumors” at Neuroscience 2005.
In one important finding, scientists have found that the molecular pathways used by brain tumor stem cells to make copies of themselves are similar to those used by normal neural stem cells.
“We can potentially use the similarity between neural stem cells and cancer stem cells to develop new avenues for treating brain tumors,” Kornblum says.
In other work, scientists have found a marker on neural stem cells that could be a target for agents to counter the ill effects of aging, including cognitive decline.
As we age, we produce fewer neurons, making us susceptible to degenerative diseases, loss of memory, and a reduced ability to think logically and clearly. Recent reports have shown that the aging brain’s reduced production of new neurons is tied to lower numbers of neural stem cells. Other studies have shown that giving elderly patients growth hormone can reduce some of the usual signs of aging including deteriorating muscles and cognitive decline.
These findings led Brent Reynolds, PhD, and his colleagues at the Queensland Brain Institute Stem Cell Research Group at the University of Queensland in Brisbane, Australia, to explore the possibility that growth hormone exerts its beneficial effects on aging by binding to receptors on neural stem cells.
Previous work showed that cells in the adult subventricular zone (SVZ)—a brain region rich in neural stem cells—have growth hormone binding sites, but it was not known which cells in the SVZ harbored the growth hormone receptors. Reynolds and his colleagues sorted the cells with growth hormone receptor from other SVZ cells and showed that growth hormone receptors were indeed present on neural stem cells.
They then studied growth hormone’s effects on neural stem cells by exposing them to growth hormone in culture and by culturing cells from mice lacking growth hormone receptors.
When growth hormone was added to stem cell cultures, the number of neural stem cells increased. Mice without growth hormone receptors had fewer neural stem cells.
“These results suggest that reduced growth hormone levels in aging may lead to fewer stem cells producing new neurons, leading to age-related cognitive decline,” says Reynolds. “Our next step is to stimulate growth hormone receptors in aged animals to try to increase stem cell numbers and restore youthful levels of neurogenesis and thus reverse or delay age-related cognitive decline.”
Scientists from Sweden have identified a compound that can activate neural stem cells to restore the neurons lost in a rat model of Parkinson’s disease (PD). The finding represents a potentially new approach for treating this devastating disorder, which afflicts 1.5 million people in the United States.
Patients with PD lose dopamine-containing neurons primarily in a brain region called the substantia nigra, leading to tremor, muscle stiffness, and slowness of movement.
The investigators, led by Olof Zachrisson, PhD, at Neuronova AB in Stockholm, Sweden, modeled PD in animals by chemically injuring dopamine-secreting neurons on one side of the brain in the same area where neurons are lost in PD patients. This caused the rats to move in an asymmetric way, as a sign of dopamine depletion similar to that seen in patients with PD.
Five weeks later, some of the rats were given the compound sNN0031 via a minipump for two weeks, and others received placebo. The minipump also delivered bromodeoxyuridine, a marker for newly formed cells.
The movements of animals given sNN0031 improved after two weeks, suggesting that the dopamine imbalance in their brains had started to improve. Their movements were almost completely normal after five weeks and remained so for the full 10 weeks of follow-up.
The investigators demonstrated that the improvements coincided with the formation of new brain cells including neurons: They found the marker bromodeoxyuridine, indicating new cells had been formed during the minipump delivery, and they found normalized levels of dopamine nerve endings in the rats after their death.
“The ability of sNN0031 to restore neurons in PD is important because the common approach of trying to protect neurons from dying has been unsuccessful in clinical trials,” says Zachrisson. “This compound represents a fundamentally new approach to treating PD.”
Another approach to reap the benefits of new brain cell formation is to transplant human neural stem cells directly into the brain.
In new work, Nobuko Uchida, PhD, of StemCells Inc., in Palo Alto, CA, and her colleagues transplanted human neural stem cells into mice that could not make myelin, the protective coating that wraps around axons and speeds the transmission of nerve impulses. The mice had a mutation in myelin sheath formation, causing them to shake violently during movement.
The transplanted stem cells developed into fully functioning oligodendrocytes, the type of nerve cell that makes myelin. The work is the first to characterize the stages of development that human neural stem cells undergo after being transplanted, Uchida says. Knowing these stages may help in the successful use of neural stem cells to aid in the treatment of diseases and disorders of white matter such as cerebral palsy, multiple sclerosis, spinal cord injuries, and several genetic diseases associated with myelin deficiency.
“This work is also novel because the stem cells used were derived from a large batch of frozen human neural stem cells, as opposed to freshly isolated oligodendrocyte progenitor cells from tissue,” says Uchida. “So the approach would be suitable for treating multiple patients, an essential advantage for widespread clinical use.”
A cocktail of growth factors can stimulate the production of neural stem cells and aid recovery after stroke in rats, Trudi Stickland, and her colleagues at the University of Calgary in Canada report.
“The ability to mobilize existing neural stem cells to assist in stroke recovery represents an exciting potential avenue for treatment,” Stickland says.
Stickland’s findings grew out of earlier work in her laboratory showing that infusing epidermal growth factor (EGF) into the rat brain resulted in an increase in adult forebrain neural stem cells. When EGF was followed by the growth factor erythropoietin (EPO), the new cells more readily differentiated into neurons than they normally would.
In the new study, rats were trained to reach through a narrow slot to grasp a food pellet, a way to measure functioning of the motor cortex, the region of the brain typically affected by stroke.
Then the rats received a lesion to their motor cortex, using one of two accepted methods for inducing stroke in rats. Both methods affect the functioning of the rats’ forepaws opposite the side of the brain lesioned.
Beginning three days after the lesions, some rats received EGF for seven days followed by EPO for seven days. Control rats received serum albumin.
Rats that received the growth factor cocktail recovered 75 percent of their forepaw functioning compared with controls, who only recovered 17 percent of their functioning.
What causes the forepaw functioning to improve is still not known, Stickland says. “We know that growth factor treatment leads to the growth of new tissue at the lesion site,” she says. “Future studies will seek to uncover whether this new tissue actually reestablishes lost connections or secretes agents that help the surrounding tissue take on new functions.”
