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Stem Cells Short-Circuit Nerve Diseases


New insulation is added to the brain’s neuronal circuits on a daily basis, and that this has the ability to change the way the circuits function.

By Kaylene Young

Brain stem cells can be stimulated to produce cells that insulate neurons, offering hope for patients with multiple sclerosis and Alzheimer’s disease.

The neurons that make up the brain’s electrical wiring need to be insulated – just like electrical cables – to prevent leakage or short-circuits. Working with colleagues around the world, we have found that new insulation is added to the brain’s neuronal circuits on a daily basis, and that this has the ability to change the way the circuits function.

Lack of insulation can lead to significant diseases such as multiple sclerosis and Alzheimer’s. We are now investigating ways of treating these conditions by boosting neuronal insulation – and it may be as simple as undertaking daily physical and mental exercise.

Neurons have been the major focus of neuroscience research for the past century. We now know a lot about how nerve cells function, how brain circuits are built and maintained, and how electrical information is transferred from one nerve to the next. But nerve cells do not exist in the brain in isolation. Over the past two decades our growing understanding of nervous system function and disease pathology has really turned the spotlight onto the brain’s support cells.

The oligodendrocyte, or “insulating cell”, is one such cell type. To transfer information quickly from one region of the nervous system to another, our nerves are insulated like electrical cables. Our oligodendrocytes produce a fatty insulating substance known as myelin, which they wrap around regions of nearby nerve cells.

Because nerve cells span long distances, carrying information from one side of the brain to the other, each nerve relies on many oligodendrocytes to provide continuous insulation along its length. If nerve cells lose their insulation they can short-circuit, and information is no longer transferred to where it is needed.

Multiple sclerosis is a well-known disease that causes severe loss of nerve insulation. Early in the disease, oligodendrocytes die and can no longer maintain their insulation. The loss of insulation disrupts the transfer of information along nerve cells, and patients experience symptoms such as blurry vision and uncoordinated movement. In the longer term, insulation loss also makes the nerve cells extremely vulnerable to damage and death.

In recent years we have also begun to understand just how important insulation is for learning, thinking and remembering information. Alzheimer’s disease is the most common cause of dementia, and is characterised by memory problems that become increasingly severe over time. Patients with Alzheimer’s disease lose a large amount of insulation from their brain. But what has been most surprising is the finding that the severity of each patient’s memory problems is proportional to the amount of insulation lost.

Our research team has been working to find ways to prevent insulation loss and promote its repair in the brain. To achieve this we tested the ability of brain stem cells to make new oligodendrocytes.

Brain stem cells are an immature population of cells in the brain that have the ability to make any brain cell type. We cultured stem cells retrieved from brain tissue samples to generate a suspension of individual cells. When given the right combination of growth factors, the stem cells start to divide and make many more new cells. We hoped to be able to direct them towards rebuilding lost brain insulation, and found that after 10–14 days the cultured brain stem cells made many new oligodendrocytes. These new cells could be very useful for transplantation therapies.

Since our primary goal was to treat people by activating stem cells already present in their brain, we had to develop a way to label stem cells that were still in the brain and trace the new cells they generated. To do this we created a mouse strain in which all adult brain stem cells were fluorescently tagged, with the label remaining in every cell they produced. Using these mice we discovered that stem cells inside the adult brain made many new nerve cells but only a few new oligo­dendrocytes.

At a similar time researchers in the United Kingdom were investigating the effect that learning had on brain structure, and using magnetic resonance imaging made the discovery that new insulation accumulated in the brain in response to learning a new task. They found that young adults and retirees who learned to juggle had more insulation added to the brain region involved in hand–eye coordination. This finding suggested that the brain must have an alternative source of new oligodendrocytes.

About 5 years ago our scientists at the Menzies Research Institute found the cells responsible for learning-driven insulation. It was another population of immature brain cells known as oligodendrocyte progenitor cells (OPC). These are star-shaped cells that continually divide and generate new brain cells, even in the elderly. These cells were much more difficult to grow in culture than adult brain stem cells, but once we determined the right combination of nutrients and growth factors they required we were able to keep them alive and grow them. These cells divided, expanding in number for a few weeks before maturing into oligodendrocytes that successfully provided insulation. In the absence of nerve cells, the oligodendrocytes spread their insulation across the bottom of the culture dish, but if nerve cells were added the new oligodendrocytes wrapped and insulated the nerve cells.

Our researchers were also able to use molecular biology to non-invasively label and trace OPCs in the brains of live mice, and discovered that OPCs made new oligodendrocytes daily. As part of a collaborative research project that spanned the United Kingdom, Australia and Japan, we determined that newborn oligodendrocytes are not passive bystanders to brain function – new insulation has the ability to change the way that entire brain circuits function. Initially, nerve cell insulation speeds up the transfer of information.

We think that brain circuits only become insulated once they are needed and become electrically active. For some circuits this can happen for the first time when we perform new activities and learn new things. The insulation would then allow the quick recall of the information that was learned.

But the new insulation generated in adulthood may also work to more subtly speed up or slow down information transfer in the central nervous system on a circuit-by-circuit basis. The precise timing of the information being transferred from one region of the nervous system to another is necessary for us to interpret and interact with the environment.

For example, our ability to track the movement of a ball, and activate an appropriate muscle response to successfully catch the ball, relies heavily on the timing of our perception of the image and the timing of our reaction. If either is even a little out we would never succeed in catching the ball – it would have passed by before we reacted.

Our researchers are now investigating ways to hijack the natural ability of OPCs to make new oligodendrocytes. In experimental models of multiple sclerosis and stroke we have found that OPCs can generate many more new oligodendrocytes. We aim to understand how this process works in order to stimulate OPCs to produce more oligodendrocytes and insulation so we can repair the insulation damage that is seen in the brains of Alzheimer’s disease patients, and more generally in the nervous system of patients with multiple sclerosis.

Stimulating OPCs in the brain is an appealing possibility since they have an additional benefit. Unlike stem cells, which are restricted to two discrete regions of the adult brain, OPCs are found throughout all regions of the brain. This means that they are already where they need to be.

If we succeed in repairing damaged brain insulation, and can rewrap any “at risk” nerve cells, we expect to protect nerve cells and prevent them from dying. This will prevent the rapid deterioration seen in people suffering from these diseases.

Research has shown that combining a mentally stimulating environment with physical exercise can enhance stem cell activity, boosting nerve cell production and survival. This approach would also help to repair brain insulation.

Memory training reduces and slows down the insulation loss experienced by patients with Alzheimer’s disease, and at the same time slows down their memory loss. It might be that participating in specially designed memory tasks, in combination with mental and physical exercise, will become a standard part of treatment for people with Alzheimer’s disease. Trials of similar treatments are already proving beneficial for stroke patients.

We hope to combine this type of behavioural therapy with a drug treatment that would boost the production of new oligodendrocytes, improve their ability to insulate and protect the nerve cells. However, this is still some years away from being a medical reality.

Kaylene Young is a Senior Research Fellow at the Menzies Research Institute Tasmania.