Stem Cells and Huntington Disease

By Samuel Weiss, Ph.D., University of Calgary

Member, Research Council, Huntington Society of Canada

from Horizon #101, Summer 2001

A great deal of interest has been generated recently around the development and uses of stem cells for cell replacement therapies. In particular, the possible use of stem cells to treat neurodegenerative disease has made headlines. Here, I provide a short perspective on what stem cells are, on their potential, and finally on what we might expect in the future which impacts on new treatments for Huntington disease.

What are stem cells?

Stem cells are the primitive cells that are responsible for creating the various tissues of the body. There are skin stem cells, blood stem cells and, most recently discovered, brain and spinal cord stem cells.

After the body is created, stem cells go into “hibernation”, only emerging when there is a call (need) for new cells. For example, when you tear and lose skin cells, skin stem cells are activated to repair the damage. It was this property that suggested to most people that such stem cells could not exist in the brains/spinal cords of mammals (humans are in that family), because brain and spinal cord does not normally repair itself. In the early 90s, our laboratory and several others discovered that the adult brain (we work on mice, a mammal that has a brain that is similar to humans) does indeed contain these stem cells – and they are very similar to the stem cells we found in the brains of fetal mice.

When taken out of the brain of an embryonic or adult mouse and grown in incubators, these stem cells respond to protein growth factors (one is called epidermal growth factor) and they can make many brain cells. One of the brain cell types that they make is a neuron that produces gamma-aminobutyric acid. It is this type of neuron that is principally lost in HD. Thus, these discoveries raised two interesting possibilities: (1) if you can grow lots of these cells in incubators, they might represent a wonderful source of neurons for transplantation into the striatum, part of the inner brain seriously affected by HD, or (2) if you can stimulate the adult stem cells “right where they live” you may be able to get them to make new neurons and “self-repair” the brain.

What is the potential for using brain stem cells – what have we learned over the past 10 years?

The past 10 years have seen remarkable advancements in our understanding of the biology and clinical potential of brain stem cells. Hundreds of laboratories around the word have moved into this area of study and the results are breathtaking.

Studies report the identification of the human counterparts to mouse brain cells. Once again, the brain stem cell is present in the developing and adult human brain. Other studies have shown that the brain stem cells in adult mice and monkeys are usually making new neurons that participate in olfaction (the ability to smell) and memory. So, it seems as though the stem cells in mammals are regenerating two principal functions – the ability to smell odours and to remember things – which may tell us that these are the most important functions for our species.

But how about movement and motor control? We don’t have the answers yet, but if the stem cells are making new neurons for controlling movement, these are being made in very small numbers. A recent study, however, found that when a mouse was made to have a small stroke, the brain stem cells sent new neurons to repair the damage. This very exciting result suggests that stem cells may respond to an injury with an attempt to repair. It further suggests that if we can learn how to “hyperstimulate” the stem cells, they may be able to repair a larger injury or degeneration that results from a chronic disease, such as HD.

Our laboratory, and many others, have discovered that certain growth factors can be instrumental in the “hyperstimulation” approach and together we are applying this knowledge to animal models of neurodegeneration, including models of HD. Our very early results suggest that you can stimulate these adult stem cells and they will send new neurons to the striatum.

What are the future possibilities for brain stem cells and Huntington diseaseWhat are the future possibilities for brain stem cells and Huntington diseaseWhat are the future possibilities for brain stem cells and Huntington disease?

The truth and reality is that we must perform a great deal of careful research to ensure that the promise of stem cells transforms into safe, ethical and effective therapy. How can this be accomplished?

First, we need to demonstrate in animal models that either transplantation of stem cells, or direct stimulation of the resident stem cells, can provide a long-lasting improvement in the motor and cognitive deficits that are characteristic of HD.

Second, if we are to consider transplantation, we must ask where such cells will come from. Recently, it has been shown that embryonic stem cells (the ones that are present in newly-fertilized embryos) can be grown in incubators and turned into brain stem cells. This approach, if warranted by the demonstration that transplantation is an effective therapy, would alleviate the need to seek donor tissue continuously because these embryonic stem cells can be kept in incubators and grown repeatedly for years. It has been suggested that spare fertilized embryos (no longer to be used) from IVF clinics represent a potential source. However, if warranted, such approaches must be in concert with the widest possible ethical and moral consultations. Of course, this applies to their potential use not just for HD but for many other diseases of the brain and other parts of the body.

Third, we need to think “outside the box.” What does this mean? Stem cells are not the magic cure. They are likely to be part of what we will need to combat the devastation of neurodegeneration as seen in HD. We need to improve our early diagnosis, reduce the severity of cell loss, combat inflammation, provide new neurons (this is where the stem cells come in) and finally utilize progressive rehabilitation to allow regeneration to be complete. A tall order, but very achievable with the advances being made in science and the bridging between the studies of brain development, imaging, repair and rehabilitation.

We should be optimistic!We should be optimistic!We should be optimistic!

These are very exciting times for medical research. We have the most elaborate and sophisticated tools at our disposal. To fulfill the dream of cures, we need: (1) the dynamic young minds that graduate students and postdoctoral fellows bring to the study of science; (2) the funds necessary to carry out the research (such as the support our laboratory receives from the Huntington Society of Canada); and (3) the spoken and spiritual support of the public, whose goals and aspirations we are privileged to serve. Along with the support of our provincial and federal governments, we can all work together to ensure the greatest quality of life for all Canadians and in particular for those who suffer from HD and other degenerative diseases.