Stem Cells and Huntington’s Disease

Professor Richard Faull and Dr Bronwen Connor
Auckland University School of Medicine

 The Promise of Stem Cell Research

A particularly exciting and novel development in the treatment of neurodegenerative diseases is the suggestion from both animal and human studies that cell transplantation offers the potential of effective future treatment for neurodegenerative disorders such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease.  In recent years, the transplantation of cells into the diseased human brain has emerged from the realm of the theoretical to that of the practical.  Grafts of embryonic cells have been shown to partially restore some neurochemical deficits and to ameliorate behavioural and locomotor impairment in animal models of these diseases.  In humans, some patients with Parkinson’s disease have shown remarkable improvements following human fetal neural transplants.  However, the use of human fetal embryonic tissue for cell transplantation therapy in neurodegenerative diseases is associated with major problems.  The scarcity of this material is compounded by practical issues such as the age of the donor, viability, contamination and heterogeneity of tissue as well as overwhelming ethical and moral concerns.

Worldwide attention is presently focused on the potential use of “stem cells” as an alternative source of tissue for cell transplantation and brain repair.  The announcement that stem cells can be obtained from aborted human fetuses or from spare embryos from in vitro fertilization procedures has been meet with both enthusiasm and opposition.  Less controversial, and probably more notable, is the recent demonstration that stem cells can be obtained from adult brain tissue, raising the exciting possibility that these cells can be utilized to generate cells for autologous brain cell transplants.  Furthermore, a recent report showing that human bone marrow stromal cells can differentiate into neurons raises the possibility of obtaining an easily accessible renewable source of material for autologous transplantation.

The Use of Neural Stem Cells in Brain Repair

Over the past year, there has been a growing interest in the use of “neural” stem cells for the treatment of brain diseases.

What Exactly is a Neural Stem Cell? 

The term “neural stem cell” is used loosely to describe cells that can generate brain cells or are derived from the central nervous system, have some capacity for self-renewal, and can give rise to cells other than themselves through asymmetric cell division.  Neural stem cells exist in both the developing and the adult brains of mammals, including human.  Neural stem cells can also be derived from more primitive cells that have the capacity to generate neural stem cells and stem cells of other tissues.  Embryonic (pluripotent) stem cells are obtained from blastocytes (fertilized eggs) and this is currently the stem cell type being proposed for use in a wide variety of commercial and clinical applications.  Most stem cells can be categorized as multipotential and only make cells that have a particular function.

The Role of Neural Stem Cells in the Adult Brain

At the Auckland Medical School, we are interested in the use of adult neural stem cells for the treatment of brain diseases.  The use of adult stem cells in cell transplantation therapy could obviate the need to use stem cells derived from human embryos or human fetal tissue.  At present, there are no legal or ethical concerns regarding research with adult stem cells.  Furthermore, adult stem cells derived directly from the patient would reduce the likelihood that the transplanted cells would be rejected.

Stem cells have been identified and isolated from specific regions of the adult brain: (i) the subventricular zone (SVZ) lining the lateral ventricles and adjacent to the region of the basal ganglia affected in Huntington’s and Parkinson’s disease, and; (ii) the subgranular zone (SGZ) in the hippocampus, the region of the brain which is primarily affected in Alzheimer’s disease and temporal lobe epilepsy.  The stem cells located in these regions have been shown to multiply and form new replacement neurons for adjacent brain structures.  In this regard it is especially exciting that stem cells located in these regions are found immediately adjacent to the basal ganglia and hippocampus that are respectively the areas of primary degeneration in Huntington’s and Parkinson’s disease, and in Alzheimer’s disease and epilepsy.  Indeed, there is increasing evidence that one function of stem cells in the adult brain may be to generate new cells in response to brain injury or disease.  When the brain is injured, it may try to “repair” itself with its own population of stem cells but, for most injuries that come to clinical attention, this repair process is restricted by the number of available stem cells and may even be counter-acted by a growth-inhibitory environment, especially in the adult brain.  In order to investigate whether neurodegenerative conditions (such as Huntington’s disease) do stimulate stem cells in the adult brain to try and repair the area of injury, we are investigating the presence of stem cells in the human brain in Huntington’s disease, Parkinson’s disease, Alzheimer’s disease and epilepsy.  In cases of advanced Huntington’s disease, our most recent and exciting studies have shown an increase in the number of stem cells in the SVZ compared to age-matched normal human brains suggesting that in Huntington’s disease the brain is trying to repair itself and replace the lost brain cells. However, this increase in stem cell proliferation is clearly insufficient to compensate for the progressive cell loss observed in the Huntington’s diseased brain.  However, if this potential for cell replacement by the brain could be stimulated and augmented pharmacologically then compensation may increase to a point where neuronal cell loss is reversed and clinical improvement observed.

Stem cells may need to be genetically and/or pharmacologically engineered to direct them to develop into the type of brain cells that die in Huntington’s disease.  Alternatively, the delivery of factors that act to stimulate neural stem cells to repair the diseased brain may have potential in the treatment of neurodegenerative diseases such as Huntington’s disease.  At present however, we do not know what chemicals and growth factors will promote neural stem cells to grow and multiply to make mature, adult brain cells to replace the cells that die in Huntington’s disease.  We are currently studying stem cells in culture in order to determine what combination of growth factors will induce them to grow, multiply and develop to replace the brain cells that are lost in Huntington’s disease.  There is still much research to do. But the exciting possibility is that the human brain has the potential, just like other organs of the human body, to repair itself.  The era of the stem cell is upon us; we hope that our exciting new findings will ultimately provide a new approach and direction for treating patients with Huntington’s disease and so provide a brighter outlook for their future.

Faull\Stem Cell Article (May 2002)