24 October, 2003
Dr Robin Franklin
University of Cambridge
Over the last few years there has been considerable media attention on the potential benefits of stem cells for treating a wide range of brain diseases including multiple sclerosis (MS). In this presentation I will talk about how these cells are able to repair damaged myelin sheaths and how they might be used therapeutically.
What are stem cells?
The body is made up of a vast array of specialised cells that perform specific functions. One such cell is the oligodendrocyte, whose purpose is to form myelin sheaths and which is damaged in MS. Specialised cells are derived from a population of cells that are less specialised by a process called differentiation. Specialised cells are therefore called differentiated cells while the cell from which they derive are called undifferentiated cells. It is these undifferentiated cells that are often generically referred to as stem cells. Stem cells are cells that can divide many times so that very large numbers of cells can be obtained. They can also give rise to one or more differentiated cell types, the range of which is called their potential. Thus, stem cells that can give rise to the three main differentiated cell types of the brain, neurons, astrocytes and oligodendrocytes, are referred to as multi-potential. The term stem cell has both a strict scientific meaning and a more colloquial use, which includes cells that are not true stem cells in the strict sense and are more accurately called progenitors. True stem cells divide infrequently and give rise to two daughter cells that are different – one resembling the parent stem cell and the other having the properties of a progenitor cell. Progenitor cells divide very easily and can do so many times (although ultimately less than a true stem cell). They also have different degrees of potential. Within the adult brain there are both stem cells and progenitors. The identity of cells that truly have stem cell properties has proved elusive but they are likely to occur within a particular region of the brain called the sub-ventricular zone (SVZ). Progenitors, on the other hand, occur widely throughout the brain and spinal cord. There are different types of progenitors, although the extent of this diversity is unclear at present. The interest in stem cells and progenitors in MS lies in their role in replacing lost oligodendrocytes – either as part of a natural healing process called remyelination or because they can be used in transplantation based therapies.
What sort of stem cells are relevant to MS?
The stem cells most relevant to MS are in fact progenitor cells called oligodendrocyte progenitors. These cells occur widely throughout the adult brain and spinal cord (the central nervous system or CNS), and resemble the oligodendrocyte progenitors that occur during the development of the CNS. They are mobile cells and divide in response to factors called mitogens. Many of the factors that induce division of oligodendrocyte progenitors are called growth factors. The oligodendrocyte progenitor cell is multi-potential – normally it gives rise to oligodendrocytes but in certain conditions can become a nerve cell (neuron) or another type of brain cell called an astrocyte. An issue that is not clear at present is whether there is a single population of oligodendrocyte progenitors or whether there are several different populations that are more or less similar to other CNS progenitors called neural progenitors.
What role do stem cells play in normal repair processes?
Oligodendrocyte progenitors (which are a type of stem cell in the colloquial use of the word) are the cells that respond to loss of oligodendrocyte and myelin (demyelination) in MS and are responsible for generating the new oligodendrocytes that then replace the lost myelin sheaths (remyelination). These cells are thus at the heart of the repair process that is so beneficial in MS but that unfortunately does not occur very consistently. Considerable attention has been focused on understanding how these cells are involved in remyelination since this will allow us to understand why remyelination fails and therefore what needs to be corrected therapeutically. Research so far has identified a number of key factors (many of which are growth factors) that determine the behaviour of oligodendrocytes in remyelination. However, it has also emerged that this process involves a bewildering complexity of factors. The recent development of powerful research techniques to identify many thousands of genes (genomics) and proteins (proteomics) will be immensely helpful in disentangling and understanding this complexity. On the basis of these studies new therapies will emerge by which the natural healing process of remyelination can be enhanced in MS patients.
What role might stem cell transplantation play in MS therapy?
An approach to repairing myelin sheaths that has attracted considerable attention over a number of years is cell transplantation, in which cells that are capable of making new myelin sheaths are transplanted into areas of damage. While one imagines that the most appropriate cell to transplant would be an oligodendrocyte since this is the cell that is lost, experimental studies have shown this to be very ineffective. This is for several reasons including the apparent inability of oligodendrocytes to make myelin sheaths on more than one occasion, and their inability to divide. There is now agreement that the most appropriate cell to transplant is an oligodendrocyte progenitor cell. In experimental models this approach has been highly successful. However, repeating these experiments with human cells has proven more difficult. It is less easy to expand the numbers of human oligodendrocyte progenitors making it difficult to obtain the large numbers of cells required for transplantation. Attempts to resolve this by growing less differentiated stem and progenitors cells and then inducing them to become oligodendrocytes progenitors suitable for transplantation are in progress but there are no published results indicating that this problem has been resolved.
The prospects of transplant-based therapy has taken a considerable step forward recently with the demonstration that neural progenitors cells (multipotent cells that can form all types of brain cells and are more immature than oligodendrocyte progenitors) can achieve impressive results when transplanted into animal models of MS. The basis of the recovery that occurs is not certain at present. While the transplanted cells appear able to differentiate into oligodendrocytes it is possible that their major benefit is the effect they have on the natural repair process. A particularly exciting aspect of this study was that the cells were injected into the blood stream rather than injected directly into the brain. From a clinical perspective the advantages of this approach are selfevident.
An intriguing area of current research is whether stem or progenitor cells from other tissue that are more easily accessible such as bone marrow or skin might also provide a source of oligodendrocytes. If this can be achieved then obtaining cells from a patient and delivering them to the CNS by way of an injection into the blood would make transplantationbased therapy a relatively straightforward clinical procedure.
Where, when and how? Resolving dilemmas in stem cell-based therapy
While scientists continue to extend their understanding of myelin repair
and develop exciting new potential therapeutic approaches in the laboratory,
clinical researchers are also developing ways of identifying which patients
with which type and stage of disease would benefit most from a particular
type of therapy. There is no doubt that research programmes over the next
few years concentrating on the role of stem cells and progenitors in myelin
repair will continue with the impressive progress that has already been
made. There can also be little doubt that these areas of research will
ultimately lead to the development of new treatments for MS.
Copyright © 2003, Multiple Sclerosis Society