Multiple sclerosis (MS) is most frequently characterised by a relapsing remitting clinical course in which the affected individual develops one or more neurologic deficits which then resolve partially or completely over subsequent days or weeks. These relapses reflect the development of new lesions within the central nervous system (CNS) as visualised by magnetic resonance imaging (MRI). Such lesions, when examined in the laboratory, feature inflammation, myelin destruction, and a variable extent of injury to the underlying axons.
A further concern is that the persistent absence of myelin contributes to the ongoing loss of axons, the apparent basis for the progressive nature of MS in some cases. Persistent loss of myelin can make axons more vulnerable to repeated injury, induce axons to make compensatory changes in their properties (changes ion channel expression) that can result in further delayed insults to the axon and remove the supportive factors required for long-term axonal survival. This issue of MS in focus concentrates on whether stem cell treatment can repair or replace the damaged myelin as a means to restore effective electrical conduction in the CNS and thus result in the recovery of neurologic function.
What are stem cells and what do they do?
Stem cells, and certain types of “progenitor cells”, are classically defined as cells that are selfrenewing (can divide and produce more of themselves) and that can differentiate into a mature cell type with the properties of cells that comprise specific organs. The initial stem cells are those which are the product of the first cell divisions following ovum (egg) fertilisation, known as conception. Such cells have the capacity to differentiate into all the various cell types that comprise the body and are referred to as pluripotent stem cells.
During this process of differentiation, there are cells that still retain a capacity to self-renew but have more restrictive potential regarding differentiation; for example, they are more limited as to what cell types they may produce. The articles in this issue will discuss specific stem cell types. Stem cells that reside within the CNS and that can develop into neural cells are referred to as neural stem or progenitor cells. Some can produce all types of neural cells whereas others appear to be more restricted, including those that can only develop into myelin-forming cells (myelin or oligodendrocyte progenitor cells). Every cell in the body is created with specialised proteins, or receptors, and each cell has a specific combination of receptors. Scientists have used this biological uniqueness of stem cell receptors to tag or mark cells. As discussed in individual articles, these cell types can be identified by their expression of specific cell markers that correlate with their state of maturation and/or expression of gene products that regulate their responses to environmental signals.
Why might stem cells have a role in MS?
Histologic and MRI studies both indicate that remyelination can occur in MS lesions. The extent of such remyelination varies between lesions. There are a number of models of MS in animals in which the experimental demyelination induced by toxins or virus/immune mechanisms is subsequently almost completely repaired. In these models the remyelination is carried out not by the cells (oligodendrocytes) which initially made the myelin but by immature progenitor cells or stem cells.
These cells move to the site of injury (where demyelination has occurred) and develop into myelin-producing cells. Such cells can be identified in various sites in the adult human CNS including in regions surrounding MS lesions.
Stem cells have the capacity to differentiate into all the various cell types that comprise the body.
What do we need to know about stem cells in MS?
A central challenge for MS research is to define what limits the capacity of progenitor cells to repair the lesions in MS. Considerations include:
• numbers of progenitor cells available
• whether the progenitors that are present are in some way defective
• whether there are deficiencies in signals needed to recruit such cells to the lesions and to stimulate them to mature into myelin-forming cells or, conversely, whether actual signals in the CNS environment inhibit such responses from occurring. Is repair limited by the extent of damage to the underlying axons?
A theme of this edition of MS in focus is to outline the approaches that are being used to understand the make-up of progenitor or stem cells.
Translating stem cell biology into MS remyelination therapy
The current issue will present specific perspectives on the biology and potential clinical therapeutic use of an array of stem cell populations. Stem cell populations that are not normally present in the CNS must be delivered to the CNS (exogenous repair) and then induce them to directly participate in the actual repair process. For stem cells residing within the CNS the potential exists to promote endogenous (within the body) repair, for example the use of biologic or pharmaceutical agents that can cross the blood brain barrier to amplify cell numbers and promote their development into useful myelin-producing cells.
The future for stem cell technology and MS This issue of MS in focus will discuss how advances in understanding stem cell biology could lead us towards potentially using stem cell therapy for MS, specifically through combining insights into the pathological features of MS lesions, therapies to control the immunemediated injury phase of MS, and MRI to dynamically monitor the MS disease process. The stronger the foundation of knowledge, the more likely it is that this “new biology” will translate into rational, safe and effective therapy.
The challenge of repairing the CNS in MS.
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