Central Nervous System Remyelination in MS
By Christian C. Poncet, PhD
Today there are three potential therapeutic strategies to treat MS, although its genesis eludes researchers. The first strategy is to reduce the relapse rate and inflammation. Currently all available pharmacologic treatments belong to this category, which employs anti-inflammatory and immunomodulator therapies. The second strategy is to protect the brain from degeneration. The third strategy is to repair the damaged myelin by building new insulating sheaths. This strategy aims at restoring a long-lasting functional myelin while conserving the neuronal integrity.
Spontaneous remyelination occurs in MS patients
The myelin is the protecting sheath enveloping the axon, an electrical-wire extension of the brain cells called neurons. Oligodendrocytes are highly specialized cell types that are present only in the central nervous system (CNS), which consists of the brain and spinal cord. These cells form this protecting myelin sheath by an extension of its cell membrane. This membrane spirals around the axon multiple times, forming a tight protective layer. The myelin is necessary for proper neuron communication. It also protects the axon, similar to how the rubber insulation surrounds and protects an electrical wire. After repetitive or prolonged destruction of the myelin, the "naked" axon degenerates, leading to permanent MS symptoms.
During an exacerbation, the myelin is damaged in multiple points. For patients with the relapsing-remitting form of MS (RRMS), this damage may be transient because the oligodendrocytes are able to spontaneously rebuild new myelin. This new myelin is imperfect in the sense that the protection is less efficient and less stable. Symptoms disappear once the inflammation is reduced and the myelin repair occurs. However, for the progressing forms of MS, myelin and axons are repetitively attacked, leaving them severely damaged. The repair is ineffective and symptoms are more obvious.
Several fundamental research projects are studying the remyelination process. Numerous pieces of evidence pave the road to potential therapeutic research projects. Among them, researchers found that the remyelination process requires new immature (or undifferentiated) oligodendrocytes rather than mature oligodendrocytes already in place. This observation is encouraging in the pursuit of stem cell therapy research. There are two strategies to repair the damaged myelin: the first one is the transplantation of cells with regeneration capacities (a cell-based therapy); the second one is to enhance or to reactivate the repair abilities of cells already present in the CNS.
Cell-based therapy
Based on more than two decades of research in cell biology, scientists found that cells with a potential of myelination (or "myelinogenic" cells), constitute an attractive hope for MS. They are mainly Oligodendrocyte Precursor Cells (OPC), as well as adult and embryonic stem cells1. Additionally, stem cells from adult bone marrow are currently being considered and tested for their remyelination potential2. The important characteristic of stem cells is their ability to become specific cells for many different tasks. Several studies using experimental animals gave encouraging results by showing the ability of embryonic stem cells to re-ensheath demyelinated axons1.
One benefit of using stem cells is that these cells could be modified, in the laboratory, in such a way that they would be more efficient in becoming myelin-making cells3. Indeed, the brain produces certain signals to transform stem cells into oligodendrocytes. The laboratory-processed stem cells would be modified in such a way that they would not need signals to become oligodendrocytes (myelin-making cells), because they would already be programmed to become oligodendrocytes. This would be a great benefit since these signals (that transform stem cells into oligodendrocytes) are suspected as being absent in patients with MS.
However, if the idea of using a cell-based strategy is appealing, numerous obstacles block the road to the therapeutic application. Among them, the transplantation and directing of these cells to the right place seems very challenging. The injection or transplanting of these cells into the brain would require delicate neurosurgery.
The second obstacle is in the nature of MS itself. Exacerbations occur in a multitude of places within the CNS. These numerous lesions might each require separate cell transplantations, which would be an impractical process. A way to circumvent this technical issue would be to design stem cells in such a way that once injected in the blood stream, they would be able to relocate themselves to the damaged sites. Once in the brain or the spinal cord, the transplanted stem cells could change into oligodendrocytes, ready to remyelinate the "naked" axons. This idea involves numerous cellular mechanisms (such as migration, blood-brain barrier crossing, finding the exact location within the brain, etc.) and raises abundant fundamental scientific questions.
The cell-based method brings specially designed cells to enhance the remyelination process. Experimental results are encouraging, but they are too preliminary to conceive large-scale clinical testing in the near future. In addition, numerous technical issues need to be resolved first.
Promoting the body to regenerate myelin
As mentioned previously, the CNS is naturally able to regenerate some of the missing myelin. However, this newly established myelin is weaker and less efficient than the original one. As an alternative to the cell-based strategy, a pharmacologic approach would promote remyelination within the brain.
In MS, the problem with remyelination is not the absence of specific cells, but rather their poor development. Indeed, oligodendrocytes and their precursors (brain stem cells) are present in the brain and spinal cord at any age from birth throughout the adult life. However, it is believed that the absence of remyelination is coming from missing signals. Producing these "positive" signals would allow stem cells and oligodendrocyte precursors to migrate into the lesion sites in the brain and to develop into fully mature oligodendrocytes. An alternative, but not exclusive view, is that inhibitory ("negative") signals could prevent OPC from maturation in patients with MS.
Meeting the challenge
While scientists consider positive and negative signals to be involved in the process, the molecular mechanisms behind the remyelination failure are largely unknown. As scientists say, "We will not know what to fix until we know what is missing." In other words, a clear fundamental understanding of the events within the cells, occurring during demyelination and remyelination, are paramount to the discovery of effective therapeutic compounds.
There are good reasons to believe that the challenge will be met in the future. Already, a gene called Olig1 was found to be involved in the process4. In the absence of this gene, mice are unable to repair damaged myelin. This gene seems to be essential to myelin repair. It is quite unlikely that this gene would be the only one involved in the remyelination failure. However, the discovery of this gene is great motivation for researchers and the MS community.
Enhancement of remyelination is an important therapeutic objective. It is a realistic and exciting prospect. Already, stem cell research and the promotion of research projects with remyelination from within the brain offer very encouraging results. There are good reasons to believe that at least one of these two strategies will ultimately succeed in remyelinating the damaged axons within the brain. Nevertheless, many critical uncertainties remain to be addressed in the forthcoming years before seeing any therapeutic agents on the market.
References
1. Pluchino S, Martino G. The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders. J Neurol Sci. Jun 15, 2005; 233(1-2):117-119.
2. Crain BJ, Tran SD, Mezey E. Transplanted human bone marrow cells generate new brain cells. J Neurol Sci. Jun 15, 2005; 233(1-2):121-123.
3. Dubois-Dalcq M, Ffrench-Constant C, Franklin RJ. Enhancing central nervous system remyelination in multiple sclerosis. Neuron. Oct 6, 2005; 48(1):9-12.
4. Arnett H. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science. Dec 2004; 306:2111-2115.
Correspondence: christianponcet@hotmail.com
