Multiple sclerosis (MS) is a central nervous system disease in which myelin is damaged by an autoimmune attack. It is not clear which factors are implicated in the development of MS, but a combination of genetic predisposition 12 and environmental factors (such as vitamin D, time of birth or smoking 13–15) which lead to an immune dysregulation, have been described to be behind MS 16. It seems to be clear that activated T cells cross the blood brain barrier (BBB), and react against the myelin. The BBB is an anatomical barrier that separates the blood from the glial cells and that carries out several important functions such as the regulation and protection of CNS cells. However, as it is mentioned in 17, the BBB is more a concept rather than a proper barrier, with dynamic properties that allows for instance immunological surveillance. Lymphocytes have been described to be able to cross the BBB under normal conditions by several routes 18. However, an increased migration of autoreactive lymphocytes across the BBB together with an aberrant immune response are thought to be the causes of multiple sclerosis outbreak and therefore myelin damage 19. This damage causes demyelinating lesions, also known as plaques. While they are distributed heterogeneously along the CNS; they appear mainly in the white matter, which are the areas with more myelin content. Demyelinating lesions are responsible, at the very beginning, for producing an inadequate nerve impulse transmission that can concur with the first clinical symptoms. Although clinical manifestations might vary from one patient to another, we could say that these are related with sensitive and motor alterations, such as paresthesia, hypoesthesia or optic neuritis 20. In addition to this, naked axons are exposed to
potential harmful factors and are deprived from trophic support, which can lead to axonal death.
Fortunately, at the first stages of the disease, the body is able to regenerate the myelin in a complex process called remyelination. It is of extreme importance because myelin regeneration will restore both metabolic support to the axon, avoiding its degeneration, and nodes of Ranvier that are required for a proper nerve conduction and function 21. This is, remyelination restores nerve impulses conduction 22.
Demyelination induces the secretion of signalling molecules and cytokines that activate astrocytes which in turn secrete a range of factors that activate progenitor cells and induce their proliferation 21,23. This activation is related to an increase in transcription factors that finally induces the regenerative process 24,25. These progenitor cells are adult oligodendrocyte precursor cells (OPC) which are abundant throughout the CNS (being a 6% of the total number of the cells in this region of the body 26) and that have been described as the major source of new oligodendrocytes 27. In addition, OPC have been described as self-renewing multipotent cells, being proposed as adult CNS stem cells 28, highlighting the role that they can play after a demyelinating insult.
Activated OPC migrate and colonize areas of demyelination in order to differentiate and generate the number of required oligodendrocytes to regenerate myelin 21 (Figure 4). Microglia, monocyte-derived macrophages, astrocytes and OPC themselves release regulators of migration and mitogens that induce the process 21. In addition, the clearance of myelin debris after demyelination made by macrophages is of extreme importance for OPC differentiation as myelin debris inhibits this process 29–31. Finally, differentiation phase begins when OPC exit the cell cycle 32 and oligodendrocytes generate new compact myelin that wraps axons.
Figure 4: Schematic meyliantion process: Proliferation of OPC is follow by their migration into the lesions, their differentiation and finally the generation of new myelin. Modified from Stangel M. et al 2017 33.
However, as it has been described, myelin generated in remyelination is thinner and with shorter internodal distances than myelin generated during development, reducing its effectiveness 34,35 (Figure 5). This can be expressed by the g-ratio, a number that relates the axon diameter to the myelin thickness. These differences between both processes have been associated with dynamic growth, having in mind that during development axons and myelin are growing at the same time sending information from one to another. On the contrary, in remyelination axons are perfectly formed and no variation in their size can be produced 36.
Figure 5 Differences shown in myelin during development (A), in an adult axon (B), after demyelination (in which no myelin is present)(C) and after remyelination (D), when myelin is thinner and with shorter internodal distances. From Franklin and Hinks 1999 36.
Remyelination has not been described to be uniform along the CNS as subcortical lesions tend to remyelinate better than perivascular ones 37. In addition, it can vary from one patient to another 38. Moreover, remyelination has been found to loss efficiency with disease evolution as 80.7% of early lesions are remyelinated compared to a 60% of chronic ones 39.
Related with this last point, after several cycles of demyelination-remyelination, and together with disease progression and aging, remyelination process terms to fail 40. It is not exactly clear why remyelination fails but researchers have postulated that it is related with a decrease in the numbers of OPCs, with an inefficient migration, with an inexistent or poor differentiation or with a combination of all these factors 41. However, other evidences indicate that there is no an aging-related decline in OPC but a lower recruitment and differentiation levels of these cells 42. Remarkably, more evidences point out that differentiation might be the key factor, as the promotion of OPC recruitment in experimental demyelination mice do not improve remyelination 43. In addition, chronic no remyelinated lesions have been described to contain OPC but not oligodendrocytes 44–47, highlighting the role that OPC differentiation stimulation can play in remyelination therapies.
As it has been previously introduced, remyelination failure makes naked axons to be unprotected, which at final term cause neuronal death and therefore neurodegeneration. This is an irreversible process that when occurs, neuronal circuits get interrupted (Figure 6).
Figure 6: Following demyelination, axon remains intact enabling the regenerative response of remyelination. However, in the absence of remyelination, saltatory conduction can not be restored leading to axonal degeneration. From Franklin 2017 21.
MS is an heterogeneous disease and the evolution that has been explained above with cycles of demyelination-remyelination with progressive disability of the patient is called relapsing-remitting MS (RRMS) and 85% of the patients develop this form of disease. It is usually followed by a secondary progressive form in which neurodegeneration is the main characteristic. Interestingly, therapies for RRMS are focused in protecting myelin to be damaged by developing immunomodulatory or immunosuppressive treatments that kill, attenuate or disable overactive and autoreactive lymphocytes 48. Although they are very effective in this task, a subclinical neurodegeneration progresses and age-associated decline in remyelination efficiency finally increases patients´ disability. Unfortunately, progressive MS is nowadays untreatable, and a big effort is being done trying to discover new and promising treatments to improve remyelination and prevent neurodegeneration.