Monday Article #48: Why does routine remyelination not slow the progression of Multiple Sclerosis?
Upon experiencing trauma to the nervous system, neurons are able to regenerate to replace the neuronal loss through differentiation and development, though the ability decreases with age (Uyeda & Muramatsu, 2020). Demyelination of the oligodendrocytes is a hallmark for disorders such as Multiple Sclerosis (MS), which is an autoimmune disease of the central nervous system (CNS). Myelin sheath ensures a normal functioning of the neuron, when absent, it could lead to fixed functional deficits (Gruchot et al., 2019). Remyelination is the generation of myelin sheath in demyelinated axons (Chari, 2007), and is able to occur through activation and maturation of oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) into myelin sheath forming oligodendrocytes (Gruchot et al., 2019).
Figure 1. Stained section of a brain from a MS patient showing areas on demyelination in green and remyelination in red (Chari, 2007).
OPCs undergo a series of developmental stages that leads to remyelination (see Figure 2):
OPCs are activated and change its shape and gene expression around the lesion site.
Proliferates and migrates to the lesion site, so there is an increased number of OPCs
It differentiates into mature oligodendrocytes and forms more myelin sheaths (Uyeda & Muramatsu, 2020).
Figure 2. a) demyelinated axon undergoing remyelination through proliferation and differentiation which are occurring at the lesion site, the blood brain barrier (BBB) gets disrupted in lesion sites which promotes OPC proliferation and differentiation (Uyeda & Muramatsu, 2020).
OPCs show heterogeneity within its population due to the differences in individual lesion sites and patients, thus there are multiple mechanisms that could potentially prevent the differentiation of OPCs to myelin-producing cells (Gruchot et al., 2019). An older age and longer disease duration have been found to have decreased the occurrence of remyelination due to a reduced release of molecules that promotes OPC differentiation by the monocytic cells and a reduced myelin debris clearance (Gruchot et al., 2019). Although post-mortem examination of MS patient’s brains have showed the excessive amount of myelin sheath found throughout the CNS and around MS lesions, however due to its failure to mature into myelin-producing cells, the environment of the lesions is unfavourable for remyelination to occur. The changes, such as blood-brain barrier disruptions, that occur in areas of the lesion could lead to multiple mechanisms that would consequently prevent OPCs and oligodendrocytes from maturing (Harlow et al., 2015).
With respect to NSCs, they are multipotent cells that are able to mature into neurons and glial cells, and have the potential to grow into oligodendrocytes in replacement of the ones that were lost. The NSCs were found in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the brain, whereby SGZ-derived stem cells naturally differentiate into neurons unless genetically manipulated to grow into oligodendrocytes and it was found that SVZ-derived stem cells that differentiate into oligodendrocytes have a significant role in remyelination (Gruchot et al., 2019). Overall, it has been identified that the number of NSC-derived oligodendrocytes are higher than OPC-derived oligodendrocytes, but why is NSC-mediated remyelination inefficient in MS patients? We will be looking into the factors that affect the rate of remyelination.
Failure to remyelinate is not caused by a single factor but by a number of several factors (Figure 3). Although OPCs were abundant around the MS lesion, they were rather inactive due to the failure to detect the nuclear proliferation antigen and oligodendrocytes were lacking in the centre of the lesion area. Furthermore, lesion sites lack factors that promote the differentiation of OPCs, making it incapable of regeneration. Although a large number of OPCs are able to be found around the lesion, OPCs that survive in the lesion and ones that colonise lesion sites from adjacent tissues are indistinguishable, providing less information about the development of the lesion. As age and duration of clinical symptoms increase, density of OPCs decrease, new oligodendrocytes become increasingly impaired, and oligodendrocytes become less populated in the lesion site (Chari, 2007). Due to the fact that neurogenesis occurs less as age increases, it was suggested that it is responsible for reducing the potential to remyelinate in progressive MS. This is supported by the reduced number of ventricle-contacting astrocytes, which are the precursors for the highly proliferative transit-amplifying cells that promote differentiation of oligodendrocytes (Gruchot et al., 2019).
Figure 3. The complexity of remyelination. (1) myelin debris generation. (2) astrocytes and microglia get activated to encourage recruitment of monocytes. (4a) (4b) differentiation of macrophage from microglia and astrocytes. (5a) (5b) astrocytes and macrophages mutually activate each other and produce factors that alter OPC differentiation and proliferation. (6) macrophages remove myelin debris. (7) OPC interacts with demyelinated axons. (8) differentiation to functional oligodendrocyte. (Chari, 2007)
As the core immune cells of the CNS, not only are microglial cells phenotypically pro-inflammatory and cause axonal damage, they are also capable of restorative functions such an anti-inflammation, tissue repair and phagocytosis of myelin debris (Gruchot et al., 2019). Phagocytosis of myelin debris plays an important role in remyelination as it initiates neuron repair and promotes OPC differentiation. Therefore, insufficient receptors, such as Fraktalkine, TREM2, MerkTK and Ax1, have been found to impact the capacity for phagocytosis and the clearing of myelin debris. This causes an abundance of myelin debris, which could lead to an inefficiency in OPC recruitment (Gruchot et al., 2019).
Experimental autoimmune encephalomyelitis (EAE) is an animal model used to study MS. Inflammation was induced into EAE models and found an association between inflammation and an altered modulation of NSC differentiation, leading to apoptosis of NSC and its progenitor cells. Inflammation causes a complex mechanism that decreases the capability of oligodendrocyte differentiation. Chemokines protein, fundamental to stem cell proliferation, limits the oligodendrocyte differentiation but increases development of neural progenitor cells. Contrasting this and despite ageing affecting NSC proliferation, research has shown that transplanted NSCs were not only involved in remyelination but also encouraged OPC-derived myelination.
OPC has been shown to have consistently contributed to inflammation, thus leading to neurodegeneration via molecular mechanisms in Figure 4, which also shows multiple obstacles in order to promote axonal growth and remyelination (Psenicka et al., 2021).
Figure 4. Molecular mechanism of OPC in response to inflammation (Psenick et al., 2021).
Due to the individuality of each lesion, remyelination differs, suggesting that environmental factors play a role in the capacity of differentiation and proliferation of both OPC and NSC. This article has touched on several physical and molecular factors, and researchers are focused on promoting OPC differentiation nearer to lesion site in order to encourage OPC differentiation.
Chari, D.M. (2007) “Remyelination in multiple sclerosis,” International Review of Neurobiology, pp. 589–620. Available at: https://doi.org/10.1016/s0074-7742(07)79026-8.
Gruchot, J. et al. (2019) “The molecular basis for remyelination failure in multiple sclerosis,” Cells, 8(8), p. 825. Available at: https://doi.org/10.3390/cells8080825.
Harlow, D.E., Honce, J.M. and Miravalle, A.A. (2015) “Remyelination therapy in multiple sclerosis,” Frontiers in Neurology, 6. Available at: https://doi.org/10.3389/fneur.2015.00257.
Psenicka, M.W. et al. (2021) “Connecting neuroinflammation and neurodegeneration in multiple sclerosis: Are oligodendrocyte precursor cells a nexus of disease?,” Frontiers in Cellular Neuroscience, 15. Available at: https://doi.org/10.3389/fncel.2021.654284.
Uyeda, A. and Muramatsu, R. (2020) “Molecular mechanisms of central nervous system axonal regeneration and Remyelination: A Review,” International Journal of Molecular Sciences, 21(21), p. 8116. Available at: https://doi.org/10.3390/ijms21218116.
This article was prepared by Fatini Khadrishah