Remyelination

As of 2022 the status of possible remyelination acceleration is of trials only, with side effects of possible drugs being one limiting issue.

Function

Remyelination is activated and regulated by a variety of factors surrounding lesion sites that control the migration and differentiation of Oligodendrocyte Precursor Cells. Remyelination looks different from developmental myelination in the structure of the myelin formed. Reasons for this are unclear, but proper function of the axon is restored regardless. Perhaps of most interest are the inhibition and promotion factors of this physiological process. One way this process can be traced is by following different protein activation sequences which have shown just how quickly remyelination begins after injury (within a few of days).

Characteristics of remyelinated axons

The most notable evidence that remyelination has taken place on an axon is its thin myelin sheath created by an oligodendrocyte, though the reason why the new myelin sheath is thinner remains unclear. This can be quantified in the g-ratio, the ratio between the diameter of the axon itself to the outer diameter of the myelinated fiber. Remyelinated axons tend to have values closer to 1, indicating a thinner myelin sheath than those myelinated naturally. The g-ratio differences are less apparent on smaller axons.

The thinner myelin not only restores protection of the axon from degradation, but also restores a faster conduction velocity. The conduction velocity, however, is not as strong as naturally myelinated axons and the Nodes of Ranvier are inclined to be wider which results in less coverage in the axon by myelin than what is natural.

OPC involvement

Oligodendrocyte Precursor Cells, or OPC's, are the main cells responsible for the remyelination of demyelinated axons. There are two physiological changes that must occur to OPC's for remyelination to occur. Once a signal is sent that remyelination is needed, OPC's will first migrate to the damaged axon. This process may be signaled or enhanced by microglia or astrocytes at the injured axon site that stimulate migratory OPC pathways From there the cells must differentiate from being progenitors to being pre-oligodendrocytes, then premyelinating oligodendrocytes, and finally mature oligodendrocytes. These oligodendrocytes can then wrap damaged axons with new myelin sheaths. This process of differentiation through several phases has many involved and direct pathways and factors necessary for the completion of this process. It is easy to completely stop remyelination with the failure of a number of pathways.

Propagation factors

One of the difficulties of studying remyelination is the variety of factors that play a role in differentiating oligodendrocyte progenitors. While some factors promote and others inhibit, still some factors that are known to be involved are yet not understood enough to know whether it promotes, inhibits, or does both. Many factors are poorly understood and subject to much change as research is done.

Cytokines and chemokines

Cytokines mediate inflammatory responses that promote pathogen and debris clearance so that further tissue damage is avoided. Too much can mean cell death but failure to propagate cytokines at all in remyelination results in a lack of debris clearance at a damaged axon site; this buildup of myelin and oligodendrocyte debris has been shown to inhibit the differentiation of Oligodendrocyte Precursor Cells. Specifically, cytokines promote TNFR2 and eventually TNF-alpha which plays a key role in OPC differentiation.

It has also been shown that chemokines are involved in guiding immune cells to sites of axon lesions to facilitate inflammation and debris clearance as well as possibly guiding OPCs migration to lesion sites. So then, chemokines are directly involved with both migration and differentiation of OPCs. The specific chemokines involved with each of these two processes is known: CXCL12 is related to migration and differentiation is increased with an increase in CXCR7 and a decrease in CXCR4. In certain demyelinating diseases CXCL12 has been shown to be decreased, possibly playing a role in demyelination failure. Still much is to be researched in this field, as certain chemokines like CXCR2 plays a role in inflammation and repair but in an unknown manner over much controversy.

Signaling pathways

LINGO1, a cell receptor, has been proposed to be involved in the regulation of remyelination. It is thought to inhibit not only axon regeneration but also regulate oligodendrocyte maturation by inhibiting OPC differentiation. Animal studies suggest that when a LINGO1 is inhibited, OPC differentiation and thus remyelination can be promoted at demyelinated sites. LINGO1 gene expression is also known to activate RhoA which may also play a part in inhibition. Myelin debris build up might be responsible for the promotion of the LINGO1 signalling and overall inhibition.

The Notch-1 receptor pathway is another pathway that inhibits the differentiation of OPCs. When the ligands Jagged1 and Delta, produced by axons, neurons, and astrocytes, are stimulated and bind to the membrane, oligodendrocyte maturation is inhibited. This pathway may also be facilitating migration despite its differentiation inhibition. In some experiments, altering the pathway so that differentiation is increased caused a decrease in the proliferation of OPCs. There may be other ligands that have either promoting or inhibiting effects when attached to the Notch-1 receptor.

The Wnt-β-Catelin pathway has been shown to also inhibit remyelination when it is dysregulated in the body. Demyelinating diseases have been shown to cause this dysregulation. Possible genes involved inside this pathway are TCF4 and OLIG2 which are both expressed in high amounts in areas where remyelination has failed from demyelinating diseases.

Transcription factors

Gene expression may be the most important factor in understanding remyelination and can hold the key to understanding how to treat demyelinating diseases. OLIG1 has been shown to be critical in developmental myelination and may also be important in remyelination. OLIG2 and TRF4 have also been shown to be important especially in the Wnt-β-Catenin Pathway, most likely in inhibiting remyelination. NKX2-2 is a gene coding for a protein that may increase the number of OPCs in low amounts, possibly working with OLIG2 in some way to differentiate OPCs to mature oligodendrocytes. As more genes involved in remyelination are found and cross linked more will be understood about promotion and inhibition.

Androgen receptor (AR) and testosterone

In a mouse model, it has been shown that testosterone, acting through the androgen receptor (AR), is important in remyelination by oligodendrocytes. Those same authors note that the AR evolved from a duplicated gene coincidentally with the development of myelin in jawed vertebrates.

Other factors

It is known that as age increases there's a decrease in the efficiency (both the speed and magnitude) of remyelination at demyelinated axons. This is probably linked with down regulation of certain expressed genes with increased age. The research of this is particularly important with the elderly whose myelin and axons are more prone to be degenerated in the CNS.

Class 3 semaphorins (SEMA3s), originally identified as axon guidance molecules, play a role in remyelination. For instance, SEMA3s modulate the recruitment of oligodendrocyte precursor cells and their differentiation into oligodendrocytes. In addition, SEMA3a is known to repel Schwann cells.

Growth factors are active polypeptides that control differentiation and biological growth in responsive cells. They have been shown to have a prominent role. Due to the wide variety of these factors it is difficult to study specifically but understanding can be big in treating demyelinating diseases. Some of the factors being researched are EGF (which is known to enhance myelination), IGF-1, PDGF, and FGF.

Toll-Like receptors are also involved in remyelination, most likely inhibiting remyelination and OPC differentiation. There are a variety of types of these receptors, but a majority of them tend to increase, especially in the chronic stages of demyelinating diseases, suggesting that they may be involved with remyelination failure.

MicroRNA is not well understood but may play a minor or major role in remyelination. MicroRNA may have a role in reduction of CD47 which promotes phagocytosis of myelin. Certain microRNAs have been shown to promote OPC differentiation by their involvement and maintenance of genes that keep OPCs undifferentiated.