Writer: Anna Pujol Castiblanque
Editor: Catherine Turnbull
Artist: Patrick Marenda

Axons in whales can be up to 30 meters long and yet the information has to go from one neuron to the next one in a matter of milliseconds. How is that possible? Luckily, evolution provided vertebrates with myelinated axons. This means that the axon is covered with a membrane that insulates and protects it. Just like the electrical cables of your computer charger which are also covered to insulate and protect them against damage. The only difference is that myelin is not a continuous sheath around an axon, unlike a cable around a wire, but rather there are periodical gaps called nodes of Ranvier. Now imagine your neuronal system is just like the roads in your country, and the axons are the highways communicating from one city to another. Your car is about to transport the electrical information from one city to the next, but since you are driving at super speed, and the two cities are far away, you need to stop at some gas stations along the way in order to keep up that speed. This is just like the nodes of Ranvier, which increase the conduction speed, allowing the potentiation of the electrical signal.

In an emergency, who are you going to call? OPCs at your service.

Who are the construction workers in charge of creating this myelin? It is the oligodendrocytes, a type of glial cell found in the central nervous system, that take charge of this domain. Analogously, Schwann cells can fulfil this same role for the peripheral nervous system. These cells wrap around the axons and protect them using myelin. Sometimes, this myelin can be broken down or degraded due to injury, pathogenic attacks or by an immune system response. In those cases, your car runs out of fuel and will eventually stop before arriving at its destination, interrupting the flow of information. In other words, the axon becomes vulnerable, unable to transmit the electrical signal, and will eventually degenerate and die. This loss of myelin, also known as demyelination, can be solved by making new myelin sheaths. Easy peasy, right? But who will you hire for the job? Our main protagonists for the task are the oligodendrocyte progenitor cells (OPCs). Under normal conditions, adult OPCs are quiescent (inactive). When there is demyelination, the adult OPCs are activated by the alarm, just like firefighters, and then they migrate to the site of injury whilst proliferating to increase in number. Finally, once they have reached their target, they start differentiating into new oligodendrocytes which will then remyelinate the axons.

When remyelination fails: treatments and therapies.

In some diseases, such as multiple sclerosis, this process is inefficient, leading to remyelination failure. This is most commonly due to an inability of  OPCs to differentiate into new oligodendrocytes. To surpass this remyelination failure, scientists have come up with two different strategies: either enhance endogenous remyelination or utilise OPC exogenous transplants.

To enhance endogenous remyelination, researchers normally enhance positive regulators of OPC differentiation (by upregulating the molecules that propitiate their differentiation) or inhibit negative regulators of it (by removing what is preventing their differentiation). 

In contrast, if your OPCs are on strike or overworked, you might need external help. In those cases, a transplant of OPCs is the solution. The market of OPCs includes samples from different origins: fetal and adult brain tissue, embryonic stem cells or induced pluripotent stem cells (iPSCs). Each one of these sources has its own pros and cons. Fetal tissue must be obtained from abortuses or pathological samples. Moreover, adult brain tissue and fetal tissue can only undergo very limited rounds of replication, and so their progeny is scarce. This can be solved by using embryonic stem cells or iPSCs. These are pluripotent cells, meaning that they can differentiate into any type of cell from the body and self-replicate many times over. This can be both a pro, as we will obtain many OPCs, but also a con, as with a high cell proliferation rate, there is an increased risk of developing tumours. Furthermore, with all exogenous transplants, we need to be aware of the rejection risk of the donor cells. The recipient body will see it as unfamiliar tissue and start attacking and destroying the foreign cells. A solution would be to use tissue or cells taken from the same body. To do this, we obtain cells from the recipient themselves, normally skin cells as these are easily accessible. Then we can reverse these differentiated cells into iPSCs, which can be later redifferentiated into any type of cell that is required, like OPCs or oligodendrocytes. These lab generated OPCs can now be placed into the recipient’s brain and won’t be attacked as they are the patient’s own cells. This might look like magic, but it’s not – it’s just science! This strategy is particularly attractive for patients with remyelination failure due to mutations in their OPCs. In those cases, the mutations can be corrected during the iPSC stage and then these will differentiate into healthy OPCs that will be grafted back into the patient.

Overall, we can see how scientists are coming up with new and imaginative strategies to treat remyelination defective diseases. It’s clear that this field is moving at a vertiginous speed, just like the electrical information in finely myelin-coated axons.

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