For all the advances we’ve made in medical science toward treatment of dangerous disorders and diseases, along with recent announcements such as a secondary success in long-term HIV remission, there are still plenty of conditions that we have a long way to go toward any sort of viable treatment. Spinal cord injuries are one such area that has seen significant progress, but that has shown at the same time that the road toward a full success is longer than we thought. One issue with this area is that these injuries are often an all or nothing proposal. Either the injury is fixed or it remain a major issue for motor functionality and far worse. There have been cases of partial recovery, but even getting to that point is fraught with problems.



That is why medical biotechnology has become such a prominent force in this area of research, due to the possibility of finally unlocking actual recovery options that are genetic in design. Rather than developing a tool-assisted treatment for spinal lesions, though that kind of research is continuing nonetheless, a biological alternative would be the best of both worlds. And the place to start is with the organisms that already have such a capability, which is why the full regenerative and duplicative properties of creatures like C. elegans has been a main organism of study in this area. But there are plenty more besides.



The Thing About Salamanders

Salamanders have a bit of a stereotype to them. Most people know about the miraculous feat of being able to lose, or even actively detach, their tails and grow new ones later with no problems whatsoever. Though this power goes quite farther than just that. When it comes to mammals and spinal cord injuries (SCIs), the normal response is for the specialized glial cells surrounding your spinal cord neurons to start to proliferate and divide in order to protect themselves. This reaction is called gliosis and causes a buildup of cells in a lesion referred to as a glial scar.



Unfortunately, while this may protect that specific neuron from further damage, it also results in biochemical releases that significantly hinder the neuron’s axons from growing back to their normal connections with their neighboring neurons. The overall process is obviously way more complicated than just this, but that serves as a good overview to then move on to discussing how salamander are very different.



When salamanders suffer an SCI, they do still have gliosis occur, but those proliferating glial cells then migrate evenly throughout the lesion and create a situation that still allows the axon to reform into its prior connective shape. This regenerative capability is shared with some other species, such as zebrafish and lampreys. What they share is that the glial proliferation is controlled and specific, rather than being reactive as in mammals, and so doesn’t interfere with other processes. In both cases, however, we don’t understand a lot about how the process is activated and how it conducts itself on a molecular basis.

The Spinal Cord Complex

What has been recently uncovered, however, is the existence of a complex of transcriptional activators known as AP-1 that are involved in not only turning on the glial proliferation promoter, but also other genes that play a role in the creation of the glial scar. This AP-1 complex is a heterodimer, meaning combined molecules, of two proteins known as Fos and Jun which can take many different forms and have activity in many cellular processes. Which genes are activated is at least in part dependent on what combined form the two proteins take and it has been seen in SCIs in mammals that they both upregulate and assist in lesion formation.



Axolotls are a bit different, comparatively. They upregulate Fos protein specifically in the cells surrounding the injury, leading to axonal regeneration. Jun protein also independently plays some sort of role in the process, but not as a heterodimer with Fos. It was not known what protein Fos binds with in axolotls.



Until now, that is.

Spot Testing Regeneration

A research team from the Marine Biological Laboratory and the University of Minnesota were able to recently identify the alternative version of AP-1 that axolotls express after SCIs and also the culprit for why finding it has been so perplexing. MicroRNAs appear to be a part of controlling the expression of this complex. While such activity in general is known, it seems that upregulation of a particular miRNA is responsible for repressing Jun in axolotls during regeneration, thus preventing the normal Fos/Jun combination from forming.



The scientists tested this by forcing overexpression of the complex in the glial cells of axolotls through the use of GFP-tagged constructs of the complex itself and they found that this did lead to problems in axon repair after an SCI. When the particular miRNA, miR-200a, was inhibited, they found the same sort of impact as with overexpression, due to there being no way to prevent Jun from forming the heterodimer with Fos.



For proper regeneration in such species, they lastly found that an alternative Jun protein, known as JunB, is the other part of the Fos complex and which allows for differential expression in the cells around the injury and successful axon regeneration. This regulatory difference appears to be of key importance in finding a way to treat SCIs in humans. A benefit of this setup is that humans share the exact same genes, but expressed in a different manner.

The Steps To Travel

The next obvious step would be to test expression of these variant forms of the genes in spinal cord neuron organoids grown from human cells to see if regeneration can be made to work in such a case. If that is accomplished, then actual human trials would be a possibility. All without having to remove or add any genes, but merely alter how existing ones are used by the spinal glial cells.



Obviously, there is a lot of research still to do and testing to see if human glial cells can indeed function the same as those from regenerating species. But we are getting there and, as our technology improves, it may become something as simple as flipping a switch.

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Photo CCs: Albinoaxolotl3 from Wikimedia Commons