The Great Wall of Glia

Unpacking the dual role of the glial scar in spinal cord injury.

Infographic by Dilan Setiya

Imagine running for your life, and then you suddenly find a towering wall of Jenga blocking your path. After a traumatic spinal cord injury (SCI), the body reacts to that injury by building that wall of Jenga with a cellular construction crew primarily consisting of astrocytes, which are support cells. Astrocytes prevent you from getting across but also block your saviors from getting to you too. Astrocytes wall off injury and prevent further damage. This metaphorical wall is called a glial scar. 

In the event of an injury, this wall protects the healthy tissue from the degradation that would ensue if the inflammation continued to spread. However, the wall also creates a physical and chemical dead zone. In this dead zone, electrical signals from the brain can’t reach downstream limbs. For example, if someone gets a severe injury in C4, a vertebra in the cervical spine closest to the skull, signals from their brain cannot reach anything lower than that vertebra, causing them to become quadriplegic, paralyzed in all four limbs. In the short term, the creation of this scar is life-saving, as it contains the spread of inflammation and prevents the toxic debris from affecting the healthy neurons further away from the injury. Over time, the inflammation reduces, but the scar, like any other, hardens, becoming a permanent wall that is essentially a dead zone.  The astrocytes that make up the scar are tightly packed and they secrete chemicals that prevent growth. Axons are the cables that neurons use to send signals, and as these axons regenerate to try to remake those connections, they physically cannot push through that wall as a result of the physical and chemical properties of the scar. The wall that kept the neurons safe in the acute phase is now responsible for blocking axonal regrowth and signal transduction. 

If you’re anything like me, you might start to wonder, what if we just remove the scar after the inflammation subsides? Seems relatively straightforward: remove the scar after healing is relatively complete, and then let the axons continue their regeneration. Over the years, scientists have tested this hypothesis, and they found that removing the scar actually worsens the injury. Radical removal of the scar doesn’t spontaneously result in axonal regrowth or functional recovery. Instead, it induces an increased spread of inflammation and less repair. Removing the scar essentially does more harm than good. Which brings us to the better question: If we can’t break down the wall, how do we get around it? 

To answer this question, researchers have turned to regenerative medicine, primarily focusing on approaches that favor tissue protection as well as axonal regrowth. Basically, what method can we use that retains the protective aspects of the glial scar while getting around the inhibition of axonal regrowth? An example of this has been the research being done using mesenchymal stem cells (MSCs) found in the bone marrow, injected into the injured environment to secrete anti-inflammatory and trophic factors that promote cell survival, growth, and differentiation. In research conducted on adult rats, MSC grafts improved recovery with increased nerve growth factor levels in less than a week but didn’t provide any significant increase in axonal regeneration. While this is a significant discovery, the axonal regeneration piece is still missing, prompting further research into this area. 

In 2019,  a breakthrough clinical trial led by stem-cell scientist Hideyuki Okano at Keio University in Tokyo, treated four paralyzed patients with induced pluripotent stem cells. The four patients were all adult males over the age of sixty, and out of the four patients, one of the patients could stand again, and another regained movement in his arms and legs, but the other two did not show measurable improvement. Despite two out of four patients showing no improvements, considering the rather small sample size, older patients, and varying results, James St John, a translational neuroscientist at Griffith University in Brisbane, Australia, says the trial was a success.

Perhaps the most famous breakthrough of all was a surgery performed by Dr. Pawel Tabakow in Poland, treating a patient with spinal cord transection, complete severing, and using olfactory ensheathing cells from the olfactory bulb right above the nasal cavity. This surgery was the first case of a patient moving up two levels, from level A to C, in the American Spinal Injury Association (ASIA) impairment scale. Due to the complexities of spinal cord injuries, typical movements along this scale are usually either none or one level at a time. The scale goes from levels A to E,  where A is a complete injury, C is some motor function preserved and depending on where their injury is, some patients can move with the help of mobility aids, E indicates normal motor and sensory functions. Considering the small sample size of one and the high risks associated with surgery, no one has attempted this surgery since then.

To understand the limitations of clinical applications of these findings, we have to contextualize the situations the patients are in post-injury. This is critical, as patients may be subject to a worse prognosis for an uncertain chance to get better. While the surgery performed by Dr. Pawel Tabakow was an impressive feat, it has not been widely replicated not only because of the risks associated but also due to the regulatory restrictions in the United States. As science progresses and clinical trials succeed, we hope to overcome the glial scar, not by breaking it down, but by working in tandem with the biological marvel. The wall has not come down all at once, but for the first time in our history, scientists are finding ways around it.

These articles are not intended to serve as medical advice. If you have specific medical concerns, please reach out to your provider.