The Future of TBI Therapy Stems from Stem Cells
Shawn Babitsky
Illustrations by Anna Bishop
You’re watching an episode of Wile E. Coyote and the Road Runner and an anvil falls out of the sky. It lands hard on Wile E. Coyote’s head and he collapses to the ground. The coyote must be dead––right? But no, a moment later he jumps back to his feet, unaffected aside from a few stars orbiting his head. Although in the cartoon Wile E. Coyote may appear healthy, in reality he would have suffered a type of severe head wound called a traumatic brain injury. Traumatic brain injury (TBI) is severe damage to the brain resulting from an outside force. TBI can fall into two categories: penetrative trauma or blunt trauma [1]. Penetrative trauma occurs when an object pierces the skull and directly damages the brain. Blunt trauma usually results from events such as falls, abuse, motor vehicle accidents, or anvils falling out of the sky, and includes any head injury that does not penetrate the skull. These blows to the head rattle the brain inside the skull, damaging brain tissue [1]. The brain is severely damaged during either type of trauma; however, the effects of the injury do not end at impact.
After the Anvil: The Body’s Response to TBI
When a person sustains a traumatic brain injury, their body initiates two responses: the primary response and secondary injury cascade. The primary response is the direct result of the initial head injury, occurring within minutes or even seconds. This can manifest as tearing, bruising, and severe bleeding in the brain, all of which can be detrimental to brain function [1]. Tissue death is one of the main components of the primary response. For example, if someone is shot in the head in an event of penetrative trauma, blood vessels burst as the bullet tears through them, preventing proper blood flow to the brain. Our cells need to be constantly supplied with oxygen-rich blood in order to function properly, so the disruption of blood flow from the burst blood vessels causes tissue death [1, 2, 3].
In the hours and days following an injury such as a gunshot, the body also responds with a series of devastating complications called the secondary injury cascade [1, 4]. During the cascade, the brain releases cytokines — proteins secreted from immune cells — which, in the case of TBI, cause inflammation of brain tissue. Neurons within the inflamed areas of the brain become dysfunctional and degrade until they eventually die [4, 5, 6]. The release of cytokines also inflames the blood-brain barrier, a sieve-like structure surrounding the brain that controls which substances are allowed to enter [7]. As cytokines are released, they tear holes in this delicate barrier, decreasing its ability to regulate what substances can pass through and therefore allowing excess fluids to enter the brain [7]. This fluid builds up and floods the tight space between the brain and the skull, putting pressure on the brain. This pressure on the brain invites potential health complications, such as blindness, abnormal breathing, and further lack of blood flow [4, 8]. The series of events resulting from the release of cytokines during the secondary injury cascade inflames the brain and causes severe damage to neurons and the blood-brain barrier [8]. This degree of damage done by TBI requires intensive medical treatment to minimize the effects of such an injury.
Current treatments for traumatic brain injuries focus exclusively on alleviating symptoms; there are no treatment options to regenerate damaged brain matter [8, 9]. One current treatment involves elevating the head to decrease pressure on the brain [9]. When the head is elevated, the force of gravity works to drain excess fluid out of the skull. While this approach is somewhat effective at relieving pressure, the brain lacks the ability to regenerate neurons on its own, so only minimal healing can occur [9]. Neurons are responsible for communication within the brain: they act as telephone lines, sending and receiving messages that keep us alive [10]. When neurons die due to inflammation, these lines of communication are severed and messages cannot go through, which can negatively affect a person’s mental and physical abilities [10]. If doctors are not able to regenerate these neurons, the effects of the brain injury will persist [8, 9].
Stem Cells: Biology’s Natural Transformers
Although current TBI therapies are unable to restore damaged brain tissue, stem cell therapy provides hope that regeneration may soon be possible [11, 12, 13]. Most of the cells in our bodies are assigned to perform a specific job. For instance, the cells in our heart muscle are programmed to help the heart pump blood through the body, and fat cells are designed to store energy [14]. Stem cells, on the other hand, are a special type of unprogrammed cell, meaning they are not specialized for any particular job. They can be manually programmed to become any type of cell through a process called differentiation, acting like the blank Scrabble tiles of the body [8, 11]. The blank tiles stand in as whatever letter the player needs them to be. Once the blank tile is assigned to a letter, however, the tile becomes that letter until the end of the game. Stem cells work within our bodies in a similar way—they can be assigned to serve as different types of cells; however, once they are assigned to a job, they cannot be reassigned to a different one. The ability of stem cells to evolve into specialized cells, like neurons, has the potential to be revolutionary in the treatment of traumatic brain injury [11, 15]. When stem cells differentiate into neurons, they can form new connections between brain structures, potentially restoring the cognitive and motor functions damaged by TBI [10].
Repair, Regenerate, Repeat
Although several types of stem cells have the ability to differentiate into neurons, TBI research typically involves mesenchymal stem cells (MSCs), which are mainly extracted from bone marrow [3]. Once extracted they must be reprogrammed in order to differentiate into neurons, a process which takes place outside of the body, in a petri dish or test tube [15]. During this process, the genes that prevent differentiation are manually “turned off” while the genes that promote differentiation are “turned on” [15]. Reprogramming is repeated until the cell has been modified to fully differentiate into a neuron [16]. The reprogrammed MSCs, now functioning as neurons, can be injected into an individual’s vein [17]. When MSCs travel to the brain via the bloodstream, they are ordinarily prevented from crossing the blood brain barrier. Following a TBI, however, the holes created in the BBB during the secondary injury cascade allow the MSCs to slip through the barrier and migrate to the injury site [17, 18].
Once MSCs reach injured tissue, they behave as neurons and form new connections, replacing those that have been damaged during the secondary injury cascade. In addition to neuron replacement, MSCs can address the other consequences of the secondary injury cascade: inflammation and blood-brain barrier damage. They produce proteins that inhibit cytokine production, preventing further inflammation in the brain [3, 5, 11]. MSCs also activate specific genes that are responsible for the permeability of the blood-brain barrier [19]. When activated, these genes enable proteins to be released that counteract the damage done by cytokines, repair the structural integrity of the barrier, and regenerate some of the tissue damaged by the TBI [19]
The Future of TBI is TBD
From their efficiency at reducing inflammation in brain tissue to their impressive ability to replace damaged neurons, mesenchymal stem cells have the potential to be at the forefront of TBI therapy [3, 5]! Despite the hope surrounding stem cells, experts are hesitant to give their use the green light. One of the fears that has prevented stem cell therapy from being widely applied is accidental tumor development [3]. If stem cells are implanted before they are properly reprogrammed and differentiated, they have the potential to form tumors within the body. Recently, however, specialists have begun implementing drug therapies during the reprogramming process to ensure proper differentiation, reducing the risk of tumor development and making stem cell therapy safer [3, 16]. Further research can maximize the ability of stem cells to treat TBI while minimizing the associated health complications, subsequently improving the lives of everyone who has suffered a traumatic brain injury [3, 20]. So the next time an anvil falls and crushes Wile E. Coyote, he would be the ideal candidate for a stem cell clinical trial.
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