For most of medical history the spinal cord has been a place of mystery and uncertainty with injuries resulting in little or no improvement in the patient’s condition. In fact, often times surgery would damage the spinal cord even further leaving the person worse off than before. Perhaps it is not surprising then that the earliest known medical text, discovered in Egypt and dating back to 2000BCE, described injuries to the spinal cord as ‘an ailment not to be treated’. With the exception of the last hundred years or so, doctors and surgeons have achieved little insight into treating spinal cord injuries. These types of approaches persisted for many years along with the assumption that the spinal cord and central nervous system as a whole were unable to regenerate. This all changed in the early 1900’s when Santiago Ramon y Cajal and his team discovered that the spinal cord was actually able to heal and regenerate itself, if only to a degree. Ever since this landmark discovery the race to ‘cure’ damaged spinal cords had begun. However, it would take one more discovery to set the medical world down a promising and realistic path to end chronic spinal cord injury once and for all. In 1981, Martin Evans, of the University of Cambridge, became the first person to identify embryonic stem cells. The implications of this discovery were sufficient enough to land Evans the Nobel prize and researchers and scientists alike have been studying the possible uses of embryonic stem cells ever since.
To understand how embryonic stem cells and stem cells in general have the potential to heal spinal cord injuries (SCI), an adequate understanding of an SCI necessary. An SCI occurs when a part of the spinal cord is damaged, usually through contusion or compression. The spinal cord is just as sensitive to trauma as the brain is and any insult to it can cause a significant loss of function. At the actual site of the spinal cord lesion many processes are taking place at the cellular and molecular level. The primary lesion can cause acute ischemia as well as inflammatory swelling that can cause secondary lesions which are often more damaging than the initial injury. Furthermore, axonal and synaptic destruction, cell death through excitotoxicity, the deregulation of ion balance and the blocking of action potentials all contribute to the chaotic and devastating environment of an SCI. Additionally, astrocytes begin to form glial scars at the lesion immediately following the injury. Glial scarring can actually promote axonal regeneration by isolating the nerve tissue from swelling. Unfortunately, because few axons can grow past the scar tissue, glial scarring can also inhibit neuroregeneration. Stem cells however, can potentially bridge this glial scar and reconnect the electrical signals from the brain to lower parts of the body. They can also minimize the inflammation and swelling rendering secondary lesions obsolete. These two issues have been at the heart of stem cell research associated with SCI and in recent years experiments around the world have shown incredible promise. In this paper an overview of the research on the major types of stem cells being researched to treat spinal cord injury is discussed.
Shwann cells (SC) are the main glial cell of the periphery nervous system (PNS) where they are able to help regrow and reconnect the axons of damagaed nerves. This is why SC are the most widely studied type of adult cell for neuroregeneration. Many in vivo experiments on animals have shown how these exceptional cells are able to repair damaged nerves in the PNS. When a nerve is damaged SC’s migrate to the broken axons where they produce and activate neurotrophic factors (NTF) such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF). These NTF are crucial for neuronal survival, axon growth and the production of extra cellular matrix. In addition to helping repair and stabilize damaged nerves in the PNS, extensive research has shown that SC’s also produce myline sheaths that surround axons and enable them to send electric impulses quickly and efficiently. It was natural for researchers to wonder how these PNS glial cells would behave in the CNS and if they would have any rehabilitative use following trauma. After further research the answer was a definitive yes. In fact, scientists made an incredible discovery when they found that Schwann cells actually migrate to the CNS following severe trauma where they aid in many endogenous processes. The problem seems to be that there is not nearly enough of them to give the spinal cord any real shot of recovering on its own. The other major problem is that Oligodentrocyte and Astrocytes (glial cells in the CNS) begin to produce molecules that form the glial scars which axons cannot grow across, even with the help of SC’s. SC’s have shown great potential but there needs to be additional approaches that can inhibit the activity of the glial cells scar forming molecules.
Olfactory Ensheathing Cells
Olfactory ensheathing cells (OEC) are a specialized glial cell that is produced in the olfactory epithelium where neurogenesis occurs throughout life. Like their name suggests, OEC’s ensheath and surround the axons of sensory neurons in the olfactory system. There is an extraordinary amount of data that has been produced since 1997 including over 100 papers on the transplantation and potential nervous system repair of OEC’s. It turns out that the excitement for treating damage to the CNS and SCI’s in general is well warranted. OEC’s have a phenotype close to that of the SC, except that they are unique in a few ways. They can behave like SC’s by mylinating and helping to grow axons, but they exist in the CNS as well as the PNS. At first this may not seem like a big deal but to researchers this is an invaluable fact. Because OEC’s exist in the CNS and the PNS they can reach their full potential for healing and repairing a damaged spinal cord. This is in contrast to the Shwann cell, which only exists in the PNS unless it is called on during incidents of trauma. At the cellular level the biological environment ( proteins, bacteria, cells, etc.) dictates how molecules interact. A big problem with some of the earlier stem cell experiments was that even though stem cells have the ability to become any cell, they didn’t know what to become because they were in a completely new environment (ie. A spinal cord). Shwann cells may not be repairing CNS damage as well as they could be for this very reason. The fact that OEC’s behave naturally in the CNS (and spinal cord) means that scientists don’t need to do much in terms of coaxing them to do what they want them to do, they already ‘know’ where they are and what they need to do. Of course the biggest deficit associated with SCI’s is paralysis but many people aren’t aware that SCI’s effect just about every organ and process below the level of injury. OEC’s have been proven by many studies to recover locomotor function even in spinal cords that have been completely transected. In addition to motor recovery OEC’s seem to be especially good at restoring bowel and bladder function as well as phrenic nerve activity which could potentially help get some SCI patients off respirators. OEC’s are very promising and are undoubtedly going to have a role in curing SCI’s although it is not exactly clear how.
Mesenchymal Stem Cells
Mesenchymal stem cells (MSC) are found abundantly in bone marrow which is why they are sometimes referred to as bone marrow stem cells. Both of these names are rather misleading as they don’t describe this cells function or potential well at all. The (MSC) is really just a multi-potent stromal cell that has the ability to differentiate into several types of cells depending on the signals it receives from the local cellular environment. The word mesenchymal, coming from the word mesenchyme which means embryonic connective tissue, gives an adequate description of what kinds of cells these MSC’s can turn into. They can turn into bone cells, cartilage cells, blood cells, and fat cells. In recent years these processes have all been reproduced successfully in the lab in culture and in animals. Researchers have also found MSC’s in all kinds of places including the placenta, the umbilical cord and its blood, amniotic fluid, corneal stroma and dental pulp. The goal of some of the early research on CNS MSC transplantation was to see how safe they were and how they would react in an area such as the spinal cord. Fortunately when the MSC’s were injected there was very little backlash from the immune system which is very important considering how much of a burden immunodepressants can be. In addition, because these MSC’s are stromal cells, which means they naturally form supportive structure in the body, researchers are hoping that they will grow into a type of axonal scaffolding through the glial scar enabling nerve signals to be reconnected. Research into how this might work and how to induce this to happen if it doesn’t automatically is ongoing. Scientists have also discovered that when the spinal cord is damaged severely many cells are destroyed leaving spaces were there should be none. This is another area where MSC’s could possibly provide structure and stability where few other cells could.
A Realistic Interpretation of the Data
Many studies have shown that stem cells seem to be an effective way to repair a damaged spinal cord after an injury has occurred, however there are some troubling confounds within the data as a whole due to the nature of the spinal cord. While it is advantageous that scientists are using a several different types of stem cell to repair spinal cords, it can also make it difficult to ascertain what exactly is going on. Additionally, there are different methods for getting the stem cells to go where they should and act like they should which complicates things further. Moreover, the different kinds of injuries a spinal cord can suffer make every case, including ones that are run in the same experiment, unique and therefore difficult to judge quantitatively. These three factors, the multitude of stem cells used, the differing treatment methods and the fact that every SCI is unique make comparing data from study to study a complex task which must take into account each variable separately. Perhaps the only facet of stem cell-treated spinal cord injury studies that does not change is the spinal cord itself.
A Not-So-Miracle Cure
While many, if not dozens of various stem cell treatment and therapy programs have produced very promising data it is paramount that we interpret the data in a reasonable and practical way. It is crucial that we limit emotion and desire from skewing the reality of what the results have shown thus far. Stem cell therapies clearly offer tremendous hope for people suffering from spinal cord injuries but the data needs to be evaluated critically and rationally, and not read blindly . For example, even though many companies, universities and hospitals have achieved tremendous success in rehabilitating rodents, primates and even humans after an SCI, reasons to be skeptical are abundant. One main reason being that the overwhelming majority of stem cell therapy models aimed at repairing damaged spinal cords have the researchers inject or transplant their stem cells into the test animals spinal cord immediately following the injury. Now this methodology could potentially be useful for improving functionality of individuals who suffer SCI’s in the future, but for the tens of millions of people who have already suffered a SCI this data has little relevance. Obviously the faster you deliver the stem cells to the damaged spinal cord the better and more significant results you will see. Furthermore, like breaking a bone, there are many ways a spinal cord can be damaged. For example, a spinal cord can be crushed, sliced, or compressed. In addition, SCI’s happen at all different levels of the spinal cord with varying intensity and damage from one patient to the next. It follows that a one-size fits all ‘cure’ is not a realistic solution. There will be no miracle vaccine to treat SCI. Rather, it is more likely that there will be a number of different methods for restoring function and feeling below the level of injury specifically tailored to reach the best possible outcome for each individual case. Another huge issue with a lot of the data coming out about SCI rehabilitation is the degree of function that these animals and in some cases humans regain after their stem cell therapy treatment. Of course any improvement in function for an SCI patient is wonderful but the data needs to be taken for what it is. Lots of data that has gotten published claims extraordinary results and in some ways it is but for some this might be an over glorification. For example, there have been numerous stem cell therapy studies done on animals who have suffered a SCI that claim the animal can now move its once paralyzed limbs voluntarily. While this may be true, it is important to find out to what degree has this animal recovered. Is the animal back to walking, running and jumping or is it just twitching it’s foot randomly? Many people who suffer from SCI have some degree of function below their level of injury but it is not substantial enough to be a substitute for a wheelchair. We need to look closely at what the data are telling us so that we understand exactly what the implications are for ourselves personally as well as future individuals. It is also important to remember that, while doing potentially life changing research, the vast majority of companies producing data for stem cell treated spinal cord injury are for profit. This means that even though some of their data may truly be remarkable it will almost always be in their best interest to over inflate and exaggerate their results for the better, whether it be to build brand awareness, build awareness about SCI as a whole or to secure additional funding.
The entire field of stem cell therapy has improved tremendously in the last two decades. Research going on around the world, whether it be in an animal model or in actual human clinical trials, is getting closer and closer to a treatment for people suffering from an SCI. Although it seems like little breakthroughs are being made every day there are still many questions to be answered and a lot of work to be done. Researchers need to identify which cell(s) are able to interact most effectively at the cellular level inside the spinal cord. Researchers also have to study better methods of decreasing inflammation directly following an SCI as well as inhibiting glial scar formation molecules from being activated. Next, they need to investigate which technique of cell transplantation gives the cells the best shot at repairing the spinal cord. Lastly, and perhaps most importantly there needs to be a better understanding of how these different types of cells interact with each other and how best to combine them into a comprehensive treatment. Because each cell type can only repair part of the complex biology of the spinal cord there will need to be some type of combination of cells. Extensive research like this may be a few years away and there may be single cell type treatments that show promise but if there is ever going to be a wide ranging cure for SCI it will have to come from a treatment of several cells working in unison.