About Spinal Cord Injury

Causes and Treatment
Can Stem Cells Help?
Research Directions
Looking to the Future
Clinical Trials
Canada
General Information

The brain and spinal cord together form the central nervous system (CNS) which is responsible for processing all the information coming from our senses, keeping our organs and reflexes functioning, and directing our movements, thoughts and feelings. The nerves that branch out from the spinal cord to the rest of the body comprise the peripheral nervous system (PNS). These nerves both receive and convey messages as part of the feedback loop, allowing us to feel sensation and to send motor commands to the muscles to enable movements.

Spinal cord injury (SCI) is an injury to the CNS that may occur anywhere from the neck to the tailbone. The spinal cord is the critical organ that connects the brain to the rest of the body by conveying electrical impulses along the long nerve fibres that are bundled within it. Nerve cells, or neurons, have a long slender projection, called the axon that acts like a transmission line coming from the cell body. Even though axons are microscopic in diameter, they may be many feet long. A fatty substance called myelin that is similar to insulation on a telephone wire speeds up the electrical signals and protects the nerves.

If the spinal cord is injured, many nerve fibre bundles are severed. In a severed nerve, the proximal axon is still connected to the cell body, but the distal axon is below the level of the lesion, or site of injury. In those nerve fibres that were initially spared, inflammation and scarring around the injury site disturbs or eliminates the transmission of nerve impulses past the point of injury. Depending on how “complete” the injury is, meaning the degree to which the spinal cord has been severed, paralysis results in the extremities and the organs below.

Causes and Treatment

Spinal cord injury affects mostly young adults, and about 80 per cent are males. Car accidents are responsible for about 50 per cent of cases. Sporting accidents, serious falls, and diseases of the spine, such as spina bifida, can also cause permanent injury to the spinal cord.

Because often the injury is the result of a terrible accident which paralyzes otherwise fit and healthy people – and usually young people – SCI causes significant and prolonged suffering. Depending on the severity of the injury, rehabilitation will help many people to regain some degree of function.

Unlike the skin, blood, muscle and other organs, for some reason the CNS does not routinely replace cells that are damaged. It is for this reason that the disability caused by spinal cord injury is usually permanent and profound. In contrast, the PNS contains Schwann cells, a type of glial cell that wraps a protective sheath containing myelin around the peripheral nerve fibres, known as the myelin sheath. They can manufacture new myelin and regenerate nerve endings.

In SCI, restoring the electrical transmission between the brain and spinal cord requires repairing the myelin sheath around the central nerves. It may also require the regrowth of severed nerve fibres across the site of injury and into the neural network that is below the lesion. This is the challenge facing scientists.

Can Stem Cells Help?

Nerve fibres in the spinal cord are made up of different kinds of neurons, which are neural cells that convey information by electrical impulse and glial cells that support them. Two kinds of glial cells are important in the spinal cord – oligodendrocytes, which make myelin, and astrocytes, which provide a healthy and supportive environment for neurons to grow.

Until about 15 years ago, it was believed that the brain could not repair itself by generating new neurons. However, we now know that patients who have partial lesions to the spinal cord do experience a degree of spontaneous functional recovery arising from the ability of the brain to reorganize itself to produce new connections. The discovery of neural stem cells in the brain of adults gave scientists a possible explanation for this and hope that they could stimulate these latent stem cells to multiply the kinds of cells that are lost through CNS injury and disease.

In fact, it appears that neural stem cells do mobilize to create new cells in the event of injury, but only to create astrocytes. This is not enough to restore functioning because it is the death of oligodendrocytes that results in loss of myelin, which then halts communication between the brain and the rest of the body.

The challenge has been to understand the signalling that would prompt neural stem cells (precursor cells) to differentiate into neurons and glial cells, and especially into the myelin-producing glial cells that can restore the protective sheath around the fibers and re-establish the connection to the brain.

During embryonic development this is accomplished with the help of neurotrophic factors that help the cells survive and grow. As scientists learn more about these chemicals that trigger specialization, they are better able to duplicate the process in the laboratory and prompt NSCs to create all of the specialized cells required for the nervous system to function.

There appears also to be a role for spinal cord stem cells. They have been discovered around the centre (central canal) of the spinal cord itself, but for reasons not yet understood, instead of migrating to the site of spinal cord injury, they move away from it.

If these obstacles can be overcome, stem cells may enable the repair of the spinal cord in several ways. They may be used to replace nerve cells that have died because of injury; they may be used to generate new supporting cells that help reform the myelin sheath; they may protect cells from further damage if introduced into the spinal cord soon after injury; and, they may guide the regrowth of severed nerve fibres..

Research Directions

The “proof of principle” that stem cells could reverse spinal cord injury was done in 1999 in the US in experiments that simulated spinal cord injury in rats and used embryonic stem cells (ESCs). Those rats injected with embryonic stem cells prior to the injury regained limited use of their legs when the stem cells from the injection site travelled to the site of injury and created new neurons and glial cells.

Now scientists are able to use embryonic stem cells from fetal spinal cord tissue and either grow them into CNS cells in the laboratory before transplanting them, or directly implant progenitor cells (partially-differentiated embryonic stem cells). In the latter scenario, they rely on signals from the brain to complete the differentiation into the right kind of cell.

These two strategies are generally known as exogenous repair (transplanting the required cell that was developed in vitro) and endogenous repair (relying on internal cues to differentiate neural stem cells in vivo). In the case of spinal cord injury, both approaches have merit and are being actively pursued by research teams in the US, Canada and the UK.

Looking to the future

Scientists continue to experiment by grafting or transplanting cells to replace lost cells and by developing cultures and drugs that direct intrinsic neural stem cell activity.

Transplanting a patient’s own stem cells avoids the problems of rejection and the need for risky immunosuppressant drugs. This is the approach being taken by researchers in Canada who have discovered that skin-derived stem cells (SKPs) can be prompted to become Schwann cells, which are the cells adept at nerve fibre and myelin repair in the PNS. This would be an unlimited source of Schwann cells. In the injured spinal cord, Schwann cells will guide regenerating nerve fibres that were severed across the lesion site. In addition, they can make new myelin around those nerve fibres that had been initially spared but lost their myelin due to oligodendrocyte death.

Another approach that is being investigated in the UK, Spain, China, Canada, Australia and the US involves exploiting the characteristics of olfactory ensheathing cells to connect the proximal and distal axons of a damaged nerve fibre. These are a unique kind of glial cell that can guide growing nerve fibres across the lesion site and thus allow the severed nerve fibers to reconnect to the spinal cord’s nerve cells below the level of injury. Scarring and other cellular damage occurs as the body responds to the trauma and only compounds the difficulties to bridge the lesion site in the aftermath of the injury. The small window of opportunity to prevent disability once spinal cord injury occurs – hours, maybe weeks – has meant that most of the research has focused on rehabilitation.

“Combination therapy” – using gene therapy in combination with stem cell therapy to promote new myelin-producing cells – has also been successful. This involved isolating stem cells from the spinal cords of embryonic rats, cells called glial-restricted precursors because they can only become specialized glial cells. These cells were genetically modified with growth factors and transplanted into damaged spinal cords. The stem cells developed into astrocytes and myelin-producing oligodendrocytes that created new “insulation” around nerve fibres and resulted in improved motor function.

Human spinal stem cells have come to the rescue in cases where restricted blood flow to the spinal cord can cause paralysis (ischemia-induced paralysis - very much like a stroke), spasticity and rigidity as a complication of heart surgery despite the spinal cord being intact. Researchers have successfully grafted human spinal stem cells into the spinal cord to restore motor function.

Human spinal stem cells may yet play a role in spinal cord repair, since the molecular cell signalling that directs them to leave the site of injury is being decoded and possibly reversed.

Clinical Trials

Geron, a US biotech company in California, has received FDA approval to begin phase 1 clinical trials to test whether it is safe to inject oligodendrocytes made from human embryonic stem cells into the spinal cord. They are hoping to replicate in humans the groundbreaking research with rats, which proved that spinal cord injury is no longer irreversible.

Researchers in Colorado and New York are developing an alternative approach, focusing on astrocytes. Astrocytes are extremely important in generating nerve fibre growth in early development of the nervous system, but they complicate spinal cord injury by creating scar tissue that prevents transmission of nerve impulses. In 2008, the scientists discovered that there are two distinct sub-types of astrocytes that support the nerve cells – one that does damage and causes pain and another that enhances cell growth and regenerates nerves.

By manipulating different growth factors to create two different kinds of astrocytes from the same precursor stem cell population, researchers found dramatically different outcomes when they injected these cells into the injured spinal cords of rats. This means that transplanting glial-restricted precursor cells (which can become all kinds of glial cells once in the body) will not be as successful as transplanting the specific astrocytes that can regenerate nerve growth without adverse effects. This approach is now being developed for clinical trials.

Canada

A milestone in spinal cord injury research using adult stem cells was achieved in 2007 with the work of Dr Freda Miller and her colleagues in Toronto and British Columbia. Dr Miller discovered that stem cells derived from the patient’s own skin (skin-derived stem cells – SKPs) share characteristics with neural stem cells and can produce Schwann cells -- cells that create a good growth environment to repair injured nerve fibres including the ability to make myelin, which is crucial for impulse conduction.

In early experiments, Miller was able to prove that Schwann cells created from SKPs produced myelin along the damaged spinal cord. She then tested whether this approach would result in functional improvement by directly transplanting Schwann cells created from skin into rats with spinal cord injury. Mobility and coordination improved after 12 weeks and there was evidence that new nerves were growing in the cavity of the spinal cord. They had created a sort of bridge that spanned the cavity allowing nerves to grow through the bridge. In addition, many spared nerve fibres near the lesion site that had lost their myelin were now remyelinated by these Schwann cells.

Researchers will now see whether stem cells derived from human skin can produce similar results.