Although relatively new to the scene of cell based therapies for reparative medicine, stem cells and their progenitors have been labelled as the ‘cell of the future’ for revolutionising the treatment of spinal cord injury, CNS injury and neurodegenerative disorders. Another stem cell source that is being pursued, and that may in fact be closer to the goal of producing a variety of spinal cord cells, is stem cells from the spinal cord itself. These are a subclass of neural stem cells and as such are restricted to generating neural tissues.
Bone marrow precursor stem cells or mononuclear cellular fractions of bone marrow contain mesenchymal stem cells and haematopoetic stem cells. These stem cells are a component of bone marrow that preferentially migrate to the site of brain injury and differentiate into neurons and cell supporting elements, improving functional outcome in animals.
Many studies have indicated that transplantation of several different types of stem cells promotes functional recovery in animal models of spinal cord injury. These studies have been confirmed by anecdotal reports of miraculous recovery in some patients with spinal cord injuries.
One approach to using stem cells for regenerative therapies may be recruitment of endogenous neural stem cells resident in the adult spinal cord. Researchers have showed that stem cell-derived motor nerve cells, when grafted, sent projections to reach muscle targets, and stem cell grafts improved motor function in animal models with acute and chronic spinal cord injury.
In some studies stem cells have promoted functional recovery in animals with spinal cord injury. These animals showed an improvement in locomotor (movement) rating scales and also showed somatosensory-evoked potentials (sensation) recovery.
Studies in humans have also shown that subarachnoid placement of stem cells is safe with no long term adverse effects. Some of the reports of treatment are truly amazing.
Three kinds of stem/progenitor cells have been used in cell therapy in animal models of spinal cord injury: embryonic stem cells, bone marrow mesenchymal stem cells, and umbilical cord neural stem cells. Neural stem cells or fate-restricted neuronal or glial progenitor cells were preferably used because they have the clear capacity to become neurons or glial cells after transplantation into the injured spinal cord.
At least a part of the functional deficits after spinal cord injury is attributable to chronic progressive demyelination. Therefore, several studies transplanted glial-restricted progenitors or oligodendrocyte precursors to target the demyelination process. Transplanted stem/progenitor cells can also contribute to promoting axonal regeneration by functioning as cellular scaffolds for growing axons, such as occurs with other stem cell treatments in multiple sclerosis.
Spinal cord injury has been recognized as one of the conditions for which stem cell transplantation may first prove beneficial. After spinal cord injury loss of localized myelinating oligodendrocytes and grey matter neurons occurs, with glial scar formation and degeneration of both descending and ascending axons. Replacement of oligodendrocytes to promote remyelination, or of neurons to assuage neuronal loss and damage through establishment of relay circuitry or release of trophic factors, are possibilities for stem cell treatments.
Currently there are no published clinical trials in humans that have been performed, mainly because the clinics giving these treatments do not have legal approval in their home country. The Seychelles has given legal approval for stem cell treatment and all results are available and documented in clinical trials and published in peer reviewed journals.
Most spinal cord injury causes permanent disability or loss of movement (paralysis) and sensation below the site of the injury. Paralysis that involves the majority of the body, including the arms and legs, is called quadriplegia or tetraplegia. When a spinal cord injury affects only the lower body, the condition is called paraplegia.
Spinal cord injury symptoms depend on two factors:
A complete spinal cord injury is defined by total or near-total loss of motor function and sensation below the area of injury. However, even in a complete injury, the spinal cord is almost never completely cut in half. Doctors use the term “complete” to describe a large amount of damage to the spinal cord. It’s a key distinction because many people with partial spinal cord injuries are able to experience significant recovery, while those with complete injuries are not.
In 1995, actor Christopher Reeve had a horse riding accident and severely damaged his spinal cord, leaving him paralyzed from the neck down. From then until his death in 2004, the Superman movie actor became the most famous face of spinal cord injury.
Fifty years ago, a spinal cord injury was usually fatal. At that time, most injuries were severe, complete injuries and little treatment was available.
Today, there is still no way to reverse damage to the spinal cord. But modern injuries are usually less severe, partial spinal cord injuries and advances in recent years have improved the recovery of people with a spinal cord injury, and significantly reduced the amount of time survivors must spend in hospital. Researchers are working on new treatments, including innovative treatments, prostheses and medications that may promote nerve cell regeneration or improve the function of the nerves that remain after a spinal cord injury. The most dramatic results are being achieved with stem cell treatments.
In the meantime, spinal cord injury treatment focuses on preventing further injury and enabling people with a spinal cord injury to return to an active and productive life within the limits of their disability. This requires ongoing care and rehabilitation.
After the initial injury or disease stabilizes, doctors turn their attention to problems that may arise from immobilization, such as de-conditioning, muscle contractures, bedsores, urinary infection and blood clots. Early care will likely include range-of-motion exercises for paralyzed limbs, help with bladder and bowel functions, applications of skin lotion, and use of soft bed coverings or flotation mattresses, as well as frequently changing the patient’s position.
It’s often impossible for a doctor to make a precise prognosis right away. Recovery, if it occurs, typically starts between a week and six months after injury. Impairment remaining after 12 to 24 months is likely to be permanent.
However, some people experience small improvements for up to two years or longer. At one point, Christopher Reeve made national headlines when he regained the ability to move his fingers and wrists and feel sensations more than five years after he was paralyzed in a horse riding accident. But many not-so-famous people with a spinal cord injury have made similar strides away from the media spotlight. Doctors are researching ways to improve and perhaps augment this late recovery with the use of stem cell treatments.
Often the cord is not completely severed during injury; even so, swelling cuts off the blood supply to the neurons and glial cells. Without a blood supply these cells die. Additional cell death occurs as cells from the immune system migrate to the injury site. In order for a connection to be re-established new neurons and glial cells must regenerate to replace the injured ones. Up until about ten years ago people believed that there was no possibility for neurogenesis of adult nerve cells. Once nerve cells were damaged they were gone, eliminating hope for complete recovery from paralysis. As a result, treatments for spinal cord injury focused on prevention of further damage (secondary damage) and rehabilitation.
While the majority of cells found in the central nervous system are born during the embryonic and early postnatal period, scientists recently discovered that new neurons are continuously added to two specific regions of the adult mammalian brain (Reynolds and Weiss 1992). Animal studies have shown that neural stem cells were isolated from the dentate gyrus of the hippocampus and the walls of the ventricular system called the ependymal layer. These pluripotent stem cells divide and the daughter cells differentiate into other neuronal cells. These stem cells also migrate along the rostral migratory stream to the olfactory bulb, where they differentiate into neurons and glial cells (Luskin, 1993). Nerve cell differentiation has been witnessed in vivo, as well as in vitro when stimulated with an epidermal growth factor (Gage, 1995).
The discovery of differentiating stem cells in the brain revolutionized the way scientists think about treating spinal cord injury. Suddenly the chance for partial or possibly full recovery from paralysis seemed like a plausible option. Attention shifted to regenerating the neurons and glial cells as a solution to spinal cord injury.
Along with pluripotent stem cells, progenitor cells, a more restricted type of stem cells, are found in the hippocampus and ependymal layer. These stem cells are immature cells that are predetermined to differentiate into neurons, oligodendrocytes, and astrocytes. In 1995 Frissen observed that the presence of nestin increases in response to spinal cord injury. Nestin is a protein expressed by stem cells: presence of it indicates neural stem cells are much more active then previously believed. Our brain naturally increases the production of stem cells to aid an injured CNS. If the brain responds in this way, why doesn’t the spinal cord repair itself?
In 1999, Johansson and Momma observed that only active progenitor cells were differentiating into astrocytes. They labeled ependymal cells with a Dil injection so migration could be followed. After making lesions in the spinal cord they waited four weeks and then observed the progress of the ependymal cells. They tested the cells found in the scar tissue around the site of injury and found that all DIL marked cells were astrocytes. This indicates that the progeny from ependymal cells had only differentiated to astrocytes. Stem cells do respond to spinal cord injury, just not for the purpose of re-establishing connection between neurons. Thus by utilising other neural stem cells to aid this process of re-establishing connection the treatment of spinal cord injury would be easily achieved.
Enzmann, GU; Benton, RL; Talbott, JF; Cao, Q; Whittemore, SR. Functional considerations of stem cell transplantation therapy for spinal cord repair. J Neurotrauma. 2006;23:479–495
Wrathall JR, Lytle JM. Stem cells in spinal cord injury. Dis Markers. 2008;24(4-5):239-50. ReviewSafety of Autologous Stem Cell Treatment for Traumatic Brain Injury in Children Charles S. Cox, Jr., M.D. The University of Texas Health Science Center, Houston
Stem cell delivery by lumbar puncture as a therapeutic alternative to direct injection into injured spinal cord. J Neurosurg Spine. 2008 Oct;9(4):390-9. Neuhuber B, Barshinger AL, Paul C, Shumsky JS, Mitsui T, Fischer I
Stem cell therapy and coordination dynamics therapy to improve spinal cord injury. Electromyogr Clin Neurophysiol. 2008 Jun-Jul;48(5):233-53. Schalow G.
Neurally induced umbilical cord blood cells modestly repair injured spinal cords. Neuroreport. 2008 Aug 27;19(13):1259-63. Cho SR, Yang MS, Yim SH, Park JH, Lee JE, Eom YW, Jang IK, Kim HE, Park JS, Kim HO, Lee BH, Park CI, Kim YJ.
Stem cell transplantation in India: tall claims, questionable ethics. Indian J Med Ethics. 2008 Jan-Mar;5(1):15-7. Pandya SK.
Stem Cell. 2008 Jul 3;3(1):16-24. Stem cells for spinal cord repair.Barnabé-Heider F, Frisén J.
Stem cells in spinal cord injury Dis Markers. 2008;24(4-5):239-50. Wrathall JR, Lytle JM.
Stem cell-based cell therapy for spinal cord injury. Cell Transplant. 2007;16(4):355-64Kim BG, Hwang DH, Lee SI, Kim EJ, Kim SU..
Neuronal repair and replacement in spinal cord injury. J Neurol Sci. 2008 Feb 15;265(1-2):63-72Bareyre FM.
Stem cells for the treatment of spinal cord injury. Exp Neurol. 2008 Feb;209(2):368-77. Coutts M, Keirstead HS.
Setting the stage for functional repair of spinal cord injuries: a cast of thousands. Spinal Cord. 2005 Mar;43(3):134-61. Ramer LM, Ramer MS, Steeves JD.
Neurological aspects of spinal-cord repair: promises and challenges. Lancet Neurol. 2006 Aug;5(8):688-94. Dietz V, Curt A
Stem and progenitor cell therapies: recent progress for spinal cord injury repair. Neurol Res. 2008 Feb;30(1):5-16Louro J, Pearse DD.
Integration and translation: driving stem cell therapies toward the clinic. Regen Med. 2008 May;3(3):269-73. Trounson A.
