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Spinal Repair Unit
Professor Geoffrey Raisman, FRS
Repair of Injuries to the Spinal Cord and Spinal Roots by Transplantation of Olfactory Ensheathing Cells: Providing the Laboratory Data needed for initiating Clinical Trials.
Spinal Repair Unit, Department of Brain Repair and Rehabilitation
The brain, the spinal cord, and the optic nerve are components of an immensely complex network of nerve fibre connections. These connections convey sensory information from the world outside, and from inside the body, they are the basis of storing memories and training, and ultimately deliver the messages by which the body is controlled and voluntary actions are carried out. When parts of this network are damaged the fibres are disconnected and functions are lost. The most obvious of these are stroke, spinal injury, and glaucoma. At present there is no way of restoring these connections, and the purpose of our research is to find a method to overcome the obstacles facing repair.
Damage to the spinal cord shows the typical features of these injuries. Below the level of damage the patient has no sensation, in unable to move voluntarily, and loses control of bowel, bladder and sexual functions. These symptoms are due to damage to the nerve fibres travelling up and down the spinal cord. What offers hope for these individuals is that the nerve fibres survive on either side of the injury, and produce sprouts which attempt to cross the injury. Our concept of repair is to re-build a bridge to enable these sprouting nerve fibres to regain their original destinations and restore lost functions.
Olfactory Ensheathing Cells (OECs)
The idea of placing a bridge across the area of damage indicates that we would have to transplant some living material into the region where the fibres have been severed. But where to get such material? It was discovered that the only part of the nervous system where nerve fibres can grow in the adult is the olfactory system – the nerve fibres passing from the nose through small apertures in the base of the skull and entering the brain. Using high power microscopy Professor Raisman discovered a unique type of cell – the olfactory ensheathing cell (OEC) which provides the pathway for these fibres. So the concept of our repair was to transplant OECs from the olfactory system, where they provide a pathway for nerve fibres to grow, into an area of damage in the spinal cord where damaged nerve fibres do not grow. The hope was that the transplanted OECs would form a bridge enabling the cut nerve fibres in the spinal cord to grow back.
Repair of Injuries to the Rat Spinal Cord
In our initial studies we examined the effect of damage to fibres travelling from the brain down to the spinal cord. Severing this tract led to a loss of function in the fore paw. Transplantation of OECs into this area of damage formed a bridge, along which the nerve fibres grew, and the new connections restored fore paw function. This forms the basis of all the research we are now undertaking. Since we could achieve this level of repair in rats, we are determined to take the steps needed to transfer this technology to human application. The ability to restore hand function in a patient with a disabled hand would be a significant contribution to relieving a major factor in the impairment of quality of life.
Brachial Plexus Avulsion
The numbers of cells we can obtain from the olfactory system are limited, and we do not yet have sufficient to bridge the extensive area of damage in spinal cord injury. We therefore chose to model a situation where a small number of cells, strategically placed, could be tested. This model is brachial plexus avulsion. It is usually a road traffic injury in which the nerves to the arm are pulled out of the spinal cord. The affected arm is totally disabled. Taking advantage of a surgical repair devised by Professor Carlstedt, one of our clinical colleagues at the National Hospital for Neurology and Neurosurgery, Queen Square, we have, with him, developed a rat model of this injury and showed that inserting a gel containing OECs allows the severed nerve fibres to grow back and restores the use of the fore paw.
Source of OECs
Much of our current effort is directed towards obtaining the human equivalent of the rat OECs. Once we are confident about these we can proceed to a trial with Professor Carlstedt in patients with brachial plexus avulsion. In the rat, OECs are obtained from adult tissue. They are thought to be derived from an adult stem cell in the nasal lining, although this is still hypothetical. We derive them from adult tissue samples. This raises the possibility that injured patients could provide tissue samples from which OECs can be derived and used as transplants to repair their brachial plexus, and later spinal cord injuries. This would avoid the immunological, ethical, and infection problems associated with using living tissue from another individual or a tissue bank.
The results so far indicate that injuries to the spinal cord and spinal roots can be repaired in rats. We believe this means it can be repaired in man. If we can learn how to obtain functional OECs from human tissue we will open the way to repair of the injury in patients now confined to wheel chairs.
The failure of severed axons to regenerate in the central nervous system leads to severe disability which is chronic and incurable. Our concept of repair is to re-build a bridge to enable the sprouts formed by the severed nerve fibres to regrow to their original destinations and restore lost functions. We call this the pathway hypothesis. Following the discovery of the unique ability of olfactory nerve fibres to grow in adult life, electron microscopy (Raisman, 1985) has revealed a unique type of cell – the olfactory ensheathing cell (OEC) which provides the pathway for the olfactory nerve fibres to enter the CNS. The concept behind our repair strategy is to use OECs cultured from tissue samples from either the olfactory bulb, or preferably the olfactory mucosa, to construct a pathway for regeneration in areas of the CNS where axotomised nerve fibres would otherwise not regenerate (Li et al., 1997).
Using this approach we have shown that transplantation of adult OECs induces structural and functional repair of specific lesions of the spinal cord (Li et al., 1998) and spinal roots (Ibrahim et al., 2009) in adult rats. The transfer of this procedure to clinical application would represent a historic advance. The project is ideally placed at the UCL Institute of Neurology, and our links with the adjoining National Hospital for Neurology and Neurosurgery provide the route for translating this work to clinical application.
Following our original demonstration of the reparative properties of transplanted OECs in a unilateral lesion of the corticospinal tract (CST), we are examining the use of OECs to repair dorsal and ventral root injuries such as occur in brachial plexus avulsion. Our current work addresses the critical issues which still need to be resolved to initiate a clinical trial of human OECs in brachial plexus repair.
To date in our rat experiments we have shown (1) OECs transplanted into re-apposed dorsal roots (with ventral roots intact) induce regeneration of afferent fibres and restore the proprioceptive functions needed for complex fore paw control (Ibrahim et al., 2009), (2) a preliminary experiment suggested that OECs transplanted into re-apposed ventral roots caused around a four-fold increase in numbers of regenerating fibres in the proximal root (Li et al., 2007).
Before a clinical trial can start we need to know: (1) to what extent does the dorsal root repair restore other sensory modalities, such as nociception? and would regeneration of sensory fibres alleviate the neuropathic pain which is a significant symptom in around 80% of patients with brachial plexus lesions? (2) does an increase in the number of ventral root fibres carry any functional benefit? (3) what are the optimal source, type and yield of OECs? and in particular, could the limitation in available cell numbers for autografts be overcome by using allografts (with or without permanent immuno-suppression)?
Fig. 1 An OEC (green, top panel) forming a bridge in a repaired C6 dorsal root, ensheathing a regenerating dorsal root axon (red, middle panel; superimposed in lowest panel) crossing between the severed spinal root and the spinal cord, where use of the fore paw is restored (Ibrahim et al., 2009).
In collaboration with Professor Carlstedt at the National Hospital for Neurology and Neurosurgery and Dr Peter Kirkwood in the Sobell Department of Motor Neuroscience and Movement Disorders at the Institute of Neurology we will set up a pilot study to determine the number of lumbo-sacral roots (between L4 and S3) which must be avulsed to produce permanent denervation of selected hind limb muscles. Based on this information we will carry out multiple re-implantations to determine electromyographically whether the degree of distal innervation is improved by adding OECs to the re-implantation sites.
The olfactory system is highly conserved between rat and human, both showing an olfactory mucosa with stem cells (Féron et al., 1998). As in the rat, the olfactory nerves arise from neurosensory cells in the mucosa, they are ensheathed by OECs, and pass through the cribriform plate to terminate in the glomerular layer of the olfactory bulbs. Based on these similarities we anticipate that OECs cultured from tissues samples from the human olfactory system will have a similar reparative effect when transplanted into human spinal cord or spinal root lesions (Bianco et al., 2004). A central plank of our current effort is directed towards obtaining the human equivalent of the rat OECs (Choi et al., 2008a;Choi et al., 2008b).
With a view to developing a procedure for obtaining adult OECs from the patient’s own olfactory mucosa we are studying the histology and culture of volunteer biopsies obtained with informed consent by (1) Mr Peter Andrews of the Royal Throat Nose and Ear Hospital, Gray's Inn Road under direct vision during routine operations involving an endonasal submucosal approach to the superior turbinate and nasal septum, and (2) Mr Michael Powell of the National Hospital for Neurology and Neurosurgery after endonasal dissection of the mucosa of the nasal septum during the approach for routine transsphenoidal surgeries.
Fig. 2 Cross sections of olfactory nerve bundles: rat on left, human on right. OECs green, nerve fibres, red.
Although the initial clinical application envisaged will be using autografts, only limited number of cells which can be obtained from a prospective patient who would also have to wait some weeks for the cells to be cultured. The ability to use allografted human material, with or without permanent immuno-suppression, represents an opportunity to build up a tissue or cell bank, and could also provide sufficient cells to undertake repair of much larger lesions of the spinal cord or brain.
- Professor Geoffrey Raisman MA, BM BCh, DM, DPhil, FRSA, FMedSci, FRS, Director
- Mr David Choi MA, MB ChB, FRCS(SN), PhD (also at the National Hospital for Neurology and Neurosurgery)
- Dr Ying Li, PhD
- Dr Daqing Li, MD, PhD
- Mr Stuart Law
- Mr Stefan Prieske
- Professor Tom Carlstedt MD, PhD (at the National Hospital for Neurology and Neurosurgery)
Information for Patients
The Spinal Repair Unit regrets that we have no facilities for answering individual enquiries.
The Unit is only a research laboratory. We are not a treatment facility and are in no position to offer individual medical advice about treatment, which must continue to be sought from the patient’s own medical advisor. But please rest assured that any findings arising from our research will be freely available throughout the medical profession.
Bianco JI, Perry C, Harkin DG, Mackay-Sim A, Féron F (2004) Neurotrophin 3 promotes purification and proliferation of olfactory ensheathing cells from human nose. Glia 45:111-123.
Choi D, Law S, Raisman G, Li D (2008a) Olfactory ensheathing cells in the nasal mucosa of the rat and human. Br J Neurosurg 22:301-302.
Choi D, Li D, Law S, Powell M, Raisman G (2008b) A prospective observational study of the yield of olfactory ensheathing cells cultured from biopsies of septal nasal mucosa. Neurosurgery 62:1140-1144.
Féron F, Perry C, McGrath JJ, Mackay-Sim A (1998) New techniques for biopsy and culture of human olfactory epithelial neurons. Arch Otolaryngol Head Neck Surg 124:861-866.
Ibrahim AG, Kirkwood PA, Raisman G, Li Y (2009) Restoration of hand function in a rat model of repair of brachial plexus injury. Brain 132:1268-1276.
Li Y, Field PM, Raisman G (1997) Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Sci 277:2000-2002.
Li Y, Field PM, Raisman G (1998) Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells. J Neurosci 18:10514-10524.
Li Y, Yamamoto M, Raisman G, Choi D, Carlstedt T (2007) An experimental model of ventral root repair showing the beneficial effect of transplanting olfactory ensheathing cells. Neurosurgery 60:734-740.
Raisman G (1985) Specialized neuroglial arrangement may explain the capacity of vomeronasal axons to reinnervate central neurons. Neurosci 14:237-254.