Raisman group ::

Repair of Spinal Cord Injury by Autotransplantation of Adult Olfactory Mucosal Ensheathing Glia: Translation from Rat to Clinical Trials

In 1985 Dr Raisman described a unique arrangement of specialised olfactory ensheathing glial cells that accompany the olfactory nerve fibres all the way to their entry into the brain. The subsequent development of a tissue culture method for obtaining olfactory ensheathing cells from adult olfactory tissue samples has enabled experiments in which such cultured cells could be transplanted into rat spinal cord lesions and their structural and functional reparative effects observed.

As a result, olfactory ensheathing cells have become one of the most promising routes for repair. They have the advantage that they may be obtained from adult patients, who can thus build up a bank of their own cells for autografting into areas of damage in the spinal cord, and in this way avoid the problems of using embryonic tissue, and the dangers of crossing an immune barrier.

The Raisman team have transplanted cultured olfactory ensheathing cells into complete unilateral lesions of the upper cervical corticospinal tract in adult rats (Li et al., 1998). They found that the grafted cells encourage the growth of the cut nerve fibres, and suppress the excessive neuromatous branching found in untreated lesions. The grafted cells take up an elongated shape, and form a tightly aligned bridge between the ends of the cut fibre tract. The regenerating nerve fibres enter the graft and follow this new, aligned bridge pathway. Within the bridge the nerve fibres are intimately ensheathed by the Schwann-like cells, and enclosed in an outer, perineurial-like sheath of fibroblasts. But, most important, once they reach the end of the graft they re-enter the host spinal cord, and continue along the distal part of the corticospinal tract to form terminal arborisation in their normal target areas. During their course through the transplant the fibres are myelinated by peripheral myelin formed by the Schwann-like cells, and when they re-enter the spinal cord, they are myelinated by host oligodendrocytes. The effect is to put a patch over the lesion, restoring the integrity of the original pathway, and results in the functional recovery of a learned forepaw retrieval task.

This repair can be achieved by transplanting at 2 months after the time of injury in rats at which time the original wound is fully scarred over by astrocytic processes.

To study the repair of a larger lesion, the team carried out a second series of investigations (Li et al., 2003) with complete hemisection of one half of the spinal cord at the upper cervical level. A specific matrix transfer method was devised (and patented) to achieve the efficient transfer of cells and their retention in these much larger, open cavities. These lesions result in a deficit in the placing of the ipsilateral forepaw during a climbing test, and the disappearance of the supraspinal respiratory rhythm in the ipsilateral phrenic nerve and hemidiaphragm. Both these functions can be restored after transplantation of cultured olfactory ensheathing cells.

In experiments on the repair of avulsed dorsal roots in collaboration with Tom Carlstedt, Royal National Orthopaedic Hospital Trust, Stanmore, the team has shown that the matrix transfer method of transplanting olfactory ensheathing cells causes major regeneration of severed dorsal root axons into the spinal cord where they both form terminal fields in the dorsal horn and also long regenerating axons ascend in the dorsal columns.

In experiments with the severed optic nerve the team has shown that transplanted olfactory ensheathing cells induce regeneration of cut adult retinal ganglion cell axons.

Clinical Translation

For clinical translation, the team need:

1. to model, in the rat, a contusion lesion (Figure 1 below) of the type seen in human spinal cord injury
2. to find how to obtain sufficient numbers of reparative cells from human nasal mucosal biopsies (Figure 2 below)
3. to devise a method of surgical implantation (e.g. via endoscopic intubation using cells in a matrix gel), which will not increase the damage, but will enable the limited numbers of cells the team can hope to obtain to form a continuous anatomical bridge
4. to satisfy the ethical and regulatory procedures needed for a limited clinical trial
   

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