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Geoffrey Raisman

Publications and source records attributed to Geoffrey Raisman.

At least 19 recordsLinked to original sources
PubMed2007

Regeneration of nigrostriatal dopaminergic axons by degradation of chondroitin sulfate is accompanied by elimination of the fibrotic scar and glia limitans in the lesion site.

Chondroitin sulfate increases around a lesion site after central nervous system injury and is believed to be an impediment to axonal regeneration, because administration of chondroitinase ABC, a chondroitin sulfate-degrading enzyme, promotes axonal regeneration of central neurons. To examine the physiological role of chondroitin sulfate up-regulation after injury, the nigrostriatal dopaminergic axons were unilaterally transected in mice, and chondroitinase ABC was then injected into the lesion site. In mice transected only, tyrosine hydroxylase-immunoreactive axons did not extend across the lesion at 1 or 2 weeks after the transection. Immunoreactivities of chondroitin sulfate side chains and core protein of NG2 proteoglycan increased in and around the lesion site, and a fibrotic scar containing type IV collagen deposits developed in the lesion center. In contrast, in mice transected and treated with chondroitinase ABC, numerous tyrosine hydroxylase-immunoreactive axons were regenerated across the lesion at 1 and 2 weeks after the transection. In these animals, chondroitin sulfate immunoreactivity remarkably decreased, and immunoreactivity of 2B6 antibody, which recognizes the stub of degraded chondroitin sulfate side chains, was enhanced. Furthermore, the formation of a fibrotic scar and a glia limitans that surrounds the former was completely prevented, although type IV collagen immunoreactivity remained in newly formed blood capillaries around the lesion site. We discuss the question of whether the chondroitin sulfate is acting as a direct inhibitor of axonal regeneration or whether the observed changes are due to a prevention of the fibrotic scar formation and a rearrangement of astrocytic membranes.

Animals↗
PubMed2007

Transplanted Schwann cells, not olfactory ensheathing cells, myelinate optic nerve fibres.

In a previous study we found that olfactory ensheathing cells transplanted into complete retrobulbar transections of the rat optic nerve mediated regeneration of severed retinal ganglion cell axons through the graft region. Although the regenerating axons were ensheathed by the transplanted cells, none of the regenerating axons became myelinated by either central or peripheral type myelin. In the present study we used the same operative procedure but transplanted Schwann cells instead of olfactory ensheathing cells. As with the olfactory ensheathing cell transplants the Schwann cells transplants also induced regeneration of the severed retinal ganglion cell axons into the graft region. In contrast to the situation with the olfactory ensheathing cell transplants, however, a considerable number of the regenerating axons became myelinated by peripheral type myelin produced by the transplanted Schwann cells. This observation identifies a further distinction between these two cell types which are phenotypically similar in many ways, but which have been shown to have major functional differences with regard to regeneration in spinal cord lesions.

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PubMed2006

Interaction of olfactory ensheathing cells with astrocytes may be the key to repair of tract injuries in the spinal cord: the 'pathway hypothesis'.

Transplantation of cultured adult olfactory ensheathing cells has been shown to induce anatomical and functional repair of lesions of the adult rat spinal cord and spinal roots. Histological analysis of olfactory ensheathing cells, both in their normal location in the olfactory nerves and also after transplantation into spinal cord lesions, shows that they provide channels for the growth of regenerating nerve fibres. These channels have an outer, basal lamina-lined surface apposed by fibroblasts, and an inner, naked surface in contact with the nerve fibres. A crucial property of olfactory ensheathing cells, in which they differ from Schwann cells, is their superior ability to interact with astrocytes. When confronted with olfactory ensheathing cells the superficial astrocytic processes, which form the glial scar after lesions, change their configuration so that their outer pial surfaces are reflected in continuity with the outer surfaces of the olfactory ensheathing cells. The effect is to open a door into the central nervous system. We propose that this formation of a bridging pathway may be the crucial event by which transplanted olfactory ensheathing cells allow the innate growth capacity of severed adult axons to be translated into regeneration across a lesion so that functionally valuable connections can be established.

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PubMed2006

Olfactory ensheathing cells: ripples of an incoming tide?

Until now, brain and spinal cord injuries that sever nerve fibres have resulted in a degree of incurable functional loss. An incoming tide of research is now beginning to challenge this as yet unbreached sea wall. One of the most promising approaches involves a recently discovered type of cell, the olfactory ensheathing cell, which can be obtained from the adult nasal lining. In animal models transplantation of cultured olfactory ensheathing cells into an injured spinal cord induces regeneration, remyelination of severed spinal nerve fibres, and functional recovery. Although several clinical centres worldwide have shown an interest in applying this approach to patients with spinal cord injury, there is no agreement on cell technology, and claims of beneficial results lack independent confirmation. Important aspects still need to be worked out at the laboratory level. Overall, the outlook is optimistic, but there is still some way to go.

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PubMed2005

Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres.

The ensheathing cells of the olfactory nerves are arranged end-to-end to form a continuous channel enclosing the olfactory axons from their origin in the olfactory mucosa to their termination in the olfactory bulb. On their outer surface, the olfactory ensheathing cell channels have a basal lamina and an outer encirclement of olfactory nerve fibroblasts. We present an anatomical model of the ensheathing arrangements for the entire transit of the olfactory axons from the horizontal basal cells of the mucosa through the nerves to the superficial astrocytes of the bulb. We used intracranial section of the olfactory nerves to induce a rapid retrograde loss of olfactory neurons and degeneration of their axons, followed by replacement of the neurons from stem cells in the mucosa and growth of the newly formed axons along the olfactory nerves. The olfactory ensheathing cells survive and play a vital role in this process. Unlike Schwann cells in damaged peripheral nerve, the olfactory ensheathing cells neither divide nor migrate. They are actively phagocytic for removal of the degenerating axons, and provide continuous stable open channels along which adventitious cells such as erythrocytes and macrophages can travel, and along which the newly formed axons can regenerate. We suggest that the persistence of these open channels is an important element in the effectiveness of the regeneration. These properties, which the olfactory ensheathing cells exert in collaboration with olfactory nerve fibroblasts, may also be involved in the reparative effects of these cells when transplanted into lesions of the spinal cord.

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PubMed2005

Inhibition of collagen synthesis overrides the age-related failure of regeneration of nigrostriatal dopaminergic axons.

To investigate the mechanism of the age-related failure of regeneration of transected axons, nigrostriatal dopaminergic axons were unilaterally transected in the lateral hypothalamus in adult mice and in immature mice aged postnatal days 7, 14, and 21. Ten days after the transection, tyrosine hydroxylase-immunoreactive axons had regenerated from caudally to rostrally across the lesion site in mice transected at postnatal day 7, whereas they stopped and did not extend across the lesion site in mice transected at postnatal day 14 or older. Reactive astrocytes bearing chondroitin sulfate proteoglycans were observed around the lesion in mice transected at all ages. However, a fibrotic scar containing type IV collagen-immunoreactive deposits, which was consistently formed at the lesion site in mice transected at postnatal day 14 or older, was not formed in mice lesioned at postnatal day 7. When 2,2'-dipyridyl, an inhibitor of collagen synthesis, was injected into the lesion site at the time of transection in both postnatal day 14 and adult mice, the deposition of type IV collagen and the formation of a fibrotic scar were completely prevented, and large numbers of tyrosine hydroxylase-immunoreactive axons extended across the lesion and reinnervated the striatum. These results imply that the fibrotic scar formed in the lesion site is a crucial impediment to the regeneration of ascending dopaminergic axons in adult mice and suggest that type IV collagen is required for the development of the fibrotic response to adult brain injury.

2,2'-Dipyridyl↗
PubMed2005

Delayed repair of corticospinal tract lesions as an assay for the effectiveness of transplantation of Schwann cells.

We have previously shown that cultured adult olfactory ensheathing cells injected after 8 weeks into functionally complete unilateral lesions of the rat corticospinal tract induce restoration of paw reaching function to about 50% of normal, starting at around 10 days after transplantation. This provides an assay for determining the effectiveness of different methods of cell preparation or different cell types. We report that transplantation of cultured adult peripheral nerve Schwann cells also restores function, but the effect is delayed until around 30 days after transplantation and reaches only around 5-10% of normal. The presence of fibroblasts in the Schwann cell cultures neither improves, nor impairs the reparative effect, but fibroblasts alone (without Schwann cells) have no reparative effect. Without transplantation of exogenous Schwann cells, the ingrowth of endogenous Schwann cells which occurs spontaneously into these lesions does not restore function.

Animals↗
PubMed2005

Disorganization of the facial nucleus after nerve lesioning and regeneration in the rat: effects of transplanting candidate reparative cells to the site of injury.

OBJECTIVE: After the facial nerve has been damaged, functional recovery is impaired by synkinesis: the abnormal movement of part of the face during voluntary movement of another part. This is primarily because of aberrant regenerating axons that fail to reach the correct distal targets. We studied the effects of transplanting Schwann cells, mixed olfactory ensheathing cells, and S-type olfactory ensheathing cells on the histological and functional organization of the connections between the facial nucleus and distal muscles. METHODS: In a control group of adult rats (n = 18), the proximal part of the extracranial facial nerve was completely severed and immediately repaired by suture. In an experimental group (n = 34), a bolus of cultured cells was applied to the cut ends before suture (Schwann cells, n = 10; olfactory ensheathing cells, n = 18; S-type cells, n = 6). A period of regeneration was permitted, after which the animals were assessed functionally by measurement of eye closure in response to a puff of air. The site of lesion and the somatotopic organization of the facial nucleus were assessed histologically, after application of different retrograde fluorescent tracers simultaneously to the buccal and temporal divisions of the facial nerve. RESULTS: The rate of recovery of eye closure was increased by the use of the cell transplants, but the disorganization of the facial nucleus and aberrant nerve branching were unchanged. CONCLUSION: Perhaps regenerating axons become misguided throughout the whole length of the nerve, not only at the site of the lesion, and strategies aimed at improving axon path-finding solely at the lesion site will therefore be inadequate.

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PubMed2004

Ensheathing cell cultures from the olfactory bulb and mucosa.

Transplantation of cells cultured from the nerve layers of the adult rat olfactory bulb has been shown to repair CNS tract injuries. The precise cellular composition of the culture appears to be important for this effect. Comparison was made of tissue cultured from the adult rat olfactory mucosa with that from the olfactory bulb. Both yielded mixtures of p75 immunoreactive cells and fibronectin immunoreactive cells. In sequential observations over 21 days in culture, the population of p75-expressing cells was maintained and continued to proliferate for longer in the samples from the olfactory mucosa. For derivation of cells for transplantation, the mucosa can be accessed without the need for intracranial surgery.

Animals↗
PubMed2004

Interaction of transplanted olfactory-ensheathing cells and host astrocytic processes provides a bridge for axons to regenerate across the dorsal root entry zone.

A single fourth lumbar dorsal rootlet was transected at the entry point into the spinal cord. The nerve fibres were labelled with biotin dextran injected into the rootlet. An endogenous matrix containing olfactory-ensheathing cells (OECs) labelled with green fluorescent protein was applied to the opposing cut surfaces of the rootlet and the spinal cord, which were then brought into apposition and held in place by fibrin glue. Two weeks later, a ladderlike bridging structure has been formed by astrocytic processes growing out for about 200-300 microm from the spinal cord. The transplanted cells remained largely confined to this area. They were elongated along the nerve axis but did not enter the spinal cord itself. Labelled dorsal root axons crossed the repaired dorsal root entry zone in alignment with the bridging astrocytic processes and the transplanted cells and then proceeded beyond the transplant to enter the grey matter of the dorsal horn and send axons both rostrally and caudally for at least 10 mm in the white matter of the ascending dorsal columns.

Animals↗
PubMed2004

Olfactory ensheathing cells and repair of brain and spinal cord injuries.

Cells generated in cultures of primary tissue from the olfactory nerves can be transplanted into areas of spinal cord damage where they induce growth of severed nerve fibers and return of lost functions. These cells are of two types, both essential for the reparative effect. The precise lineage relationships are not fully understood. The limitation of numbers of cells obtainable from human samples currently restricts their use to repair of small lesions.

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PubMed2003

Functional repair of the corticospinal tract by delayed transplantation of olfactory ensheathing cells in adult rats.

Adult rats were trained to use their forepaws to retrieve a piece of food. Destruction of the dorsal corticospinal tract on one side at the level of the first cervical segment abolished the use of the ipsilateral forepaw for retrieval for at least 6 months after operation. Where a variable amount of the corticospinal tract was spared, there was a proportionate persistence of retrieval. In lesioned rats that had shown no retrieval for 8 weeks after operation, a suspension of olfactory ensheathing cells was injected into the lesion site. Starting between 1 and 3 weeks after transplantation, all rats with transplants bridging the lesion site resumed retrieval by the ipsilateral forepaw. Biotin dextran anterograde tracing shows regenerating corticospinal axons crossing the bridge, traveling caudally for approximately 10 mm in the distal part of the corticospinal tract and forming terminal arborizations in the spinal gray matter. Functional recovery can occur when only approximately 1% of the corticospinal tract axons are present.

Animals↗
PubMed2003

Transplanted olfactory ensheathing cells promote regeneration of cut adult rat optic nerve axons.

Transplantation of olfactory ensheathing cells into spinal cord lesions promotes regeneration of cut axons into terminal fields and functional recovery. This repair involves the formation of a peripheral nerve-like bridge in which perineurial-like fibroblasts are organized into a longitudinal stack of parallel tubular channels, some of which contain regenerating axons enwrapped by Schwann-like olfactory ensheathing cells. The present study examines whether cut retinal ganglion cell axons will also respond to these cells, and if so, whether they form the same type of arrangement. In adult rats, the optic nerve was completely severed behind the optic disc, and a matrix containing cultured olfactory ensheathing cells was inserted between the proximal and distal stumps. After 6 months, the transplanted cells had migrated for up to 10 mm into the distal stump. Anterograde labeling with cholera toxin B showed that cut retinal ganglion cell axons had regenerated through the transplants, entered the distal stump, and elongated for 10 mm together with the transplanted cells. Electron microscopy showed that a peripheral nerve-like tissue had been formed, similar to that seen in the spinal cord transplants. However, in contrast to the spinal cord, the axons did not reach the terminal fields, but terminated in large vesicle-filled expansions beyond which the distal optic nerve stump was reduced to a densely interwoven mass of astrocytic processes.

Animals↗
PubMed2003

Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing.

One of the most devastating effects of damage to the upper spinal cord is the loss of the ability to breathe; patients suffering these injuries can be kept alive only with assisted ventilation. No known method for repairing these injuries exists. We report here the return of supraspinal control of breathing and major improvements in climbing after the application of a novel endogenous matrix transfer method. This method permits efficient transfer and retention of cultured adult rat olfactory ensheathing cells when transplanted into large lesions that destroy all tracts on one side at the upper cervical level of the adult rat spinal cord. This demonstrates that transplantation can produce simultaneous repair of two independent spinal functions.

Animals↗
PubMed2002

Somatotopic organization of the facial nucleus is disrupted after lesioning and regeneration of the facial nerve: the histological representation of synkinesis.

OBJECTIVE: After facial nerve repair, involuntary movement of part of the face during voluntary movement of another part of the face is common. We describe an animal model of facial nerve lesion, repair, and regeneration that demonstrates abnormal organization of the facial nucleus; this model may be used to study synkinesis. METHODS: In 18 rats, the facial nerve was cut completely, proximal to the parotid gland, and immediately sutured end-to-end. After a period of regeneration of 1 to 10 months, retrograde fluorescence labeling of the distal branches of the facial nerve was performed. The distribution of the tracers in the facial nucleus was assessed in both the lesioned animals and in a nonlesioned group (n = 20). RESULTS: In the control animals, muscle groups were somatotopically represented in the facial nucleus. After lesioning, repair, and regeneration, the somatotopy of the facial nucleus was disrupted. Axons projected from the facial nucleus to incorrect peripheral muscle groups, and aberrant branches were observed to simultaneously innervate different subdivisions of the facial nerve. The numbers of aberrant axons and branches did not change significantly during periods of regeneration ranging from 1 to 10 months. CONCLUSION: Our model provides a clear demonstration of the failure of adult facial nerve axons to make correct connections with their distal targets during regeneration. This model may be used to assess strategies aimed at minimizing synkinesis and, by assessing histology together with behavior, provides a more robust model than those previously described.

Animals↗
PubMed1992

Monoclonal Antibodies to Late-differentiating Epitopes Identify Mossy Fibre Terminals Innervating Normal and Transplanted Hippocampal CA3 Pyramidal Cells.

We have derived two monoclonal antibodies, MF-1 and MF-2, which both recognize the same 58-kD antigen. Light and electron microscopic immunocytochemistry showed that this antigen is highly expressed in the large mossy fibre terminals innervating the proximal portion of the apical dendrites of pyramidal neurons in hippocampal field CA3. Staining was seen in the adult hippocampus in rats and mice, and in a post mortem human sample. Comparison with the Timm stain showed that the antibodies recognize mossy fibres from all parts of the adult dendate gyrus except for the tip of the infrapyramidal blade (the latest part of the dentate gyrus to develop). The MF antigen is expressed by mature terminals, and is not detected immunohistochemically in developing hippocampal mossy terminals until the end of the first postnatal week (i.e. later than the Timm-positive material). It was also found in host mossy fibre terminals innervating embryonic CA3 pyramids transplanted into adult hosts, but not in areas of the graft containing transplanted CA1 pyramids. These results indicate that this previously undescribed, late-developing antigen provides a useful specific marker for the mossy fibre projection in both the normal hippocampus and in situations of experimentally manipulated connectivity.

Journal Article↗