Brain, Vol. 125, No. 1, 2-3,
January 1, 2002
© 2002 Oxford University Press
Editorial |
Obtaining olfactory ensheathing cells from extra-cranial sources a step closer to clinical transplant-mediated repair of the CNS?
University of Cambridge, Cambridge, UK
The extraordinary regenerative properties of the peripheral olfactory system, and the role played by olfactory ensheathing cells (OEC), have been known for many years (Doucette, 1990
). However, until recently this niche of neurobiology remained relatively obscure, attracting the attention of an enthusiastic, but relatively small band of scientific devotees. The OEC’s sudden rise to prominence has happened because of the recent confluence of the OEC biology tributary with the mainstream of clinically orientated neurobiology, aiming to overcome the regenerative shortcomings of the CNS by cell transplantation. The concept of removing cells from an area that regenerates efficiently and relocating them in one that does not is not a new one, and transplantation of Schwann cells from the periferal nervous system, where regeneration occurs with tolerable efficiency, into the CNS has a long track record. Given the pro-regenerative properties of OECs one can reasonably ask why the OEC transplantation field has taken so long to get going? The answer lies in part in the inadequacies of transplanted Schwann cells; evident from the fact that Schwann cell transplantation is not in widespread clinical use despite occasional reports of success in rodent models. Hence the quest for alternative cells to transplant, and hence the current enthusiasm for OECs, which is based on several observations. Firstly, transplanted OECs support regeneration of long tract axons and functional recovery in models of spinal cord injury making them a strong candidate to help restore function following traumatic injury to the spinal cord (Li et al., 1997; Ramon-Cueto et al., 2000). Secondly, transplanted OECs will remyelinate persistently demyelinated axons and restore efficient conduction thereby making them a candidate transplant cell to repair foci of persistent demyelination in multiple sclerosis (Imaizumi et al., 1998). This repair repertoire is similar to that of Schwann cells, but whereas the latter’s value is limited by their unfavourable interactions with reactive or scarring astrocytes, there is some evidence both in vitro and in vivo that transplanted OECs are not similarly affected (Ramón-Cueto et al., 1998; Lakatos et al., 2000). A case can therefore be made that OECs are the preferable cell to transplant.
Results such as these trigger efforts to convert promising experimental data into effective clinical practice. This conversion involves a broad range of problems, many of which are difficult to overcome, and make the initial proof-of-principle experiments seem relatively straightforward by comparison. Nevertheless, attempts are under way. Recently it has been established that OECs can be cultured from the adult human nervous system, although much remains to be learnt about how best to obtain large numbers (Barnett et al., 2000). In the paper by Lu and colleagues that appears in this issue of Brain, together with an earlier study by the same group, the question of where one might mostly easily obtain OECs is addressed, another issue highly relevant to making the transition to clinical practice (Lu et al., 2001a; b). Unlike rats, who depend heavily on their sense of smell and so have a prominent and large olfactory bulb, the olfactory bulb in humans is comparatively small, and relatively inaccessible. This makes harvesting olfactory bulb derived OECs from a patient for autologous transplantation a less than attractive proposition. However, OECs are not confined to the olfactory bulb but ensheath the axons of the first cranial nerve along their entire length from their origin in the olfactory mucosa, through the cribriform plate and into the nerve fibre layer of the bulb. Lu and colleagues have identified the lamina propria that resides immediately beneath the olfactory epithelial layer of the mucosa as an accessible source of OEC, and have gone on to demonstrate that this OEC-containing tissue has regenerative properties similar to those of cultured OECs obtained from the bulb.
A further important and clinically relevant point established is that transplantation need not be made in the acute phase of injury, when a neurosurgeon might to reluctant to intervene in a situation that has yet to stabilise for fear of making the outcome worse, but rather can be delayed for several weeks without significantly reducing the procedures efficacy. Whether the effects described are entirely attributable to the OECs or whether they are contributed to by the connective tissue elements also transplanted is an important issue to resolve. Indeed, it may be preferable not to purify OECs since they may work optimally in concert with other cells or connective tissue elements. If this were the case then it would not be necessary to invest effort in overcoming the technical hurdles that purification would involve. On the other hand, the relative sizes of the olfactory mucosa and spinal cord in the rat are very different from those in the human, and so it is unlikely that the olfactory mucosa lamina propria alone will provide sufficient cells in humans without the need to expand their number ex vivo.
While clinically orientated studies such as these must and should be encouraged to continue, it is worth remembering that the OEC is still something of an unknown entity. The use of Schwann cells for transplant-mediated repair has been developed upon a substantial bedrock of information about their developmental and cell biology. By comparison, the gathering momentum to develop OEC-based therapies is occurring with a cell about which we know surprisingly little. From many perspectives, such as the antigenic markers it expresses and the manner in which it myelinates axons, the OEC is scarcely distinguishable from a Schwann cell, and yet it is generally held that it behaves differently following transplantation. What then is the true extent of the similarities and dissimilarities between the two cells? Can we be certain that OECs really are preferable to Schwann cells unless a direct comparison is made using the same numbers of cells, in the same experimental models and analysed by the same criteria? Is it even the case that we should choose one cell type over the other when perhaps both cells together will achieve better results? Fortunately, the increasing interest in this fascinating cell means that the answers to these and other questions are likely to emerge sooner rather than later.
References
Barnett SC, Alexander CL, Iwashita Y, Gilson JM, Crowther J, Clark L, et al. Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain 2000; 123: 1581–8.
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Imaizumi T, Lankford KL, Waxman SG, Greer CA, Kocsis JD. Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. J Neurosci 1998; 18: 6176–85.
Lakatos A, Franklin RJ, Barnett SC. Olfactory ensheathing cells and Schwann cells differ in their in vitro interactions with astrocytes. Glia 2000; 32: 214–25.[Web of Science][Medline]
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Lu J, Feron F, Mackay-Sim A, Waite PME. Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord. Brain 2001b. 125: 000–000.
Ramón-Cueto A, Plant, GW, Avila J, Bunge MB. Long distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J Neurosci 1998; 18: 3802–15.
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