REVIEW
Olfactory ensheathing cells and spinal cord repair
Alan Mackay-Sim
Institute for Cell and Molecular Therapies, Grifﬁth University, Brisbane, Qld, Australia(Received for publication on August 18, 2004)

Abstract. The olfactory ensheathing cell is a specialized glial cell that assists in growth of the axons of
the olfactory sensory neurons as they are generated and regenerated throughout adult life. There isincreasing evidence in animal models that transplantation of olfactory ensheathing cell promotes
recovery after transplantation into the injured spinal cord. Olfactory ensheathing cell transplants havepromoted regrowth of axons across the injury site and led to recovery of functional behaviours
including climbing, walking, reaching, and breathing. Most evidence comes from olfactory ensheathingcells derived from the olfactory bulb. This is an impractical site for human biopsy compared to the easy
accessibility of olfactory ensheathing cells from the olfactory mucosa in the nose. Our experiments
demonstrated that nasal olfactory ensheathing cells led to functional improvement after complete spinal cord transaction in rat. After devising methods to grow human olfactory ensheathing cells fromnasal biopsy we recently initiated a Phase I clinical trial of transplantation into the human paraplegic
spinal cord. (Keio J Med 54 (1): 8–14, March 2005)
Key words: spinal cord injury, cell therapy, paraplegia, glia

In the 7 years since 1997 there have been 50 papers
published describing olfactory enheathing cell transplantation, 51 describing the biology of olfactoryensheathing cells and 31 review articles featuring olfactory ensheathing cells, mostly in reference to nervous
system repair. Clearly olfactory ensheathing cells havearoused the interest of the scientiﬁc community, especially those interested in repair of the spinal cord. Table
1 summarises the studies of olfactory ensheathing cells
in spinal cord repair. What are olfactory ensheathingcells? What makes them of interest in spinal cord repair?
What can they do to repair the injured spinal cord?
The olfactory ensheathing cell is a specialized glial
cell that associates with the olfactory nerve, surrounding the sensory axons as they leave the olfactory epithelium and accompanying them from the nose to thebrain where they synapse with the mitral cells of theolfactory bulb.9 The olfactory ensheathing cell has
properties of both Schwann cells and astrocytes, with aphenotype closer to the Schwann cell.10 There are two
properties of the olfactory ensheathing cell that make it
unique. The ﬁrst is that it exists both outside the central
nervous system (like Schwann cells) and inside thecentral nervous system (like astrocytes). The second

Introduction
The adult olfactory epithelium is a site of continuing
neurogenesis throughout life.1 Replacement of olfactory sensory neurons is a highly regulated via multiple
growth factor pathways.2 The stem cell source of new
sensory neurons is unknown but thought to be one of
the basal cells of the olfactory epithelium.3,4 This regenerative capacity of the olfactory epithelium provides
the context in which operate the specialized glia of theolfactory nerve, the olfactory ensheathing cells.
It is 20 years since the ﬁrst paper was published on
the biology of olfactory ensheathing cells.5 In the following 10 years there were 13 research papers on the
biology of olfactory ensheathing cells and 3 reviews. In
1994 Ramon Cueto and Nieto-Sampedro6 published theﬁrst paper demonstrating that olfactory ensheathingcells assisted sensory axons to regrow into the spinal
cord after dorsal rhizotomy. This was followed by apaper from Doucette’s lab describing the survival ofolfactory ensheathing cells after transplantation into thebrain7 and a paper from Raisman’s group demonstrating functional recovery from corticospinal tract lesions
after transplantation of olfactory ensheathing cells.8

Presented at the 1357th Meeting of the Keio Medical Society in Tokyo, July 1, 2004
Reprint request to: Alan Mackay-Sim, PhD, Professor, School of Biomolecular and Biomedical Science, Deputy Director, Institute for Cell andMolecular Therapies, Grifﬁth University, Brisbane, Qld 4111, Australia, email: A.Mackay-Sim@grifﬁth.edu.au8Keio J Med 2005; 54 (1): 8–14
Table 19Transplantation of Olfactory Ensheathing Cells into Injured Spinal Cord

Transplant model (see Notes)
Lesioned corticospinal tract
Lesioned corticospinal tract
Demyelinated spinal cord
Demyelinated spinal cord
Demyelinated spinal cord, primate
Demyelinated spinal cord
Demyelinated spinal cord, cryopreserved cells
Photochemical lesion of spinal cord
Photochemical lesion of spinal cord
Transected spinal cord
Transected spinal cord, pig OEC
Transected spinal cord, nasal OECs
Transected spinal cord, delayed transplantation, nasal OECs
Transected spinal cord
Transected spinal cord
Transected spinal cord, OECs genetically engineered to produce GDNF
Transected spinal cord, cryopreserved cells
Hemisection of spinal cord
Hemisection of spinal cord, delayed transplantation
Hemisectioned spinal cord
Hemisectioned spinal cord, nasal OECs
Dorsal hemisection of spinal cord, OECs geneticallyengineered to produce BDNF
Spinal cord injury, OEC cell line
Contused spinal cord
Contused spinal cord
Contused spinal cord

Outcome

Reference

Regeneration, recovery of function
Regeneration
Remyelination
Remyelination
Remyelination
Remyelination
Remyelination
Axon regeneration/sparing, recovery of function
Regeneration, recovery of function
Regeneration, recovery of function
Axon regrowth
Regeneration, recovery of function
Regeneration, recovery of function
Axon conduction
Regeneration, recovery of function
Axon regeneration, recovery of function
Regeneration, recovery of function
Regeneration, recovery of function
Regeneration, recovery of function
Regeneration, recovery of function
Scar and cavity reduction
Regeneration, recovery of function

8
18
19
20
21
51
53
57
58
13
22
24
25
50
52
48
59
14
15
17
28
47

Regeneration, recovery of function
No regeneration at 6 weeks
Axon regeneration/sparing
Axon regeneration/sparing

55
29
54
56

1. All experiments done on rodent models except where noted ‘‘primate’’. 2. All transplantations were done at time of spinal cord injury except
where noted ‘‘delayed transplantation’’. 3. All olfactory ensheathing cells were derived from olfactory bulb except where noted ‘‘nasal OECs’’.
4. ‘‘Pig OECs’’ indicates OECs from olfactory bulb of genetically engineered pig. 5. ‘‘OECs genetically engineered’’ indicate olfactory bulb cells
engineered to produce BDNF or GDNF, where noted. 6. ‘‘Cryo-preserved cells’’ indicates OECs that were grown in vitro, frozen, thawed andthen transplanted.

special property arises from the fact that there is acontinual neurogenesis within the olfactory epitheliumthat produces new sensory neurons throughout adultlife, including human.11 This neurogenesis is a highly
regulated process in which olfactory ensheathing cells
assist, although the speciﬁc mechanisms of that assistance remain undescribed. The olfactory ensheathingcell is therefore ‘‘Schwann cell-like’’ in assisting axon
growth, but ‘‘astrocyte-like’’ in being able to live within
the central nervous system. It was this combination ofproperties that made it a candidate for nervous system
repair.6–8,12 It remains a strong candidate with the vast
majority of the 53 published transplant studies reporting positive outcomes.
Olfactory ensheathing cells have been used in a variety of spinal cord repair models including complete
transection, hemisection, tract lesion, contusion, anddemyelination. They have also been transplanted inother nerve repair models including dorsal rhizotomy(Table 2), peripheral nerve transection, and optic nerve
repair (Table 3).

Table 2 Transplantation of Olfactory Ensheathing Cells after Dorsal
Rhizotomy
Level of rhizotomy

Sensory axon regeneration?

Reference

Lower thoracic
L3-L6
L6-L2
C3-T3
L4
cervical and lumbar
cervical and lumbar

Yes
Yes
Yes
No
Yes
No
No

6
60
16
61
62
63
64

The most exciting results of transplantation of olfactory ensheathing cells into the injured spinal cord has
been the functional recovery of paw preference, after
corticospinal tract lesions,8 the recovery of coordinatedwalking after complete spinal cord transection13 andrecovery of paw use and climbing after spinal cordhemisection.14,15 These and other reports illustrate thelong sought for goal of stimulating recovery of locomo-10

Mackay-Sim A: Olfactory ensheathing cells and spinal cord repair

Table 3 Transplantation of Olfactory Ensheathing Cells into Brain
and Peripheral Nerves

Repair of the Spinal Cord with Olfactory Ensheathing
Cells from the Nose

Transplant modelWithin the olfactory mucosa, the olfactory ensheathing cells lie in the lamina propria, beneath the olfactory
epithelium, and towards the caudal part of the nasal
cavity the lamina propria is dominated by the presenceof the olfactory nerve bundles as they course posteriorly and dorsally to enter the skull at the cribriform
plate. In an initial series of experiments we transplanted
pieces of olfactory lamina propria into the gap formed
when the spinal cord was sectioned at the mid-thoracic
level in the rat.24 The control animals received pieces
of respiratory lamina propria, a tissue containing manyof the same non-olfactory cell types such as ﬁbroblasts,
endothelium, and peripheral nerve Schwann cells. Ten
weeks later the animal receiving olfactory lamina propria showed movement of the hind limbs, behaviour thatwas dependent on intact descending spinal cord tracts.
These transplants also improved reﬂex inhibition of
spinal motor circuits, which suggests that descending
pathways have regenerated. Cells from the transplants
migrated into the spinal cord, both rostrally and caudally, and axons could be seen within the transplants.
Retrograde tracing demonstrated that axons frombrainstem serotonergic nuclei had penetrated the lesion
and grown into the spinal cord caudal to the lesion andtransplant. Immunochemistry veriﬁed the presence ofserotonergic ﬁbres caudal to the transplant. None ofthese changes were seen after transplants of respiratory
lamina propria although similar recovery was seen after
transplantation of dissociated olfactory ensheathingcells that were grown in vitro from the adult lamina
propria.24 These experiments demonstrated that adultolfactory ensheathing cells could assist recovery whentransplanted at the time of the spinal cord injury.
Our next experiments addressed the question ofwhether olfactory tissue transplants could assist recovery if transplantation was delayed. It was expectedthat any human trial of these cells would be delayed
until after the acute phase when the patient’s condition
had stabilized. The olfactory lamina propria was transplanted into the region of the lesion four weeks after
complete spinal cord transection of the spinal cord in
the rat.25 Ten weeks later, animals receiving olfactorylamina propria transplants were able to move theirhindlimbs and they showed histological evidence for
regrowth of brainstem serotonergic neurons across thesite of lesion and transplantation. This was notobserved in animals receiving transplants of respiratory
lamina propria.25
These experiments established the feasibility of using
nasal olfactory ensheathing cells for spinal cord repair.26 Recently they were shown to inhibit cavity andscar formation when transplanted into the injured spi-

Fimbria-fornix transection
Fimbria-fornix transection
Abducens tract lesion
Optic nerve transection
Optic nerve transaction
Parkinsonian rat,
co-transplantation withdopaminerigic neurons

Outcome

Reference

Regrowth of axons
across lesion
Regrowth of axons
across lesion
No regeneration of tract
Regrowth of axons
Regrowth of axons
Regeneration,functional recovery

7
65
66
67
33
68

tion in human paraplegics and quadriplegics (Table 1).
Despite the excitement generated by these ﬁndings it
should not be forgotten that advances in aspects otherthan locomotion would also improve the management
and quality of life of these persons. For example, bowel
and bladder control remain among the most sought
after improvements and recent results indicate that olfactory ensheathing cell transplants can assist recoveryof bladder function.16 Similarly, olfactory ensheathingcells show promise in assisting repair of descending
pathways regulating phrenic nerve activity,14,17 a result
which, if repeated in human has the potential to takemany quadriplegics off assisted respiration. Olfactoryensheathing cells do not normally myelinate the olfactory nerve but when transplanted into the spinal cord
they appear to myelinate the regrowing axons in theregion of injury after corticospinal tract lesions18
and they remyelinate axons in several demyelinating
models.12,19–21
Olfactory ensheathing cells are present in the olfactory bulb, the region of termination of the olfactory
sensory axons within the central nervous system. Initialtransplantation studies used these cells isolated fromthe newborn olfactory bulb.6,8,18,19 For human therapy,
the olfactory bulb was initially suggested as a potential
source for these cells, either from cadavers or frompersons having skull-base surgery or from pigs.21,22
These sources are unlikely to gain wide acceptance forhuman therapy because of ethical concerns, as well as
the immunological and other technical issues to overcome. In any case these non-autologous sources are notnecessary because olfactory ensheathing cells are theoretically available within the olfactory mucosa, anaccessible site for biopsy in all individuals.23 Several
years ago we set out to determine whether olfactoryensheathing cells from the adult nose would assist recovery from spinal cord injury in the same way that
olfactory ensheathing cells from the newborn olfactorybulb. If so this would make feasible a human clinical
trial.

Keio J Med 2005; 54 (1): 8–14

nal cord,27 and to promote angiogenesis and extensive
sprouting of sensory and motor axons into and throughthe lesion site.28 As previously, they also promoted
regrowth of brainstem serotonergic axons through thelesion site as well as regrowth of brainstem tyrosinehydroxylase-positive axons.28 Olfactory ensheathingcells from the adult olfactory bulb were not successfulwhen transplanted into the contused spinal cord.29
The mechanisms by which olfactory ensheathingcells permit or promote recovery after spinal cord injury are not known. This provides the stimulus for many
investigations into the biology of olfactory ensheathingcells and into their interactions within the spinal cord
after transplantation. The growth factors secreted byolfactory ensheathing cells are also being investigated.2
In vitro olfactory ensheathing cells provide both soluble and contact signals to promote sprouting of neurites.30–34 Similarly, experiments indicate that bothsoluble and contact signals are important for inducing
axonal sprouting within the spinal cord. When transplanted into the spinal cord in porous capsules olfactoryensheathing cells stimulated axonal sprouting of corticospinal tract axons, although not to the same extent as
olfactory ensheathing cells injected directly into thespinal cord.35
The interaction of olfactory ensheathing cells withother glial cells seems to contribute to their efﬁcacy inthe spinal cord. In mixed cultures olfactory ensheathingcells migrate over both Schwann cells and astrocytes
but tend to associate with astrocytes, rather than
Schwann cells and unlike Schwann cells they do notpromote hypertrophy of astrocytes.36 This may help
explain why olfactory ensheathing cells can associatewith astrocytes within the central nervous system, incontrast to Schwann cells. Paradoxically there is evidence that transplantation of olfactory ensheathing cells
into the spinal cord promotes migration into the injured
region of host Schwann cells which may participate in
the regenerative process.37 Other cells are also proposed to be involved, with evidence that meningeal
cells also migrate into the injured region, either fromthe host or from the less-than-pure cultures of olfactoryensheathing cells used in transplantation. The conditions used to culture olfactory ensheathing cells havealso been an area of active investigation. Like Schwann
cells, but unlike astrocytes, olfactory ensheathing cells
express the low afﬁnity nerve growth factor receptor,
p75NTR .38 This allows it to be immuno-separated fromthe astrocytes of the olfactory bulb. This is now themost commonly used method for obtaining a starting
population of olfactory ensheathing cells, although O4
expression is also used39 and a recent method describes
a method of differential adhesion.40 In addition to olfactory ensheathing cells, the olfactory lamina propria
contains a population of Schwann cells associated with

11

Fig. 1 Olfactory ensheathing cells from the olfactory lamina propria
grown in vitro expressing GFAP (red) and p75 NTR (green). The nuclei
are stained with bisbenzimide (blue).

the trigeminal nerve.41 This makes immuno-puriﬁcation
problematic because of the shared p75NTR and O4
epitopes.10,42 We developed a method of purifying
olfactory ensheathing cells from human olfactory lamina propria using differential adhesion followed by culture in a serum-free medium containing the neurotrophins.43 Olfactory ensheathing cells express NGF
and BDNF44 and their high afﬁnity neurotrophin
receptors, TrkA and TrkB.43 They also express TrkC
but not its ligand NT3.43 Of the neurotrophins, NT3
was the most effective in stimulating olfactoryensheathing cell proliferation and survival in vitro.43 A
serum-free medium containing this growth factor was
effective in sustaining only olfactory ensheathing cells
and allowing us to generate many millions over a few
weeks (Fig. 1). These cultures did not contain Schwann
cells as judged by expression of HNK1, a molecule
expressed by trigeminal Schwann cells but not olfactoryensheathing cells.39 These methods establish anothermilestone in the path to using these cells autologously
in human trials, providing the means to grow millions ofcells from single biopsies. Olfactory biopsies do notaffect the sense of smell.45,46
Repairing the Spinal Cord in Humans
There are several outstanding question relating to
the use of olfactory ensheathing cells in future therapies. Certainly the optimal time for transplantation is
yet to be established, although it would seem thatavoiding the early acute inﬂammatory is advisable.
Other surgical aspects need to be optimized such as thesite and route of administration and the optimal number of cells delivered. Rather than intraspinally it may
be advantageous to inject cells into the cystic cavity or
into the cerebrospinal ﬂuid. Future therapies may also

12Mackay-Sim A: Olfactory ensheathing cells and spinal cord repair

use olfactory ensheathing cells genetically engineered
to produce growth factors that may assist their survival
or promote regenerative mechanisms within the hosttissue.47,48 It is even possible that co-transplantationof olfactory ensheathing cells with other cells such ashematopoetic stem cells, neural stem cells, or embryonic stem cell-derived cells may become the therapy ofchoice.49 The ﬁrst step is to demonstrate the safety ofolfactory ensheathing cell transplantation into the human spinal cord. To this end we commenced a Phase I
clinical trial in which autologous olfactory ensheathingcells are transplanted into the injured spinal cord ofparaplegic humans with complete injuries at T4-T10.
The primary aim of the trial is to test the safety of thetransplant procedure designed to assess adverse outcomes across a broad range of medical, neurologicaland psychosocial examinations. A secondary aim was toassess positive outcomes comparing a transplantedgroup and in a non-surgical control group over a periodof three years post-surgery.
Acknowledgements: Thanks to J. Bianco for the image in Figure 1.

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13
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