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Olfactory ensheathing cellsHistorical perspective and therapeutic potential.

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THE ANATOMICAL RECORD (PART B: NEW ANAT.) 271B:49 – 60, 2003
SPECIAL ARTICLE
Olfactory Ensheathing Cells: Historical Perspective
and Therapeutic Potential
J.G. BOYD, V. SKIHAR, M. KAWAJA,
AND
R. DOUCETTE*
Olfactory ensheathing cells (OECs) are the glial cells that ensheath the axons of the first cranial nerve. They are
attracting increasing attention from neuroscientists as potential therapeutic agents for use in the repair of spinal cord
injury and as a source of myelinating glia for use in remyelinating axons in demyelinating diseases such as multiple
sclerosis. This review mainly addresses the cell biological aspects of OECs pertinent to addressing two questions.
Namely, where do OECs fit into the groupings of central nervous system (CNS)/peripheral nervous system (PNS) glial
cells and should OECs be viewed as a clinically relevant alternative to Schwann cells in the treatment of spinal cord
injury? The evidence indicates that OECs are indeed a clinically relevant alternative to Schwann cells. However, much
more work needs to be done before we can even come close to answering the first question as to the lineage and
functional relationship of OECs to the other types of CNS and PNS glial cells. Anat Rec (Part B: New Anat) 271B:49 – 60,
2003. © 2003 Wiley-Liss, Inc.
KEY WORDS: olfactory ensheathing cells; OEC; regeneration; remyelination; spinal cord; Schwann cells; neuroscience
INTRODUCTION
Although there are exceptions to the
rule (Doucette, 2001), in general, the
regeneration of axons within the central nervous system (CNS) is not successful. In contrast, axons regenerating within the peripheral nervous
system (PNS) are often successful in
reinnervating sensory and effector organs so that almost normal function is
restored (Kiernan, 1979; Baher and
Bonhoeffer, 1994; Brecknell and
Fawcett, 1996; Fawcett, 1998; Fawcett
and Asher, 1999; Fraher, 1999; Behar
et al., 2000). Both oligodendrocytes
and astrocytes undoubtedly play a
Dr. Boyd and Dr. Kawaja are with the
Department of Anatomy and Cell Biology, Queen’s University, Kingston, Ontario, Canada. Dr. Skihar and Dr. Doucette are with the College of Medicine,
University of Saskatchewan, Saskatoon.
*Correspondence to: Dr. R. Doucette,
Department of Anatomy and Cell Biology, College of Medicine, University of
Saskatchewan, 107 Wiggins Road,
Saskatoon, SK S7N 5E5, Canada. Fax:
306-966-4298; E-mail: rondouc@duke.
usask.ca
DOI 10.1002/ar.b.10011
Published online in Wiley InterScience
(www.interscience.wiley.com).
© 2003 Wiley-Liss, Inc.
major role in this abortive regeneration of CNS axons due to the presence
of inhibitory molecules as well as to
the lack of sufficient growth promoting molecules (Reier and Houle, 1988;
Hoke and Silver, 1994; Moore and
Thanos, 1996; Gebicke-Haerter et al.,
1996; Frisen, 1997; Ridet et al., 1997).
For example, the cell surface of astrocytes and the extracellular matrix in
which they are embedded are believed
to be more of a hindrance than a help
during the growth of axons in vivo in
the adult mammalian CNS (Reier,
1986; Reier and Houle, 1988; Reier et
al., 1989; Ridet et al., 1997; Fraher,
1999). Myelin also, at least partially,
contributes to the decreased permissiveness of adult mammalian CNS tissue for supporting axonal growth (Caroni et al., 1988; Cadelli and Schwab,
1991; Schwab, 1991; McLaurin and
Yong, 1995; Fawcett and Asher, 1999).
Microglia, which are extraordinarily
sensitive
to
microenvironmental
changes within the CNS (Barron,
1995; Gebicke-Haerter et al., 1996;
Kreutzberg, 1996; Moore and Thanos,
1996), also appear to play a prominent
role in creating a nonpermissive environment for axonal growth after CNS
injury.
Neuroscientists working on brain
and spinal cord injury (see Santos-Benito and Ramon-Cueto, 2003; De Lucia et al., 2003), as well as on demyelinating diseases such as multiple
sclerosis (see Franklin, 2003), have developed a considerable interest in another glial cell that is found only in the
first cranial nerve. These glial cells,
which are referred to as olfactory ensheathing cells (OECs), provide ensheathment in vivo for the unmyelinated olfactory axons within both the
CNS and PNS portions of the olfactory nerve (Doucette, 1984, 1986,
1993; Raisman, 1985). Two reasons
why these cells have become so popular are their ability to promote long
distance growth in vivo of regenerating axons (Ramon-Cueto and NietoSampedro, 1994; Smale et al., 1996; Li
et al., 1997; Perez-Bouza et al., 1998;
Ramon-Cueto et al., 1998; Nash et al.,
2002; Pascual et al., 2002;) and to remyelinate spinal cord axons (Franklin
et al., 1996; Imaizumi et al., 1998) in
the adult mammalian CNS. The
present review will mainly address the
cell biological aspects of OECs pertinent to addressing two questions.
Namely, where do OECs fit into the
groupings of CNS/PNS glial cells, and
50 THE ANATOMICAL RECORD (PART B: NEW ANAT.)
should OECs be viewed as a clinically
relevant alternative to Schwann cells
in the treatment of spinal cord injury?
For a general overview of the cell biology of these glial cells the reader is
referred to several reviews on the subject (Doucette, 1990, 1995; Franklin
and Barnett, 1997; Ramon-Cueto and
Avila, 1998; Franklin, 2002a,b).
WHO ARE OLFACTORY
ENSHEATHING CELLS?
OECs (Figure 1) provide ensheathment
for olfactory axons, all of which are unmyelinated (Doucette, 1984, 1993; Raisman, 1985). Due to their ability both to
support CNS axon regeneration and to
remyelinate the regenerated axons,
these cells have attracted attention as
potential therapeutic agents for the
treatment of demyelinating diseases
and for repairing the damaged spinal
cord. Recent studies, however, have
questioned the axonal growth promoting (Takami et al., 2002) and remyelinating (Plant et al., 2002) ability of
adult CNS-derived OECs. Thus, despite
enthusiasm surrounding the therapeutic potential of OECs, it is important to
emphasize the need for caution in moving too quickly from animal models to
clinical trials. This need for caution is
further exemplified by our inability to
identify unequivocally the relationship
of OECs to the currently accepted
groupings of CNS and PNS glial cells. It
is pertinent, therefore, to ask the question: Who are OECS?
OECs Normally Differentiate
into Nonmyelinating Glia
In vivo, OECs express a nonmyelinating phenotype (Figure 2), providing
ensheathment for small C fibers (i.e.,
the olfactory axons; Doucette, 1984,
1990; Raisman, 1985). They also express a nonmyelinating phenotype in
neuron-free cell cultures, as demonstrated by Barnett et al. (1993) and by
Doucette and Devon (1994, 1995).
This phenotype is the one OECs
should express in vitro, because they
would not have expressed any myelinassociated molecules at the time of
plating. OECs express a curious mixture
of
astrocyte-specific
and
Schwann cell–specific phenotypic features (Doucette, 1990, 1995; RamonCueto and Valverde, 1995; Franklin
and Barnett, 1997; Ramon-Cueto and
Avila, 1998; Franklin, 2002a) and have
been reported to perform the roles of
both astrocytes and Schwann cells
(Doucette, 1990, 1993; Doucette and
Devon, 1993). For example, they contribute to the formation of the glia
limitans of the olfactory bulb (Berger,
1971; Barber and Lindsay, 1982;
Doucette, 1984, 1990, 1993; Valverde
and Lopez-Mascaraque, 1991), a role
that elsewhere in the mammalian
CNS is the exclusive domain of astrocytes (Peters et al., 1990). They also
have the ability to assemble a PNStype myelin sheath around nerve fibers in vitro (Devon and Doucette,
1992, 1995) as well as in vivo (Franklin et al., 1996; Imaizumi et al., 1998;
Smith et al., 2002), thus being induced
by axons to express a phenotype more
like that of Schwann cells.
In vivo, the differentiation of OECs
is intimately tied to the development
Two reasons why OECs
have become so
popular are their ability
to promote long
distance growth in vivo
of regenerating axons
and to remyelinate
spinal cord axons in the
adult mammalian CNS.
of the first cranial nerve. The progenitor cells giving rise to OECs are derived from the olfactory placode. During embryonic and fetal development,
these cells migrate away from the placode toward the rostral wall of the
telencephalic vesicle where they eventually contribute to the formation of
the nerve fiber layer (NFL) of the presumptive olfactory bulb (Doucette,
1989; Marin-Padilla and Amieva,
1989). Upon entering the mesenchyme separating the placode from
the telencephalic vesicle during early
embryonic development, these immature OECs begin expressing the
N-CAM and L1 cell adhesion molecules (Miragall et al., 1989), both of
which may contribute to making the
OECs an adhesive surface for the
SPECIAL ARTICLE
growth of olfactory axons from the
olfactory epithelium into the developing olfactory bulb (Doucette, 1993).
These OECs also begin to express the
p75 neurotrophin receptor (Gong et
al., 1994), the brain-fatty acid binding
protein (B-FABP; Kurtz et al., 1994),
and the diazepam binding inhibitor
(Yanase et al., 2002). Although the
function of p75 expression by OECs
remains to be determined, it could potentially play a role in providing chemotactic guidance to growing olfactory axons (Doucette, 1993). In OECs,
B-FABP is coexpressed with the diazepam binding inhibitor; these molecules may play a role in lipid metabolism, including perhaps even in
retinoid metabolism. As OECs continue to differentiate during fetal
stages of development, they begin to
express the L14 lectin (Mahanthappa
et al., 1994) and the O4 antigenic
epitope (Doucette and Devon, 1994;
Franceschini and Barnett, 1996). The
L14 lectin binds to molecules containing polylactosamine chains (Zhou and
Cummings, 1993; Cooper et al., 1991)
and was shown by Mahanthappa et al.
(1994) to promote the adhesion of primary olfactory neurons to laminin in
vitro in an integrin-independent manner. The O4 mouse monoclonal antibody (Sommer and Schachner, 1981)
recognizes a cell surface epitope that
is also expressed by glial cells in the
O2A lineage (Gard and Pfeiffer, 1989;
Trotter and Schachner, 1989) and by
Schwann cells (Mirsky et al., 1990;
Morgan et al., 1991).
Postnatally (in rats and mice) OECs
begin to express glial fibrillary acidic
protein (GFAP) and connexin 43
(Cx43; Miragall et al., 1992), but neither Cx26 nor Cx32 are expressed by
OECs in vivo in mice of any age (Miragall et al., 1992). Cx43 is also expressed by astrocytes, thus raising the
question of whether OECs and astrocytes might communicate in the NFL
by means of gap junctions. OECs also
express DM-20 (Griffiths et al., 1995),
which is an isoform of proteolipid
protein (a CNS-specific myelin protein) and the PNS-specific myelin protein Po (Lee et al., 2001). Although the
exact role of the DM-20 isoform remains to be determined, it may play a
role in the development and differentiation of myelinating glia that is completely unrelated to myelin formation
SPECIAL ARTICLE
THE ANATOMICAL RECORD (PART B: NEW ANAT.) 51
phenotype by the olfactory axons. It
should be noted, however, that olfactory axons may still contribute to the
OEC’s expression of a nonmyelinating
phenotype since Barber (1982b)
showed these axons could induce
Schwann cells to ensheath many of
them in a common mesaxon, a type of
ensheathment normally only seen in
developing peripheral nerves.
Inducing OECs to Express a
Myelinating Phenotype
Figure 1. Olfactory ensheathing cells (OECs) provide ensheathment for the primary olfactory axons from their exit from the olfactory epithelium (lower right) to their termination
within the glomeruli (open circles) of the olfactory bulb. The OECs form the glia limitans at
the point where the olfactory axons leave the peripheral nervous system to enter the
central nervous system (the PNS–CNS transitional zone) and, along with astrocytes of
the nerve fiber layer (NFL), also contribute to the glia limitans along more distal portions of
the pial surface of the bulb. In this diagram, the astrocytes of the NFL are distinguished from
the astrocytes of deeper layers to emphasize that the former cells express protease nexin-1,
a chemotropic factor that is not expressed by astrocytes elsewhere within the adult
mammalian CNS.
(Griffiths et al., 1995). Similarly, although Po is a PNS-specific myelin
protein, its expression long before myelination begins is suggestive of additional functions besides the assembly
of a myelin sheath (Lee et al., 2001),
perhaps even in axon– glial cell interactions during the growth of nerve fibers in embryos. OECs also express
3-phosphoglycerate
dehydrogenase
(Yamasaki et al., 2001), which is a key
enzyme in the synthesis of L-serine; it
was suggested by Yamasaki et al.
(2001) that the L-serine made by
OECs could be supplied to immature
neurons (e.g., newly formed olfactory
receptor neurons) in support of local
membrane synthesis. Both OECs and
astrocytes within the NFL of the olfactory bulb also express protease
nexin-1 (PN-1; Reinhard et al., 1988;
Scotti et al., 1994), whereas astrocytes
elsewhere in the CNS do not express
this enzyme. PN-1 has been demonstrated to function as a chemotropic
factor for neurites in vitro (Monard et
al., 1973; Guenther et al., 1985; Zurn
et al., 1988) and could potentially be
functioning in the same manner
within the primary olfactory pathway.
Most OECs eventually down-regulate their expression of the p75 neurotrophin receptor (Gong et al., 1994),
whereas others, specifically those
OECs contributing to the formation of
the glia limitans of the olfactory bulb,
continue to express the p75 receptor
along the basal lamina-apposed portions of their plasma membrane
(Vickland et al., 1991). In addition,
OECs residing within the PNS but not
the CNS portion of the primary olfactory pathway begin to express the
tight junctional protein ZO-1 during
early postnatal development (Miragall
et al., 1994). The function of ZO-1 in
OECs remains to be determined, but
its differential expression by OECs of
the PNS and CNS is supportive of the
concept that these glial cells may well
be heterogeneous not only in phenotype but also in function. At no time
during development in vivo, however,
have OECs ever been observed to express a myelinating phenotype. This
latter observation perhaps has more
to do with the absence of an instructive myelinating signal from the axons
than it does with the OECs being induced to express a nonmyelinating
Devon and Doucette (1992, 1995) provided the first evidence that OECs
could assemble a myelin sheath when
they cocultured these glial cells with
dorsal root ganglion (DRG) neurons.
These DRG cultures were first cleared
of all non-neuronal cells by using fluorodeoxyuridine, with the purity of
the cell cultures being confirmed by
microscopy before the addition of
OECs. The OECs added to the purified
DRG cultures were prelabelled with a
lipophilic fluorescent dye (PKH26) before coculture. The data unequivocally demonstrated that PKH26⫹ve
OECs could express a myelinating
phenotype; an electron microscopic
examination of sister cultures demonstrated the OECs assembled PNS-like
myelin around the DRG neurites. A
few years later, Franklin et al. (1996)
used an O4⫹ve clonal ensheathing
cell line, derived from cells of the newborn rodent olfactory bulb and
showed these cells would remyelinate
spinal cord axons in vivo after transplantation into an ethidium bromide/
x-irradiated demyelinated area of the
adult rat spinal cord, thus providing
the first in vivo evidence of the myelinating ability of OECs.
Subsequently, Imaizumi et al.
(1998) replicated these in vivo experiments. More importantly, this report
showed that the OEC remyelination of
axons in the posterior columns enhanced axonal conduction across the
previously demyelinated area, thus
demonstrating a functionally significant degree of remyelination. Li et al.
(1998) provided evidence that OECs
also remyelinate corticospinal axons
that have regenerated into and
through the site of an OEC graft subsequent to an electrolytic lesion of the
corticospinal tract. Curiously, however, an attempt by Plant et al. (2002)
52 THE ANATOMICAL RECORD (PART B: NEW ANAT.)
SPECIAL ARTICLE
to study the myelinating ability of
OECs obtained by using the technique
of Ramon-Cueto and Nieto-Sampedro
(1992) failed to identify any OEC myelination of neurites when OECs were
cocultured with DRG neurons. To
what extent the purification procedure used by Plant et al. (2002) contributed to the lack of myelination in
vitro by OECs, perhaps by selecting
for cells with the least myelinating
ability, remains to be determined. It is
also known that OECs have similar,
but not identical, requirements to
Schwann cells for the expression of a
myelinating phenotype (Barnett et al.,
1993; Devon and Doucette, 1995;
Doucette and Devon, 1994, 1995) so
the discrepant results could be due as
well to methodologic differences
rather than to the actual myelinating
ability of the OECs.
Nevertheless, the contrasting results do highlight the paucity of information on the molecular mechanisms
controlling the expression of a myelinating phenotype by OECs and underscore the need for more work in this
area. Smith et al. (2001) made an initial attempt to identify which transcription factors might be expressed
by OECs engaged in remyelinating
spinal cord axons, but they did not
present data at the cellular level to
confirm that the cells expressing each
of the transcription factors were indeed the same ones remyelinating the
axons. The expression of a myelinat-
Figure 2. Olfactory ensheathing cells
(OECs) of the peripheral nervous sytem (A)
and the central nervous system (B,C). A: An
example of an olfactory nerve fascicle travelling within the subarachnoid space of the
cranial cavity. Note the relative paucity of
OEC perikarya with respect to the abundance of unmyelinated olfactory axons; the
OECs ensheath large numbers of olfactory
axons within the same mesaxon. OECs
sometimes can be seen lying within such
fascicles (as shown here) but are more
commonly seen along the periphery of the
fascicle. B: Both astrocytes (As) and OECs
contribute to the glia limitans of the olfactory bulb. This photomicrograph shows how
the cytoplasmic process of an astrocyte interdigitates with those of two adjacent
OECs with no intervening basal lamina.
C: The plasma membranes of astrocytes
and OECs are also intimately apposed in
areas where the OECs do not contribute to
the formation of a glia limitans. Scale bars ⫽
10 ␮m in A, 5 ␮m in B, 2 ␮m in C.
SPECIAL ARTICLE
ing phenotype by OECs is heavily dependent on axonal contact (Devon
and Doucette, 1992, 1995; Barnett et
al., 1993; Doucette and Devon, 1994,
1995), a requirement that also applies
to Schwann cells (Brunden and
Brown, 1990; Brunden et al., 1990).
Although myelinating OECs (in vivo
as well as in vitro) assembled peripheral type myelin around those neurites large enough to be myelinated, in
comparison to Schwann cells they
have different growth media requirements for the assembly of a basal lamina and a myelin sheath. As reported
by Devon and Doucette (1995), OECs,
unlike Schwann cells, myelinated
DRG neurites and assembled a basal
lamina in vitro regardless of whether
ascorbic acid was included in the
growth medium.
When neuron-free cultures of OECs
are fed with a serum-free growth medium containing insulin, hydrocortisone, or triiodothyronine, these glial
cells were not induced to express either galactocerebroside (Gal-C) or
myelin basic protein (MBP; Barnett et
al., 1993; Doucette and Devon, 1994,
1995). Gal-C and MBP are two molecules that are expressed by myelinating glia as they assemble a myelin
sheath. Oligodendrocytes, on the other
hand, are known to synthesize significant levels of myelin-associated molecules in vitro, even in the absence of
axonal contact, provided the growth
medium contains insulin, hydrocortisone, or triiodothyronine (McMorris et
al., 1986, 1990; Lopes-Cardozo et al.,
1989; Ved et al., 1989; Poduslo et al.,
1990; Mozell and McMorris, 1991).
These results point toward a different
regulatory control over the promoter
region of the MBP gene in oligodendrocytes and OECs (Doucette and Devon,
1994, 1995) in much the same way as
this promoter region is believed to be
controlled differently in oligodendrocytes and Schwann cells (Foran and
Peterson, 1992; Gow et al., 1992). Doucette and Devon (1994, 1995) found that
a more effective inducer of Gal-C expression by OECs in neuron-free cultures was increasing the intracellular
level of cAMP (Doucette and Devon,
1994, 1995), which nevertheless still
failed to induce these cells to express
MBP (Doucette and Devon, 1995).
Thus, although much has been
learned as to how ensheathing cells
THE ANATOMICAL RECORD (PART B: NEW ANAT.) 53
differ from both oligodendrocytes and
Schwann cells, very little is actually
known about the factors regulating
the OEC’s expression of a myelinating
phenotype or even whether all OECs
possess the ability to myelinate. This
latter point is important to keep in
mind, because OECs are a heterogeneous population of cells. In vivo,
some of them contribute to the formation of a basal lamina covering (Doucette, 1984, 1990, 1991, 1993); some
continue to express the p75 receptor,
whereas others do not (Vickland et al.,
1991); and the OECs in the PNS portion of the pathway express ZO-1,
whereas those centrally do not (Miragall et al., 1994). Heterogeneity of the
OEC phenotype is also observed in
vitro (Pixley, 1992; Franceschini and
Barnett, 1996; Ramon-Cueto and
Avila, 1998). Thus, any technique designed to separate OECs from other
mucosal or CNS cells to obtain purified cell cultures runs the risk of selecting for specific functional abilities
during the purification process.
Can We Say Who OECs Are?
Because they share a common phenotype, Nieto-Sampedro and his collaborators (Gudino-Cabrera and NietoSampedro, 2000) have suggested that
OECs, pituicytes, and tanycytes are
three members of a common family of
Schwann-like macroglia of the CNS.
Specifically, Gudino-Cabrera and Nieto-Sampedro (2000) have suggested
these three glial cell types belong to a
separate family of CNS macroglia,
which they referred to as aldynoglia, a
term derived from a Greek word
meaning “to make grow.” OECs, tanycytes, and pituicytes all appear to
make the CNS microenvironment
more hospitable to growing axons,
thus making them ideal candidates
for glial cell transplantation into areas
of CNS injury. Tanycytes (Prieto et al.,
2000) and olfactory ensheathing cells
(Ramon-Cueto and Nieto-Sampedro,
1994; Smale et al., 1996; Li et al.,
1997, 1998; Ramon-Cueto et al., 1998,
2000; Navarro et al., 1999) have both
been shown to promote the growth of
CNS axons after grafting into the CNS
of adult rats. Furthermore, all three
putative Schwann cell–like macroglia
possess the ability to myelinate DRG
neurites in vitro (Gudino-Cabrera and
Nieto-Sampedro, 2000). Are OECs
one member of a family of aldynoglia?
It is too early to draw a definitive conclusion, but it would also be premature to rule out the possibility of
OECs, tanycytes, and pituicytes comprising members of a new family of
glial cells.
Other clues also point toward there
being something different, although
we hesitate to say unique, about the
glial cells of the primary olfactory
pathway. Within the NFL of the olfactory bulb (i.e., the CNS portion of the
primary olfactory pathway), the only
glial cells that are consistently
present, in the absence either of experimental injury or of inflammation
affecting the olfactory mucosa or
nerve, are astrocytes and OECs. Personal and published ultrastructural
observations (Doucette, 1984, 1991,
1993, 1995) made over a period of 20
years by one of the authors (R.D.) consistently support the view that these
glial cells are the only ones comprising the glial cell environment of the
unmyelinated NFL. It has been suggested that unmyelinated pathways in
the adult mammalian CNS may also
contain precursor cells with the potential to differentiate into oligodendrocytes (Levine, 1989). Because the
origin of the progenitor cells giving
rise to the astrocytes of the NFL remains to be determined, one intriguing possibility with respect to the NFL
is that these glial progenitor cells, perhaps in response to an instructive signal from the differentiating OECs, differentiate exclusively into astrocytes
as opposed to a mixture of astrocytes
and oligodendrocytes, as typically
happens elsewhere in the CNS.
There is circumstantial evidence
supporting a functionally relevant interaction between OECs and astrocytes in the NFL because these astrocytes are, to a certain extent,
phenotypically distinct from astrocytes elsewhere in the adult mammalian CNS. The expression of PN-1 by
astrocytes of the NFL raises the question of whether the intimate contact
with OECs during the differentiation
of these two cell types might be responsible for the expression of this
chemotropic factor by a select group
of astrocytes. The cellular interactions, if any, between OECs and astro-
54 THE ANATOMICAL RECORD (PART B: NEW ANAT.)
cytes is a relatively unexplored area
(Pollock et al., 1999; Lakatos et al.,
2000). It is entirely natural to assume,
as suggested above, that the astrocytes
of the NFL are derived from CNS progenitors in much the same way as astrocytes are formed in other parts of
the nervous system. However, it is
also plausible the PN-1 expressing astrocytes of the NFL of the bulb are
derived from OEC progenitors, rather
than from the CNS progenitors giving
rise to astrocytes elsewhere in the
brain. Pixley (1992) reported the appearance of astrocyte-like and
Schwann cell-like glial cells in cultures of olfactory mucosa, thus providing support for the possibility that
OECs could differentiate into astrocyte-like cells.
This entire area of OEC biology is in
dire need of investigation, because the
answers will undoubtedly provide
clues to the identity of OECs. At the
present time, however, it is not possible to make a definitive statement as
to where OECs fit into the currently
accepted groupings of CNS and PNS
glial cells.
ARE OECs A CLINICALLY
RELEVANT ALTERNATIVE TO
SCHWANN CELLS?
In the absence of experimental intervention, olfactory axons are usually
successful at reinnervating the olfactory bulb (Graziadei and Monti Graziadei, 1978; Monti Graziadei and
Graziadei, 1979; Barber, 1982a; Doucette et al., 1983; Doucette, 1990), but
the regenerative effort of most other
types of axons within the CNS fails to
support more than a minimal amount
of growth (Kiernan, 1979; Reier et al.,
1989; Fawcett, 1998). This dichotomy
in the success of axonal growth appears due, at least in part, to the different glial cell environments through
which olfactory and nonolfactory axons must grow (Doucette, 1990, 1995;
Ramon-Cueto and Valverde, 1995;
Franklin and Barnett, 1997; Fawcett,
1998; Ramon-Cueto and Avila, 1998).
Macroglia of the CNS play a major
role in the normally abortive regeneration of nonolfactory CNS axons, due
most likely both to the presence of
inhibitory molecules as well as to the
lack of sufficient growth promoting
molecules (Reier and Houle, 1988;
Hoke and Silver, 1994; GebickeHaerter et al., 1996; Moore and Thanos, 1996; Frisen, 1997; Ridet et al.,
1997). It is commonly believed that
the cell surface of astrocytes and the
extracellular matrices in which they
are embedded are more likely to
hinder rather than facilitate the
growth of axons in vivo in the adult
mammalian CNS (Reier, 1986; Reier
and Houle, 1988; Reier et al., 1989;
Ridet et al., 1997; Fraher, 1999). However, it is also clear that astrocytes are
not always nonpermissive for axonal
growth. In fact, there appear to be
differences in the ability of astrocytes
to support axonal growth, depending
on the degree of differentiation of the
cells (Baehr and Bunge, 1989; Hatten
et al., 1991; Lucius et al., 1996); on
Over the past several
years, a number of
studies have
demonstrated the
effectiveness of OECs in
supporting the growth of
nonolfactory CNS axons
in vivo, although there
have also been a
couple of negative
reports.
whether the astrocytes have formed a
two- or three-dimensional substratum
for the growing axons (Fawcett et al.,
1989); on the part of the CNS that is
injured (Alonso and Privat, 1993a,b;
Chauvet et al., 1998; Prieto et al.,
2000); and on the presence or absence
of macrophages (David et al., 1990),
Schwann cells (Berry et al., 1992;
Dezawa et al., 1999) or OECs (Li et al.,
1997, 1998; Ramon-Cueto et al., 1998,
2000).
Over the past several years, a number of studies have demonstrated the
effectiveness of OECs in supporting
the growth of nonolfactory CNS axons
in vivo (Lustgarten et al., 1991; RamonCueto and Nieto-Sampedro, 1994;
Smale et al., 1996; Li et al., 1997, 1998;
Perez-Bouza et al., 1998; Ramon-Cueto
SPECIAL ARTICLE
et al., 1998; Navarro et al., 1999), although there have also been a couple
of negative reports (Gudino-Cabrera
et al., 2000; Takami et al., 2002). The
driving force behind these experiments was to manipulate the cellular
environment of the lesion site in the
brain or spinal cord so as to create one
more conducive to supporting axonal
growth across the lesion and into the
tissue on the distal side. Even though,
as mentioned above, macroglia of the
CNS appear to play a major role in the
abortive regeneration of axons in the
brain and spinal cord (Liuzzi and
Lasek, 1987; Reier and Houle, 1988;
Reier et al., 1989; Fawcett, 1991; Hatten et al., 1991), it was hypothesized
that the presence of OECS would create a more favourable and supportive
environment for axonal growth
(Doucette, 1990, 1995; Wozniak, 1993;
Ramon-Cueto and Valverde, 1995;
Franklin and Barnett, 1997).
The data on the growth of primary
sensory afferents across the dorsal
root entry zone of the spinal cord support this hypothesis because, in the
presence of grafted OECs, the regenerating fibers even crossed the midline
to enter the contralateral dorsal horn
(Ramon-Cueto and Nieto-Sampedro,
1994; Navarro et al., 1999). OECs also
promoted cholinergic fibers of the
fimbria/fornix pathway to grow into
OEC-containing collagen gels that
were placed into a cavity left behind
when a large portion of the fiber pathway was destroyed by aspiration
(Smale et al., 1996). Raisman and his
colleagues (Li et al., 1997, 1998) and
Nash et al. (2002) lesioned the corticospinal tract in adult rats and
showed that an OEC graft promoted
the growth of corticospinal fibers
through the lesion and into the distal
portion of the pathway. Ramon-Cueto
et al. (1998) showed a quite remarkable regrowth of axons within the
adult rat spinal cord when they removed an entire spinal cord segment
before grafting OECs into the proximal and distal stumps of the
transected cord; their study demonstrated long-distance regrowth of the
damaged fibers, with some axons
growing as far as 12–14 spinal cord
segments.
Schwann cells are good promoters
of axonal growth, and under certain
conditions, even astrocytes have been
SPECIAL ARTICLE
shown to possess growth-promoting
properties (Smith et al., 1986; Ard et
al., 1987; Ard and Bunge, 1988;
Neugebauer et al., 1988; Silver 1988;
Bahr and Bunge, 1989; Hatten et al.,
1991; Kawaja and Gage, 1991). However, promoting axonal growth in the
injured spinal cord of adult mammals
is only one of many problems that
must be overcome in the treatment of
spinal cord injury (Collins and West,
1989). Although it is unlikely that any
one glial cell type can correct all of
these problems, what is sorely needed
is a cell that can adopt several different roles as the need arises. This feature is exactly what OECs appear to
do (Doucette and Devon, 1993), being
able for example to switch their phenotype from that resembling an astrocyte to one more like that of a myelinating Schwann cell (Devon and
Doucette, 1992, 1995). It is very likely
that OECs will be able to combine the
roles of astrocytes and Schwann cells
when transplanted into a lesion cavity, due to their having such a highly
malleable phenotype (Doucette and
Devon, 1993).
These findings are mentioned not to
suggest that OECs will promote axonal growth better than either
Schwann cells or immature astrocytes. Rather, it is hypothesized that
they will differ from Schwann cells in
reconstituting the glia limitans and
blood brain barrier and in allowing
maximal re-entry of axons into the
host tissue on the caudal side of the
lesion. Admittedly, these roles can
also be performed by immature astrocytes when transplanted into a lesion
cavity, but such glial cells, being obtained from aborted human fetuses,
would be more difficult to obtain.
Schwann cells, on the other hand, not
only fail to become integrated into the
CNS, but astrocytes somehow perturb
the neuron–Schwann cell interactions
that lead to myelination (Blakemore
and Crang, 1989; Franklin et al., 1992;
Guenard et al., 1994b). Cellular migration of Schwann cells within the
CNS parenchyma is also limited. For
example, when they are transplanted
into the cerebral hemisphere of newborn shiverer mice, the migration is
mostly confined to the vicinity of the
graft; the grafted Schwann cells are
also eventually extruded from the
CNS parenchyma (Baron-Van Everco-
THE ANATOMICAL RECORD (PART B: NEW ANAT.) 55
oren et al., 1992). It has been suggested that astrocytes inhibit the migration of Schwann cells within the
parenchyma of the CNS (Fawcett and
Asher, 1999). Lakatos et al. (2000)
have shown that Schwann cells and
astrocytes avoid one another when
they are present in the same culture
dish. This dismal ability of Schwann
cells to integrate into and to migrate
within the CNS may be responsible, in
part, for the poor regenerative growth
of CNS axons distal to the site of injury.
OECs, in contrast, are able to migrate within the CNS parenchyma of
adult animals (Skihar and Doucette,
2001), thus highlighting another important distinction from Schwann
cells. Successful regeneration along
the distal portions of the fiber tracts
There are certain
conditions in which the
CNS microenvironment
can be made very
supportive of axonal
growth, effectively
enabling sufficient
numbers of axons to
regenerate that some
functional recovery may
even be observed.
may well require the presence of cells
that provide a microenvironment
more conducive to growth. In regard
to the latter point, Ramon-Cueto et al.
(1998) found in their spinal cord transection study that axons entered the
distal stump of the cut cord only in
those animals in which OECs had
been grafted adjacent to the cut surface. Furthermore, they will differ
from astrocytes in being able to remyelinate the regenerating axons, as
demonstrated by Li et al. (1998). We
hypothesize that OECs, by virtue of
their ability to integrate and migrate
within the CNS microenvironment,
effectively modify the response of astrocytes and microglia to create a
more supportive environment for the
regeneration of axons. The microglial
cell response to tissue injury has been
shown to be modified by the presence
of Schwann cells (Zeev-Brann et al.,
1998; Dezawa et al., 1999), and some
studies have found that CNS axons
can regenerate through areas of tissue
injury containing microglial cells/
macrophages (Prewitt et al., 1997;
Rabchevsky and Streit, 1997; LazarovSpiegler et al., 1998; Stichel et al.,
1999).
Although it is known that OECs
possess the ability to migrate within
the adult mammalian CNS in animal
models of spinal cord injury (RamonCueto and Nieto-Sampedro, 1994; Li
et al., 1998; Ramon-Cueto et al.,
1998), there has been no systematic
examination of the factors inducing
or guiding this migration. The reason
this is important to consider is because it is still an open question as to
whether grafted OECs are “leaders” or
“followers” with respect to regenerating axons. Thus, the regeneration of
primary sensory afferents across the
midline into the contralateral dorsal
horn (Ramon-Cueto and NietoSampedro, 1994; Navarro et al.,
1999), the regeneration of corticospinal axons into the distal portion of the
respective fiber tract (Li et al., 1997,
1998), and the multisegmental growth
of axons after spinal cord transection
in the study of Ramon-Cueto et al.
(1998) were all associated with the migration of OECs away from the site of
the graft. In each study, the regenerating axons were also always seen in
areas that also contained migrating
OECs.
Could it be that the OECs are creating a more favourable and supportive
environment for axonal growth? An
intriguing question that, for the moment at least, cannot be answered.
There are published data, however, to
support the idea of grafted glial cells
modifying the microenvironment to
facilitate the growth of axons. For example, there are certain conditions in
which the CNS microenvironment
can be made very supportive of axonal
growth, effectively enabling sufficient
numbers of axons to regenerate that
some functional recovery may even be
observed (Smale et al., 1996; Beattie
et al., 1997; Li et al., 1997, 1998; Berry
et al., 1998; Ramon-Cueto et al., 1998,
2000; Huang et al., 1999). For exam-
56 THE ANATOMICAL RECORD (PART B: NEW ANAT.)
ple, grafts of embryonic astrocytes
(Smith et al., 1986; Kliot et al., 1990;
Wunderlich et al., 1994; Sievers et al.,
1995), which are known to reduce the
inflammatory response and gliosis after CNS injury (Smith et al., 1986;
Kliot et al., 1990), are known to support the growth of regenerating axons
in the adult mammalian CNS. Silver
and colleagues (Smith et al., 1986; Silver, 1988) were one of the first groups
to explore the use of embryonic astrocytes to promote axon regeneration in
adult animals. They showed that
transplants of “immature” astrocytes,
so called because they were obtained
from a wound cavity in the cerebral
cortex of neonatal rats, supported the
regeneration of axons across the lesioned corpus callosum, even when
transplanted into the CNS of adult animals. When given a choice, the regenerating callosal fibers preferred to
grow directly on the plasma membrane of these immature astrocytes
rather than on the basal lamina that
the transplanted cells had formed in
vivo (Smith et al., 1986).
In the absence of experimental intervention, it is also known that axons
in the adult mammalian CNS grow
within areas containing Schwann
cells, but poorly or not at all within
areas lacking Schwann cells (Berry et
al., 1992; Dezawa et al., 1999). Host
Schwann cells migrate toward lesion
cavities in the adult mammalian spinal cord where they appear to support
the regrowth of axons (Matthews et
al., 1979; Ohi et al., 1989; West and
Collins, 1989; Li and Raisman, 1995).
It has even been suggested that
Schwann cells can regulate the gliotic
response to CNS trauma (Senoo et al.,
1998). Thus, in the presence of
Schwann cells, the astrocytes and
other cells repopulating and sealing
the wound in the adult mammalian
CNS appear to be more supportive of
axonal growth, or at least less of an
obstruction, than they are in the absence of Schwann cells (Matthews et
al., 1979; Ohi et al., 1989; Dezawa and
Nagano, 1996; Senoo et al., 1998;
Dezawa et al., 1999). In fact, PNS axons will even regenerate into an optic
nerve graft provided Schwann cells
are present, as occurs in the optic
nerve of the Browman-Wyse mutant
rat (Hall et al., 1992). Axons of the
sciatic nerve of adult rats also regen-
erate into astrocyte-seeded semipermeable guidance channels provided
Schwann cells are present in sufficient
numbers (Guenard et al., 1994a). It
remains to be determined whether
Schwann cells directly interact with
regenerating CNS axons and/or promote their growth by modifying the
CNS microenvironment.
We hypothesize that the in vivo axonal growth promoting ability of
OECs is intimately tied to at least two
features of the cells, which collectively
with their support of axonal growth
can be considered a triad of interconnected functions: (1) their ability to
integrate into the CNS microenvironment, and (2) their ability to migrate
long distances within the neuropil of
the CNS. In light of these features, it is
In light of the
enthusiasm generated
by these findings, it is
somewhat disheartening
that we still know so little
about the molecular
mechanisms driving the
growth promoting and
remyelinating ability of
OECs or where they fit
into the glial cell family.
surprising that, in the recent study of
Takami et al. (2002), grafted OECs
simply disappeared from the lesion
cavity with no evidence that they had
migrated away into the surrounding
neuropil. In the study by Gudino-Cabrera et al. (2000), the only other
study in which grafted OECs failed to
support the regeneration of CNS axons, it was noted that the OEC migration was solely in the proximal direction back toward the neuronal cell
bodies, which could possibly explain
why the axons failed to regenerate.
But in the Takami et al. (2002) study,
the cells seemed simply to disappear.
CONCLUSIONS
Research performed over the past decade demonstrated that OECs are
SPECIAL ARTICLE
a clinically relevant alternative to
Schwann cells for promoting neural
repair in the CNS of adult mammals
(Doucette, 1990, 1995; Franklin and
Barnett, 1997; Franklin, 2002a,b). The
potential therapeutic usefulness of
OECs is presently being explored in
two major research areas, and the evidence thus far is very encouraging!
OECs promote long-distance regeneration of axons in the adult mammalian spinal cord and remyelinate CNS
axons such that the conduction velocities of previously demyelinated axons
are restored to normal levels. OECs
are also becoming increasingly easier
to obtain from extracranial sources,
such as from human peripheral olfactory tissue or from similar tissue in
the nasal cavity of rodents (Lu et al.,
2001, 2002; Franklin, 2002b), thus
providing the attractive proposition of
a patient having the opportunity to
provide their own olfactory tissue for
autologous transplantation. Furthermore, the available evidence supports
the view that OECs are more likely to
integrate into the CNS parenchyma
after grafting to repair the injured or
demyelinated spinal cord (Li et al.,
1998; Lakatos et al., 2000) than are
Schwann cells (Baron-Van Evercooren et al., 1992; Blakemore, 1992;
Duncan and Milward, 1995), as suggested by Doucette (1990, 1995) several years ago. One possible explanation for the failure of Schwann cells to
integrate as easily into the CNS parenchyma is that astrocytes are known
perturb the neuron–Schwann cell interactions normally leading to myelination (Franklin et al., 1992; Guenard
et al., 1994b), and these cell– cell interactions appear also to inhibit the migration of Schwann cells toward the
site of injury (Fawcett and Asher,
1999). In light of the enthusiasm generated by these findings, it is somewhat disheartening that we still know
so little about the molecular mechanisms driving the growth promoting
and remyelinating ability of OECs or
where they fit into the glial cell family.
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