COMMENTARY
The peripheral nervous system-central nervous system regeneration
dichotomy: a role for glial cell transplantation
R. J. M. FRANKLIN and W. F. BLAKEMORE
Wellcome Laboratory for Comparative Neurology, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road,
Cambridge CB3 OES, UK
Introduction
The events that follow axonal interruption (axotomy)
reveal an important and fundamental difference between
the peripheral and central components of the adult
mammalian nervous system. Following transection of
peripheral nerve axons, the proximal axonal portion is
able to regenerate through the distal part of the nerve and
may, under appropriate conditions, re-innervate the
original target (sensory or effector organ), thereby restoring pre-lesion anatomy and function (Guth, 1956).
Within the central nervous system (CNS), however, the
regenerative response of interrupted axons is, with few
exceptions, abortive, and the restoration of original
synaptic contact does not occur (Cajal, 1928). This
difference in the response to injury has clinical implications, CNS trauma carrying a much poorer prognosis
than injury to peripheral nerves. This commentary will
briefly review the possible reasons for the failure of
effective axon regeneration in the CNS, and discusses the
potential of glial transplantation to shed light on this
complex problem.
What features of the peripheral nervous system
allow regeneration?
Following axotomy in the peripheral nervous system
(PNS) the isolated axonal segments in the distal stump,
and their associated myelin, undergo degeneration,
whereas the Schwann cells and connective tissue components persist. The Schwann cells in the distal stump
become orientated in longitudinal columns (bands of
Bungner) and are contained within basal lamina tubes
rich in extracellular matrix (ECM) constituents such as
laminin, collagen (types IV and V), fibronectin, entactin
and heparan sulphate (Bunge and Bunge, 1983; Carbonetto, 1984). These provide a substratum that supports
the regenerating neurites that emerge from the proximal
axonal stump (Ide et al. 1983). The arrangement of
Schwann cells and ECM in the original basal lamina
tubes of the distal section also provides a conduit to guide
the regenerating axons towards their eventual targets. If
Journal of Cell Science 95, 185-190 (1990)
Printed in Great Britain © The Company of Biologists Limited 1990
the basal lamina remains intact at the site of axon
interruption, such as occurs in a nerve crush injury, the
regenerating axons are directed towards their original
target and full functional recovery can occur (Thomas,
1974). Recent evidence that Schwann cells deprived of
axonal contact in the distal stump produce nerve growth
factor (NGF) and express NGF receptors on their
plasma membrane surface suggests that the production of
neurotrophic factors is important in encouraging peripheral nerve regeneration (Johnson et al. 1988). Thus, in
the PNS, cellular, acellular and neurotrophic factors
combine to support axon regeneration.
Why do CNS axons fail to regenerate?
The subject of axon regeneration failure in the CNS has
long been a concern of neurobiologists (reviewed by, e.g.,
Cajal, 1928; Windle, 1956; Clemente, 1964; Guth, 1975;
Kiernan, 1979; Berry, 1979; Reier and Houle, 1988).
Hypotheses explaining the failure of effective regeneration of CNS axons have revolved around two basic
questions; (1) are CNS axons inherently incapable of
regeneration ('inherent incapacity hypothesis')? or (2)
does the environment of the severed axon, possessing an
inherent regenerative capacity, prevent effective regeneration from occurring ('neural environment hypothesis')?
Inherent incapacity hypothesis
This hypothesis has been tested by providing severed
CNS axons with an environment in which PNS axons are
able to regenerate. Thus, numerous workers have grafted
segments of peripheral nerve into the CNS (Tello, 1911;
Cajal, 1928; Sugar and Gerard, 1940; Le Gros Clark,
1943; Kao et al. 1977; Aguayo et al. 1981) and demonstrated the re-innervation of the graft. Richardson and
co-workers, using a retrograde horseradish-peroxidase
(HRP) axon labelling technique, have provided unequivocal evidence that the axons that re-innervate peripheral
nerve grafts are of CNS origin (Richardson et al. 1980).
CNS axons are capable of extending considerable distances within the environment of a peripheral nerve
(Benfey and Aguayo, 1982), although when re-directed
185
back into the CNS further axon elongation is arrested
(David and Aguayo, 1981). However, on re-entering the
CNS the regenerating axons are able to form anatomical
synapses, albeit at a short distance from the point of entry
(Vidal-Sanz et al. 1987).
Peripheral nerve grafting experiments have produced a
substantial body of evidence to show that, when provided
with an appropriate environment, central axons will
regenerate over significant distances and are able to form
synaptic contact with target cells. However, the intrinsic
regenerative capacity of central neurons does not appear
to be uniform. In general, unmyelinated and phylogenetically old central fibre systems have a considerable
capacity for regrowth. Thus, monoaminergic (Bjorklund
and Stenevi, 1979), hypothalamo-hypophyseal (Dellman, 1973) and primary olfactory axons (Graziadei and
Monti-Graziadei, 1978) possess relatively robust regenerative potential. There is some evidence that the axons of
ventral horn motor neurons are capable of more vigorous
regeneration than dorsal root ganglion axons (Meier and
Sollman, 1977). Attention has been focused on the role of
axonal transport systems (Forman, 1983) and metabolic
responses (Baron, 1983) of axotomised neurons in
explaining variable regenerative capacities. The synthesis
of new axonal components in the cell body, and their
subsequent transport along the axon to the regenerating
tip, are mechanisms that underlie axonal elongation.
Thus, differences in regenerative capacity may be related
to differences in synthetic and axoplasmic transport
characteristics of axotomised neurons.
Neural environment hypothesis
It is evident from peripheral nerve grafting experiments
that the explanation for the widespread failure of axon
regeneration in the CNS lies in the environment that
surrounds the damaged axon. Numerous hypotheses
have been advanced; for example, the absence of sufficient neurotrophic and/or neurotropic factors (Cajal,
1928; Berry, 1979); inappropriate formation of synapses
(Bernstein and Bernstein, 1971; Carlstedt, 1985); absence of neurite-supportive ECM components in the
CNS (Carbonetto, 1984; Liesi, 1985); the necessity for
regenerating axon tips to be bathed in extracellular bloodderived protein following breakdown of the blood-brain
barrier (Heinicke and Kiernan, 1978); and the autoimmune-inhibition hypothesis of Berry and Riches (1974).
Many of these hypotheses have highlighted differences
between PNS and CNS, and have inevitably considered
the different glial cell populations of the two systems. It is
clear that Schwann cells promote axon regeneration in
the PNS. What role do central glia play in axon regeneration in the CNS?
The concept that astrocytes play a critical role in
preventing axon elongation has received considerable
attention (reviewed by Reier et al. 1983; Reier and
Houle, 1988). Following injury to the CNS astrocytes
proliferate and hypertrophy ('reactive gliosis') giving rise
to the glial scar (e.g. see Cavanagh, 1970; Bignami and
Dahl, 1976; Topp et al. 1989). The glial scar fills in the
extracellular space left by the degeneration of neuronal
and glial elements. In situations where the integrity of the
186
R. jf. M. Franklin and W. F. Blakemore
CNS has been breached by trauma the glial scar can
consist of both reactive astrocytes and mesenchymal
elements. This type of glial scar results in the reconstitution of a glial limiting membrane (glia limitans) along
interfaces where the CNS parenchyma is exposed,
thereby redefining the CNS/non-CNS boundary. The
observations of early workers (e.g. see Cajal, 1928;
Brown and McCouch, 1947), that the regrowing tips of
damaged axons are arrested by the dense aggregation of
astrocytes and collagen that follow trauma, led to the
barrier hypothesis. This hypothesis maintains that the
glial scar presents an impenetrable barrier through which
a regenerating axon is unable to pass.
Of the many hypotheses that have been suggested to
explain the inability of most CNS axons to regenerate,
the barrier hypothesis has received the most attention. In
its original form the glial scar was thought to act as a
purely physical barrier (e.g. see Cajal, 1928). Early
support for this view came from the work of Windle and
his colleagues (reviewed by Windle, 1956), who demonstrated that administration of steroids or a pyrogenic
agent reduced the extent of glial scar formation and
thereby enhanced axonal outgrowth. The most compelling evidence for the glial barrier hypothesis has come
from studies of regeneration of injured dorsal spinal
roots. Axotomy of the central axon segment of dorsal root
ganglion neurons is followed by axon regeneration within
the peripheral environment of the dorsal root. However,
axon regeneration is arrested at the PNS-CNS interface
and few, if any, axons are able to enter the CNS
environment of the spinal cord (e.g. see Moyer et al.
1953; Perkins et al. 1980). Ultrastructural analysis of the
dorsal root entry zone (DREZ) has indicated that reactive
astrocytes, arranged as a glia limitans, are responsible for
preventing regenerating dorsal root axons from entering
the CNS (Stensaas et al. 1987).
Are these astrocytes merely presenting an impenetrable
physical barrier? The observations of Liuzzi and Lasek
(1987) suggest a more subtle mechanism. A purely
physical impediment to axon growth, such as ligation of a
peripheral nerve, results in the accumulation of neurofilaments at the point of obstruction. However, no such
neurofilamentous accumulations are found in regenerating axons in contact with the astrocytic glia limitans at the
DREZ in the dorsal root regeneration model. It is
therefore argued that astrocytes activate an intrinsic
axonal mechanism that prevents further axon elongation
(the so-called 'physiological stop pathway'). Other evidence indicates that astrocytes restrict axon elongation by
more dynamic mechanisms than physical impenetrability. For example, the inverse relationship between the
prevalence of intramembranous orthogonal arrays in
astrocytes and the absence of axonal elongation has led to
the idea that specific surface properties of adult astrocytes
are non-permissive to axon regeneration (Wujek and
Reier, 1984; Wolburg, 1987). The continuing expansion
of our knowledge about cell-surface-bound adhesion
molecules may yield important information in this respect. Adhesion molecules play a critical role in orchestrating the development of the nervous system (Linnemann and Bock, 1989), although their role in
regeneration is less clear. Particularly intriguing in this
context, however, is the expression of the adhesion
molecule LI on Schwann cells (Mirsky et al. 1986), but
apparently not on astrocytes (Rathjen and Schachner,
1984). A further suggestion is that mature astrocytes fail
to support axon growth because they are unable to
produce localised extracellular proteolysis (Kalderon,
1988). It has also been suggested that adult reactive
astrocytes do not produce sufficient amounts of appropriate neurotropic and/or trophic factors (Schwab and
Thoenen, 1985). Thus, although the glial scar presents a
physical environment that is not conducive to extensive
axon growth, mature mammalian astrocytes may restrict
axon regeneration by specific mechanisms that have yet to
be fully described.
Recent findings by Schwab and associates have indicated that the other class of macroglial cell, the oligodendrocyte, may be a key protagonist in axon regeneration
failure (Caroni et al. 1988). When neurons are cultured
on cryostat sections of CNS tissue, neurite outgrowth
tends to occur on grey matter rather than on myelin-rich
white matter (Crutcher, 1989; Savio and Schwab, 1989;
Watanabe and Murakami, 1989). This observation can be
related to the findings of Schwab and Caroni (1988) that
isolated oligodendrocytes and CNS myelin are nonpermissive substrata for neurite growth in vitro. Further
work on the non-permissive substratum properties of
CNS myelin has led to the identification of a 35 X 103Mr
and a 250xl0 3 M r myelin-associated protein that both
inhibit neurite outgrowth (Caroni and Schwab, 1988a).
Addition of these proteins to otherwise permissive substrata, such as PNS myelin, appears to render them nonpermissive. Furthermore, antibody against these inhibitory proteins will neutralise the non-permissiveness of
CNS myelin in vitro (Caroni and Schwab, 19886). The
non-permissive nature of oligodendrocytes has also been
reported by Fawcett et al. (19896), who have analysed
time-lapse video recordings of the interactions between
cultured axonal growth cones and oligodendrocytes. The
advance of axonal growth cones is arrested when they
contact an oligodendrocyte and, after a short period, they
collapse with subsequent retraction of the axon. These in
vitro studies have led to the suggestion that oligodendrocytes, and in particular central myelin, may be crucially
involved in preventing axon regeneration in the injured
CNS, although this hypothesis has yet to be convincingly
demonstrated in vivo.
Immature astrocytes and axon regeneration
The immature astrocytes of the developing nervous
system have a fundamentally different role in axon
elongation when compared with their counterparts in the
adult CNS. In contrast to the inhibitory role of astrocytes
in the fully developed mammalian CNS, immature
astrocytes play an important role in guiding and supporting the growth of developing axons (Silver et al. 1982;
Poston et al. 1988). Will immature astrocytes also support
the regrowth of interrupted adult axons? Kalderon (1988)
has shown that regenerating peripheral nerve axons will
grow through a silicone chamber containing immature
astrocytes (postnatal day 9), but not through a chamber
containing adult astrocytes (>postnatal day 19). Similar
findings have been reported by Fawcett et al. (1989a),
who have shown that axons from dorsal root ganglia
(DRG) and retinas are unable to grow through a threedimensional matrix of astrocytes from cultures 3 weeks or
more old, but some DRG axons grow through astrocyte
cultures that are 10 days or less old. This age-dependent
behaviour may be related to the observation that immature astrocytes have greater plasminogen activator activity than mature astrocytes (Kalderon et al. 1988). The
permissive nature of immature astrocytes is reflected in
the remarkable ability of the embryonic or early postnatal brain to repair itself after injury. An example of this
phenomenon is provided by the dorsal root regeneration
model described above. After a dorsal root crush lesion in
the newborn rat, dorsal root axons regrow across the
root—spinal cord junction and extend into the CNS
(Carlstedt, 1988). Similarly, ventral horn motor neurons
will extend regenerating axons into ventral roots after
intramedullary axotomy in neonatal rats (Carlstedt et al.
1989). The glial limiting membrane at the PNS-CNS
interface does not seem to exert the same barrier effect in
the immature animal as it does in the adult.
Transplantation of immature astrocytes into the
adult CNS
Within the last decade or so transplantation into the
mammalian CNS has developed as a major experimental
paradigm in neurobiology with potentially important
clinical applications. Transplantation techniques present
a useful approach to influencing the outcome of various
pathological states of the CNS. Various tissues and cell
types have been transplanted, including astrocytes (e.g.
see Bridges et al. 1987; Emmett et al. 1988). The
behaviour of immature astrocytes suggests that these cells
may be able to facilitate repair processes when transplanted into the injured adult CNS. Silver and coworkers have used the acallosal mouse model to test this
possibility. During normal development axons of the
corpus callosum are guided across the cerebral midline by
an astrocytic structure ('glial sling') (Silvered al. 1982). If
the corpus callosum is cut in adult animals a glial scar
forms and attempts by regenerating axons to re-establish
connectivity between the two hemispheres fail. Successful regeneration can be achieved when Millipore strips
coated with immature astrocytes are implanted into the
lesioned corpus callosum and act as a prosthetic glial
sling. In contrast, Millipore coated with mature astrocytes does not support regeneration (Smith et al. 1986).
Immature astrocyte-coated Millipore implants have also
been used in a partially successful attempt to augment
regeneration of dorsal root axons past the DREZ in adult
rats (Kliot et al. 1988). In addition to providing a
permissible environment for regenerating CNS axons,
these experiments have suggested that transplanted
immature astrocytes may reduce the extent of glial scar
formation in adult animals (Smith et al. 1986). Similar
Glial cell transplantation in regeneration
187
experiments have been conducted by Schroeder and
Muller (1989), who have transplanted a suspension of
cerebral astrocytes from neonatal rats into an axotomy
lesion in the postcommissural fornix. Preliminary results
have indicated that enhanced regeneration may occur
through the transplanted astrocytes.
Transplantation of other glial cells
In recent years a number of research groups have been
using transplantation of myelin-forming cells to investigate the biology of myelination (e.g. see Blakemore and
Crang, 1985, 1988, 1989; Duncan et al. 1988; Friedman
et al. 1986; Gumpel et al. 1989). In these experiments,
cells with myelinating potential (Schwann cells, oligodendrocytes and their precursors) are introduced into the
CNS of dysmyelinating mutants, or into focal areas of
chemically induced demyelination, and their ability to
form myelin sheaths is determined. These studies have
shown that it is possible to replace one population of
myelinating cells with another, and have indicated that
transplanted glial cells can reconstruct a total glial
environment around demyelinated axons. Thus, Blakemore and Crang have demonstrated that glial-free areas
of demyelination, created by the local injection of the
gliotoxic agent ethidium bromide, can be reconstructed
by injecting cultures containing oligodendrocytes and
astrocytes, and have used this model to gain an insight
into the complex interactions between glial and neuronal
components that occur during repair of demyelinating
lesions in the CNS (reviewed by Blakemore et al. 1990).
When demyelinated central axons are present in astrocyte-deficient lesions they can recruit, and subsequently
be remyelinated by, Schwann cells. Thus, in normally
repairing glial-free areas of demyelination in the spinal
cord, which have not received a glial cell transplant, the
majority of axons becoming remyelinated with peripheral
myelin. Transplantation of glial cell suspensions of
different composition has highlighted the key role of the
type-1 astrocyte in enabling remyelination by oligodendrocytes in the face of competition from Schwann cells.
When type-1 astrocytes are absent from the transplant the
extent of central type remyelination is poor, irrespective
of the oligodendrocyte content (Blakemore and Crang,
1989). Conversely, when type-1 astrocytes are included
Schwann cell remyelination is limited and axons either
remain demyelinated or become remyelinated by oligodendrocytes (Blakemore and Crang, 1988, 1989). However, further experiments using type-1 astrocyte-containing transplants in which the number of oligodendrocytes
has been varied have indicated that a minimum number
of oligodendrocytes may be necessary to enable type-1
astrocyte to establish normal CNS relationships that
exclude Schwann cells (Crang and Blakemore, 1989).
Concluding remarks
The causes of axon regeneration failure in the adult
mammalian CNS are undoubtedly multifactorial. Trans188
R. jf. M. Franklin and W. F. Blakemore
plantation of glial cells into CNS lesions provides an in
vivo approach for investigating the interactions between
glia and damaged axons. By using glial transplants of
specific content in combination with techniques that
specifically remove all or part of the recipient animal's
glial population, such as the local injection of ethidium
bromide or lysolecithin, it may be possible to create new
glial environments for interrupted axons. Improvements
in techniques for manipulating the nature of CNS glial
cultures by the use of growth factors and selective
removal of specific glial cells, either by immunocytolysis
or by cell sorting, will enable the formulation of glial
transplants with a specific and predetermined content. In
addition, the techniques of molecular biology will permit
the production of 'designer glia' in which specific molecules, known to facilitate regeneration in the PNS and
developing CNS, are expressed on central glia.
R. J. M. Franklin holds a Wellcome Research Training
Scholarship.
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