Download New Challenges in CNS Repair: The Immune and

Current Immunology Reviews, 2012, 8, 87-93
87
New Challenges in CNS Repair: The Immune and Nervous Connection
Valter R.M. Lombardi*
EBIOTEC, Department of Cellular Immunology, La Coruña, Spain
Abstract: The Central Nervous System (CNS) is the organ with the least capacity for repair in mammals. Diseases of the
CNS may follow developmental deficits, inappropriate environmental factors and acquired damages after maturation. The
latter damages may consist of neuronal cell death, like Alzheimer's disease and/or to a lesion of the axon, like in the
paraplegic patients. Hopes of obtaining a functional recovery after trauma or neurodegeneration, are very low and
clinicians have very low possibilities for therapeutic interventions. The causes of the regenerative block in the adult CNS
are only partially attributable to the neural component. Direct or indirect interactions with glial cells, the resident CNS
immune cells, and with the extracellular matrix play a crucial role in determining the relative inability of adult CNS
connections to be modified: adult neurites find themselves within an environment rich in molecules strongly inhibitory for
regrowth and sprouting. A further complication arises from the fact that regenerative processes are always accompanied
by an inflammatory reaction with the consequent activation of astrocytes and microglia; this activation alters the
properties of the extracellular milieu. Thus, research on post lesional plasticity must not only study the molecular
mechanisms active in neurons but also consider the role of glial cells and the extracellular environment.
Keywords: Axon regeneration, myelination, neuron survival, neuronal growth factors.
INTRODUCTION
For many years, neurologists seem to have worked in the
therapeutic doldrums. Now, there are expectations that the
enormous investments made in basic neuroscience will
transform the treatment and management of common
neurological diseases. At least these are the hopes of the
many individuals around the world who suffer from
disorders of the central nervous system (CNS).
In many respects, the principles underlying the
development, organization and response to injury of the
brain and spinal cord are the same as for other tissues. But
there is one important difference. Damage to the CNS
usually has a much more profound effect on the individual.
Whereas recovery of other tissues is generally the rule, brain
and spinal cord repair is invariably limited, and persistent
functional deficits are commonplace following disease and
injury.
Strategies for repairing the CNS depend largely on
context. After traumatic injury of the spinal cord, axons are
disconnected from their targets. Although the parent neurons
initially remain intact, they do not indefinitely survive
axotomy. In situations where neurons and glia are focally
destroyed, as is the case following a stroke, functional
recovery depends on compensatory mechanisms and much
plasticity as the adult nervous system might possess. In
neurodegenerative disorders, such as Parkinson’s,
Alzheimer’s and Huntington’s diseases, one or more
anatomical systems is targeted, inhibiting essential activities
such as motor control or memory. Here, cells need to be
replaced or a chemically defined neuronal pathway and its
connectivities restored. Where a diffusely distributed cell
type is affected, for example, the oligodendrocyte and its
*Address correspondence to this author at the EBIOTEC, Department of
Cellular Immunology, Polígono Industrial de Bergondo, C/ Parroquia de
Guísamo s/n, Parcela A6 NaveF, 15166 Bergondo, La Coruña, Spain; Tel:
+34 981 784848; Fax: +34 981 784845; E-mail: [email protected]
17-;/12 $58.00+.00
myelin sheath in multiple sclerosis, neurological activity is
compromised in a number of separate pathways. The
challenge is, firstly, to contain the disease process and then
to restore the missing cell populations in strategically placed
lesions.
Axotomy, neuronal loss in defined systems, and
widespread neuronal or glial depletion present a hierarchy of
increasingly difficult challenges to “brain repair”. A simple
view is to consider repair as the re-establishment of normal
development, albeit within the context of disease. But a
number of basic questions immediately arise with respect to
the practicalities of achieving this “holy grail” of
neuroscience. Are stem cells for neurons and glia present in
the adult human nervous system? If so, can they migrate
from germinal centres to the sites of injury? Will growthfactor therapy prove to be effective and well tolerated as a
means of protecting cells from injury? Can the adult nervous
system be made amenable to axon regeneration? Will the
implantation of neurons and glia restore the structure and
function of the adult human nervous system? In this review
some of these questions will be addressed.
DEVELOPMENT OF THE CNS
The fully developed CNS contains neurons that have
been organized into functional systems. These systems have
been integrated to achieve complex behaviours which allow
individuals to respond to their external and internal
environments. During development, stem cells proliferate
before migrating from their places of birth to differentiate
into neurons or glia. Many of each are lost “en route” while
others are strategically sacrificed to ensure the density and
distribution needed to establish functional circuits within the
mature CNS. From a few pluripotential stem cells emerge
many millions of highly specialized neurons, supported by a
network of glia, which communicate through cell-cell
contacts and the release of soluble factors. Multipotential
© 2012 Bentham Science Publishers
88 Current Immunology Reviews, 2012, Vol. 8, No. 1
stem cells and lineage-committed progenitors are also found
in adult nervous systems, albeit in small numbers [1-3].
Elongation of axons occurs through the extension of
growth cones. Growth is determined and directed by the
intrinsic cytoskeletal activity of migrating cells, the
expression of adhesion and repulsion molecules within the
extracellular environment (including the collapsins, netrins,
and connectins) [4-6] and guidance by target-derived
neurotrophins [7, 8].
Axon regeneration, like axon development depends both
on the intrinsic ability of nerve cells to extend new growth
cones and on a permissive environment. Under favourable
circumstances, regenerating axons can reach distant
structures in the CNS and re-form synapses [7, 9, 10]. But
the mature CNS is essentially non-permissive. This can be
considered as the price that must be paid for needing an
inhibitory environment to guide axons through development,
and for stabilizing arrangements in the post-mature CNS.
The main inhibitions are imposed by differentiated glia.
Mature oligodendrocytes inhibit neurite outgrowth (through
molecules designed NI-35 and NI-250) [11, 12]. These
myelin-associated growth-inhibitory factors are present in
species, such as fish, in which axons do spontaneously
regenerate, possibly because inhibition is transiently reduced
following injury through the local release by macrophages or
microglia of interleukin-2.
Poorly regenerating axons are usually found in contact
with the star-shaped cells known as astrocytes. The
inhibitory properties of astrocytes correlate with the
expression of fibronectin [13], laminin [14], neural cell
adhesion molecule [15], januscin and tenascin [16], and
chondroitin sulphate proteoglycans [17]. The ability of
embryonic growth cones to penetrate their surrounding
astrocyte matrix depends on local secretion of protease, and
on the availability of serine protease inhibitors.
Neurons and their processes are embedded in a network
of microglia, astrocytes (of which there are probably many
types) and oligodendrocytes, which synthesize and maintain
the myelin sheath needed for salutatory conduction of the
nerve impulse. During development, radial glial cells serve
as a scaffold for migrating neurons. The differentiated forms
of mature astrocytes adopt diverse functions, providing an
architecture for neurons and defining anatomical boundaries,
acting as a source of growth factors and cytokines, assuming
a physiological role in nerve conduction, and participating in
the response to injury by producing many growth and
neuroprotective factors [18].
Oligodendrocyte
precursors
are
born
from
neuroectodermal cells in the subventricolar zones [19]. They
proliferate and migrate, with their progeny being found in
the forebrain, cerebellum, optic nerve and spinal cord by the
time of birth. Early on in embryonic life, oligodendrocyte
precursor cells can already be obtained from a cortical
multipotential precursor that is able to generate neurons,
oligodendrocytes and astrocytes. Although precursor cells
which generate oligodendrocytes are found in several parts
of the developing nervous system, there may be regional
specification, with particular concentration in the ventricular
zones and striatal rudiment.
Valter R.M. Lombardi
One much-characterized step in glial development
features the proliferative olygodendrocyte-type 2 astrocyte
(O-2A) progenitor [20]. At least in vitro, it is bipotential,
developing into either an oligodendrocyte or astrocyte; after
differentiation, it loses the ability both to proliferate and
migrate. The status of this cell remains controversial, since it
has been difficult to identify in vivo.
Cells that behave in vitro like O-2A progenitors can also
be recovered from the mature rat CNS, presumably
maintaining
the
potential
for
generating
new
oligodendrocytes. A glial precursor has also recently been
recovered from the adult human CNS, albeit in small
numbers. In vitro, this precursor proliferates in response to
astrocyte-derived factors and differentiates into both
astrocytes and oligodendrocytes [21]. This extends the
earlier demonstration of a non-proliferative adult human preoligodendrocyte.
Myelination occurs when the membranous processes of
oligodendroglia contact axons, then spiral and compact to
form the sheath needed for conduction of the nerve impulse.
Differential regulation in the expression of adhesion
molecules stabilizes the emerging glial-neuron unit.
Preliminary evidence suggests that the adult human
oligodendrocyte progenitor associates with human neuronal
cell lines to produce myelin, while comparative studies with
xenogenic-co-cultures identify the step between initial axonglial adhesion and membrane wrapping as crucial for the
establishment of compact myelin lamellae [22-24].
Microglia, are primary immunocompetent cells of the
CNS. Ultimately, they are derived from bone-marrow
macrophages, and may be replenished from the systemic
circulation during life. They shape the developing and
injured nervous system by removing redundant or
compromised
material,
and
act
as
primary
immunocompetent cells by presenting antigen, producing
cytokines, and mediating cytotoxicity [25-27].
GROWTH FACTORS
Acting together or in sequence, growth factors
orchestrate development within the nervous system,
influencing cell proliferation, migration and differentiation.
Many also support survival of fully differentiated cells. In
some senses, nerve growth factors have been misnamed,
since they have actions on non-neuronal cells and are
produced by cell other than neuronal targets. Some have
autocrine and paracrine functions, while cytokines also
possess nerve growth activity. Factors that regulate the
growth and survival of neurons include nerve growth factor
(NGF), brain-derived nerve growth factor (BDNF),
neurotrophin (NT)-3, NT-4/5, glial-cell-line-derived nerve
growth factor (GDNF), fibroblast growth factors (FGFs), and
ciliary neurotrophic factor (CNTF) [28-34]. Each
preferentially, but not exclusively, supports one or more
functional or anatomical neuronal systems.
Growth, differentiation and survival are influenced by
platelet-derived growth factor (PDGF), insulin like growth
factors (IGF-1 and 2), interleukin-6 and leukemia inhibitor
factor (LIF) [3537]. Combinations of factors optimize
growth and survival in vitro.
New Challenges in CNS Repair
It is clear that proliferation, migration, survival and
differentiation of glia are controlled by separate factors
produced by astrocytes, microglia and neurons. PDGF and
FGF indefinitely suspend O-2A progenitor differentiation,
maintaining cell proliferation until these growth factors are
withdrawn [38]. NT-3 has proliferative effects both in vitro
and in vivo. The onset of oligodendrocyte differentiation
coincides with transforming growth factor (TGF) beta
production. In vitro, O-2A progenitors differentiate into type
2 astrocytes under the influence of CNTF, extracellular
matrix molecules, and other, as yet unidentified, signals [39].
Survival factors for the oligodendrocyte lineage include IGFI and II, LIF, IL-6 and TN-3, as well as PDGF and CNTF
[40]. Reduced availability of survival factors leads to the
strategic loss of a high proportion of newly formed
oligodendrocytes in parts of the developing nervous system.
This is comparable to the way in which the number of
neurons is adjusted by programmed cell death.
Growth factors also protect from injury those cells that
they support during development. The discovery of each new
neutrophin, and the identification of its neuronal or glial
dependents, has in most instances been followed by the
demonstration of growth factor-specific protection from
axotomy or toxic injury [41-43].
From this and other evidence emerges the general
principle that the signals transduced by cells during growth
and physiological activity are overloaded during pathological
events leading to cell injury and death. The extent to which a
cell can survive injury is modulated by its growth-factordependent state of health. It follows that cell death may
occur in response to injury from which protection could be
anticipated under more favourable growth-factor conditions
[44-47]. Conversely, an optimal growth-factor environment
may save cells from otherwise lethal signals transduced
across the cell membrane [48].
THE LESSONS OF TRANSPLANTATION
Transplantation has helped in the identification of factors
that influence axonal regeneration in the CNS. Implanted
embryonic axons grow through white-matter tracts that are
not yet myelinated, and adult neurons regenerate best
through unmyelinated pathways.
These observations confirm that myelin-associated
molecules are important in the inhibition of axon growth in
the mature CNS. Paradoxically, neuroblasts transplanted
from the embryonic human nervous system into rat brain and
spinal cord have an enhanced growth potential compared
with rodent cells [49]. These results can be interpreted as
reflecting the longer period of growth needed by the
developing human nervous system, as well as the greater
distance that growing axons need to cover. They also
illustrate the relative growth potential of some neurons
independent of their environment.
Axon regeneration improves when central myelin and
oligodendrocytes are replaced by the more permissive
environment of peripheral glia. Schwann cells in intact
peripheral nerves promote axon regeneration in the CNS,
perhaps by making neurotrophic factors (NGF, BDNF and
CNTF) available and by expressing adhesion molecules that
support neurite out-growth [50-53].
Current Immunology Reviews, 2012, Vol. 8, No. 1
89
Treatment in neurological diseases currently aims at
prevention and limitation of disease processes, activities
which are underpinned by research into causation and
mechanism. It is possible that disease limitation will produce
the unexpected dividend of promoting spontaneous recovery
if the potential for endogenous repair can be released in a
disease-free environment, perhaps with support from growth
factors. If this optimism proves misplaced, neurobiologists
and clinicians will have to confront the socially, ethically
and biologically demanding task of implanting cells from an
extrinsic source in order to restore lost structure and
functions.
A survey of the entire range of experimental situations in
which neural grafting has been assessed clarifies that a wide
variety of systems can be reconstituted. These include visual,
endocrine, cognitive and motor pathways. Implantation,
survival and local production of neurotransmitters are not
necessarily sufficient to restore complex behaviours [54, 55].
Functional success also requires axonal growth and
connectivity [56]. In this case, the limitations are that
implanted cells may not migrate from sites of engraftment
and their processes must grow through an inhospitable
environment to reach the right targets. Ectopic graft
placement overcomes this requirement for growth, but limits
the extent to which implanted cells can explore their target
area and connect appropriately. Thus, the limitations on
migration and axonal growth in the CNS represent a tradeoff between restoration of orthodox anatomical arrangements
and what can realistically be achieved.
Of particular interest is the recent demonstration that
neural progenitors implanted into the cerebral ventricles of
newborn mice are found distributed throughout the neuraxis
at maturity, demonstrating the potential for rapid widespread
dissemination of transplanted cells throughout the nervous
system, at least during development [57]. As expected, the
viability of transplanted neurons is enhanced by factors
which promote the growth and survival of these same
neurons in vitro.
The assessment of grafts has required the development of
behavioural tasks that can be reliably reproduced in
experimental animals and that mimic the defects of
neurodegenerative disease. Grafting restores akinesia [58],
sensory neglect [59] and memory [60], in relation to learned
tasks of motor and cognitive performance in rodents and
primates.
MYELINATION
What can be learned about myelination from
transplantation? Glial cells at the appropriate stage of
differentiation necessary for the synthesis of myelin may still
lack essential properties for remyelination, such as the ability
to proliferate and migrate [61]. The major limiting factor for
restoring glial arrangements in the mature CNS does indeed
appear to be the poor survival and migration of implanted
cells, whereby they are unable to explore gliopaenic areas
and recapture enough naked axons to restore electrical
conductance through white matter pathways [62].
Astrocytes, oligodendrocytes and myelin can each be
detected after implantation of clonal progenitor glial cell
lines, which are established using the temperature-sensitive
90 Current Immunology Reviews, 2012, Vol. 8, No. 1
mutant of SV40 large T gene and CG4 cells. The potential for
remyelination by glia that have been derived from the adult
nervous system has been studied using rodent and human
cells [63-66]. Transplanting a mixed population of
progenitor and fully differentiated adult rat cells into the
spinal cord (previously demyelinated by ethidium bromide
and X irradiated to prevent host remyelination) leads to
expansion of the donor oligodendrocyete pool (by
proliferation of progenitors) and to extensive remyelination.
Human progenitor cells, transplanted in a mixed glial cell
culture, survive in clumps within the rodent lesion, but fail to
migrate [67-69]. Their oligodendrocyte progeny extend
processes that enwrap and separate rat axons, but do not
form myelin sheaths. In time, stem cells expanded in vitro
with epidermal growth factor (EGF) and bFGF before
grafting could be used to generate myelin-forming cells.
These histologically oriented studies leave unanswered
the question of whether remyelination will restore function.
Conduction velocity is severely reduced in mice that are
myelin-deficient due to the absence of proteolipid protein
[70]. Morphologically normal myelin is found after
transplantation of cells from normal litter mates [71]. This
overcomes conduction block and improves the velocity of
conducting fibres by three-fold.
APPLICATIONS FOR NEUROLOGICAL MEDICINE
There is experimental evidence that axons sprout around
an area of damaged spinal cord stimulated with NT-3.
Axonal regeneration, routed around the lesion, is enhanced
by also blocking inhibitory molecules on the surface of
mature oligodendrocytes [72-76]. Anti IN-I antibodies placed
in the parietal cortex of animals undergoing spinal
hemisection partially restore motor function by enhancing
recovery of corticospinal fibres, and by promoting plasticity
of surviving motor neurons [77]. The improved ability of
embryonic neurons to grow and reach distant targets has
been used experimentally to show that both ends of a foetal
spinal cord graft will connect and restore function across a
complete spinal lesion. Growth-factor therapy and
immunological restoration of a permissive environment for
regeneration constitute possible clinical applications in the
management of spinal cord and, perhaps, also head injury
[78-80].
Neurodegenerative disease is another important subject
for neural repair researchers. Calcium overload mediated by
the excitotoxin glutamate has been proposed as the
mechanism of cell death in motor neuron disease [81, 82].
This observation has prompted clinical trials of the presynaptic glutamate release inhibitor riluzole [83]. This
inhibitor is reported to slow the progression of motor neuron
disease and to improve survival in patients with bulbar onset
of symptoms. Since CNTF salvages motor neurons in
genetically determined neuromuscular disorders of mice, its
trophic and survival effects on motor neurons have led to the
launching of therapeutic studies in animal models of motor
neuron disease and amyotrophic lateral sclerosis [84-86].
Despite good theoretical arguments for the use of CNTF,
practical problems have been encountered. Attention has
now switched to IGF and BDNF, in the hope that one or the
other will promote survival of spinal motor neurons, without
causing serious adverse effects [87].
Valter R.M. Lombardi
Preliminary evidence for the disease-modifying effect of
the free radical scavenger alpha tocopherol (vitamin E) and
the selective monoamine oxidase B antagonist deprenyl in
Parkinson’s diseases (PD) has not been confirmed [88-92].
Cell implantation may eventually be needed in situations
where large numbers of neurons have already been lost [93,
94]. Several hundreds of patients with PD have already
received brain cell implants [95]. Fluorodopa ligand positron
emission tomography shows that the implanted cells survive.
In the most intensively studied cases, steady improvement in
function has occurred several months after grafting. This
would seem to suggest that the viability of the engrafted
material and the local production of dopamine are clinically
useful only when connectivity has also been restored.
In the future, the difficulties of using a human tissue
source for treating PD may be overcome by having access to
engineered fibroblast cell lines for implantation therapy, with
the graft survival and function being improved through the
use of adjuvant therapy to protect the implanted cells.
Experimental studies indicate that there may also be
opportunities for patients with Huntington’s disease [96].
Striatal grafts restore structure, as well as cognitive and
motor function after excitotoxic injury of the rat striatum
with ibotenic acid. Ideas are also developing regarding the
possibility of repairing focal areas of cortical damage
resulting from ischemic injury. Foetal neocortex grafts have
been assessed using sensory stimulation, monitored by
deoxyglucose utilization in grafted areas of focal ischaemia
with neuronal degeneration. Thalamic projections capture
and connect with the engrafted neurons, but the extent to
which these restore independent cortical activity remains
uncertain.
Recent developments in therapeutic immunology suggest
that it should be possible to stabilize the erratic, widespread
and recurrent inflammation that undermines saltataory
conduction in multiple sclerosis (MS) [97]. Remyelination is
seen in animals and humans after oligodendrocyte depletion.
However, it is still not clear whether remyelinating cells are
the progeny of migrating progenitors or of mature
oligodendrocytes that have re-entered the proliferative cell
cycle. Since the adult human nervous system contains small
numbers of oligodendrocytes precursors, the persistent
failure of glial progenitors to repair damaged nerve fibres
may result either from the lack of recruitment into zones of
demyelination, resulting from deficient signals to those
progenitors, which could, under more favourable
circumstances, reach the naked axons, or from difficulty in
penetrating the astrocytic scar which develops around areas
of demyelination. Bi-potential progenitors that successfully
reach gliopaenic areas in vivo might encounter naked axons
and differentiate inappropriately.
Assuming an immunologically stable environment,
remyelination could be enhanced by direct implantation of
oligodendrocyte lineage cells [98-101]. Growth factors
might first be used to increase their numbers in vitro, and
cells could even be harvested from the nervous system of
individuals who are themselves to benefit from
transplantation, thus overcoming some ethical dilemmas and
the problems of graft rejection [102, 103].
New Challenges in CNS Repair
CONCLUSIONS
Information transfer in the nervous system is emerging as
an extreme complex process. An increasing number of
actors, especially proteins, seem to play a role through
interactions that are still poorly understood. Similarly, the
search of novel therapeutic tools and strategies for
neuropsychiatric disorders still awaits the identification and
characterization of new molecular targets at the synaptic
level. Clearly, if synaptic proteins (receptors, transporters,
transducing systems, ion channels, etc.) work as multimers
rather than as individual molecules, novel therapeutic targets
may originate from the detailed knowledge of the
interactions in which these proteins are engaged. Thus, it
seems crucial that new drugs will not only be exclusively
directed against a single protein, but also will be able to
correct the faulty functions of interacting protein complexes.
To reach this objective, our knowledge of the functional
proteomics of the synapse needs to be enriched under both
physiological and pathological aspects. New possible areas
of research will involve: 1) the characterization of the
protein-protein interactions involved in synaptic vesicle
trafficking and exocytosis under physiological conditions
and in genetic models of deficits of synaptic transmission; 2)
the receptor-receptor and transporter-transporter interactions
involved in the modulation of neurotransmitter release as
new pharmacological targets; 3) the identification of the
molecular determinants of innervation and synaptic plasticity
in the cerebellar cortex under physiological conditions and in
models of cerebellar pathology; 4) the identification of the
molecular determinants of neuronal and glial degeneration
and survival and as new potential targets for the treatment of
neurodegenerative diseases.
Current Immunology Reviews, 2012, Vol. 8, No. 1
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
ACKNOWLEDGEMENT
Declared none.
[21]
CONFLICT OF INTEREST
Declared none.
[22]
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Revised: October 15, 2010
Accepted: November 4, 2010