Download Endogenous adult neural stem cells: Limits and potential to repair

Journal of Neuroscience Research 76:223–231 (2004)
Endogenous Adult Neural Stem Cells: Limits
and Potential To Repair the Injured Central
Nervous System
Nathalie Picard-Riera, Brahim Nait-Oumesmar, and Anne Baron-Van Evercooren*
Institut National de la Santé et de la Recherche Médicale, U546, Laboratoire des Affections de la Myéline et
des Canaux Ioniques Musculaires, Institut Fédératif des Neurosciences, CHU Pitié-Salpêtrière, Paris, France
Mitotic activity persists in various regions of the adult
mammal CNS. While evidences of neurogenesis appeared, many studies focused on the features of the
adult stem cells from germinative areas such as the
subventricular zone of the lateral ventricles, the dentate
gyrus of the hippocampus, the cortex, the fourth ventricle
and the central canal of the spinal cord. In the present
paper, we review the potentialities of the adult germinative areas in terms of proliferation, migration and differentiation in non pathological situation and in response to
different type of CNS injury. Adult endogenous stem cells
are activated in response to various injuries but their
capacities to migrate and to undergo either neurogenesis
or gliogenesis differ according to the lesion-type and the
germinative zone from which they arise. Different works
demonstrated that epigenic factors such as growth factors can enhance the repair potential of the adult stem
cells. Reactivation and mobilization of endogenous stem
cells as well as demonstration of their long-term survival
and functionality appear to be interesting strategies to
investigate in order to promote endogenous repair of the
adult CNS. © 2004 Wiley-Liss, Inc.
Key words: neurogenesis, germinative zone, oligodendrogenesis, proliferation, migration
The first evidence for neurogenesis in the adult
central nervous system (CNS) was published 40 years ago
(Altman and Das, 1965; Lewis, 1968; Altman, 1969; Privat
and Leblond, 1972), but the notion that new neurons are
generated really has found acceptance during the last decade. The use of proliferation markers such as tritiated
thymidine, 5-bromo-2⬘-desoxyuridine (BrdU), and retroviral labeling highlighted neuronal renewal in at least two
areas of the adult mammalian brain, the granule cell layer
(GCL) of the dentate gyrus (DG) in the hippocampus and
the olfactory bulb (OB). These new neurons are generated, respectively, from the subgranular zone (SGZ) of the
DG and the subventricular zone (SVZ) of the lateral
ventricles. In vitro studies have underscored the stem cell
properties of cells residing in these germinative areas.
Adult neural stem cells have been shown to display undifferentiated, self-renewable, and multipotent features.
© 2004 Wiley-Liss, Inc.
The neural stem cell is considered as a primary progenitor
that is the precursor of a multipotent secondary progenitor. The secondary progenitor then gives rise to a precursor committed to a specific lineage of the CNS. Although
the primary progenitor (stem cell) appears to have astroglial characteristics in the adult CNS, it retains the capacity
to undergo neurogenesis (Alvarez-Buylla et al., 2002;
Tramontin et al., 2003).
Since the neurogenerative capacity of the adult CNS
was established, many strategies designed to repair neurodegenerative diseases have been developed. Most studies
explore the potential for repair by embryonic or perinatal
stem cells using transplantation paradigms. However, the
use of perinatal material implies ethical considerations, the
availability of the cells, and their amplification and manipulation in vitro prior to intra-CNS transplantation. However, cell therapy may not be the most optimal strategy to
enhance repair in multifocal diseases, such as multiple
sclerosis (MS). The ability to isolate neural stem cells from
the adult human brain raises the possibility of autologous
transplantation. Therefore, experimental strategies designed to enhance reactivation and mobilization of endogenous stem cells have appeared and may lead to novel
therapeutic approaches to neurodegenerative or demyelinating diseases. In this paper, we review the germinative
areas of the adult mammalian CNS and summarize their
potentialities in terms of cell reactivation, migration, and
self-repair of the injured CNS.
THE SVZ
The SVZ is a remnant of the enlarged perinatal
periventricular germinative area. During development,
this germinative area narrows to the most rostral part of the
lateral ventricle and forms the SVZ, which persists through
*Correspondence to: Anne Baron-Van Evercooren, U546, Laboratoire des
Affections de la Myéline et des Canaux Ioniques Musculaires IFRNS,
Faculté de Médecine Pitié-Salpêtrière, 105 bd. de l’Hôpital, 75634 Paris
Cedex 13, France. E-mail: [email protected]
Received 22 October 2003; Revised 3 November 2003; Accepted 5
November 2003
Published online 8 March 2004 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/jnr.20040
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Picard-Riera et al.
adulthood (Tramontin et al., 2003). During development
the SVZ generates the three major cell types of the CNS,
but only neurogenesis persists in adulthood. However, in
vitro, the adult SVZ stem/progenitor cells can be expanded in serum-free medium containing epidermal
growth factor (EGF) and fibroblast growth factor 2
(FGF-2) and form neurospheres, which generate neurons
and glia (Reynolds and Weiss, 1992; Lois and AlvarezBuylla, 1993). However, in vivo, BrdU and retroviral
tracing demonstrates that only neurogenesis occurs in the
OB, from SVZ cells migrating through the rostral migratory stream (RMS; Luskin, 1993; Lois and Alvarez-Buylla,
1994; Lois et al., 1996). The nature of the stem cells in the
SVZ is a subject of controversy. According to the original
theory, the SVZ stem cells are ependymal cells lining the
lateral ventricle (Johansson et al., 1999), whereas other
authors claim that the stem cells originate from the subependymal layer of the lateral ventricle (Morshead et al.,
1994; Chiasson et al., 1999). Eventually, this latter theory
was confirmed by the work of Alvarez-Buylla and colleagues, identifying the SVZ stem cell as a subependymal
cell with a low proliferation rate (Doetsch et al., 1999).
Electron microscopy studies show that SVZ stem cells
have the ultrastructural characteristics of astrocytes, which
extend a single cilia into the ventricle lumen through the
ependymal barrier (Tramontin et al., 2003). A nomenclature for the SVZ organization was established by the
Tramontin et al. group. The slowly proliferating stem cells
expressing glial fibrillary acidic protein (GFAP; type B
cells) differentiate to become rapidly dividing immature
progenitors (type C cells) and generate neuroblasts (type A
cells), which migrate in chain through the RMS to the
OB. It has recently been demonstrated that the RMS and
the OB also contain stem cells and thus can be considered
by themselves as germinative areas (Gritti et al., 2002). In
this study, although all regions gave rise to neurons, astrocytes, and oligodendrocytes, in vitro, the rostral part of
the RMS generated more oligodendrocytes. Cells arising
from the SVZ and migrating through the RMS to the OB
were also described for the adult primate forebrain (Pencea
et al., 2001a; Kornack and Rakic, 2001). Although a
detailed study of the localization of neural stem cells in the
adult human brain is still lacking, neurospheres can be
generated from the adult human subependymal zone of
the lateral ventricle. Similarly to the case for rodents, these
adult human neurospheres give rise to functional neurons
and glia (Kukekov et al., 1999; Westerlund et al., 2003).
However, they seem to have a limited life span in culture
and generate very few oligodendrocytes (Kukekov et al.,
1999; Roy et al., 2000). Neural stem cells can also be
isolated from the adult human OB (Pagano et al., 2000).
They display the same characteristics as human embryonic
stem cells (Vescovi et al., 1999). They self-renew in vitro
with EGF and FGF-2 and retain their multipotentiality.
However, whereas embryonic stem cells keep these properties as long as 2 years, adult OB stem cells have been
studied only until 40 days in vitro.
Several models have been utilized to determine the
real involvement of SVZ cells in CNS repair of acute or
chronic injury. Most of these models have involved rodents and have demonstrated that SVZ cells are reactivated
in response to different insults. Indeed, the proliferation
rate of SVZ cells is increased after seizure (Parent et al.,
2002), ischemia (Zhang et al., 2001; Arvidsson et al., 2002;
Takasawa et al., 2002), transection (Weinstein et al.,
1996), and also demyelination (Calza et al., 1998; NaitOumesmar et al., 1999; Picard-Riera et al., 2002). Recent
studies have shown reactivation of the SVZ in the brains of
patients affected with Huntington’s disease (Curtis et al.,
2003) and in nonhuman primates exposed to ischemia
(Tonchev et al., 2003). However, reactivation of the SVZ
in demyelinating diseases, such as MS, has not been reported so far.
The mobilization and recruitment of SVZ cells by
lesions and their subsequent differentiation have been assessed in most of these models. After pilocarpine-induced
status epilepticus in rats, Lowenstein and colleagues demonstrate that SVZ cells migrate more numerously in the
RMS, although some are ectopically recruited in the
neighboring injured regions to differentiate into neuronal
precursors (Parent et al., 2002). However, few of these
SVZ-derived neurons survive after a period of 5 weeks,
and that they differentiate appropriately and are incorporated into the normal circuitry has not been demonstrated.
The induction of stroke by transient middle artery occlusion is a model of focal ischemia that leads to the selective
death of striatal neurons. When stroke is induced in adult
rats, SVZ cells are selectively recruited in the injured
striatum, whereas this phenomenon rarely occurs in the
contralateral noninjured striatum (Arvidsson et al., 2002).
Recruited cells coexpress doublecortin (Dcx), a marker of
migrating neuroblasts, and Meis2, a specific marker of
medium-sized spiny neurons of the striatum. Four weeks
after stroke, the number of mature neurons increases,
indicating that the neuroblasts underwent differentiation.
However, functional evidence was not provided by this
study. The authors indicated that 80% of newly generated
neurons die between 2 and 6 weeks postischemia and that
only a small proportion (about 0.2%) of striatal neurons are
replaced. By using global ischemia, which selectively induces CA1 pyramidal neuron death, coupled to growth
factor (EGF and FGF-2) infusion, Nakafuku and colleagues selectively traced caudal SVZ cells and demonstrated that they are mobilized to the CA1 region of the
hippocampus, where they contribute to the replacement
of pyramidal neurons (Nakatomi et al., 2002). Retrograde
labeling, electron microscopy, and electrophysiology show
that these newly generated neurons receive synaptic inputs
and establish connections between the CA1 domain and
the subiculum. Hippocampal neurons are involved in
learning and memory functions, so testing in a Morris
water maze has confirmed the recovery of brain functions.
Although the neurogenic potential of adult SVZ cells
in brain repair has been investigated, few authors have
asked whether these cells could also generate oligoden-
Neural Stem Cells and CNS Repair
drocytes. During early postnatal development, SVZ cells
generate oligodendrocytes whose fate is to integrate into
white matter (Levison and Goldman, 1993). This activity
persists in the brain of juvenile animals but ceases during
adulthood. We assessed the reactivation of adult SVZ cells
in murine models of focal (Nait-Oumesmar et al., 1999)
and multifocal inflammatory demyelination, experimental
autoimmune encephalomyelitis (EAE; Picard-Riera et al.,
2002). In both models, the demyelination induces the
proliferation of cells in the SVZ, their robust migration in
the RMS, and their mobilization to the lesion sites. In
both cases, cells differentiate into astrocytes and oligodendrocytes, whereas inflammation leads only to astroglial
differentiation. In the multifocal model of EAE, cells are
not exclusively recruited in the corpus callosum but are
also found in the striatum. However, their mobilization
seems to be restricted to the regions in the vicinity of the
SVZ and RMS. Some of the SVZ cells undergo oligodendrogenesis after demyelination in the corpus callosum
and also in the OB. Three weeks after EAE induction, cell
death is not observed, suggesting that these newly generated oligodendrocytes are not the target of inflammatorydemyelination within this time frame. However, the fate
and functionality of these oligodendrocytes in terms of
myelin repair have yet to be demonstrated. To date, the
mechanisms involved in the proliferation and mobilization
of SVZ cells in response to inflammatory demyelination
are unknown. However, Aloe and colleagues reported
that this phenomenon seemed to be correlated with a
selective uptake of 125I-nerve growth factor, suggesting
that nerve growth factor could participate in these phenomena (Calza et al., 1998).
Studies of the SVZ’s response to injury in human and
nonhuman primate brains are rarely undertaken. Recently, evidence of induced neurogenesis was suggested in
a macaque model of ischemia (Tonchev et al., 2003).
Although migration was not assessed, the authors demonstrated increased proliferation in the SVZ compared with
control animals. This study demonstrated the activation of
a population of mitotic cells with a neuronal, astroglial or
oligodendroglial phenotype. Moreover, a recent study reported the induction of proliferation in the SVZ of patients affected with Huntington’s disease (Curtis et al.,
2003). The rate of proliferation, assessed by PCNA labeling, increased with the severity of the disease. The authors
gave evidence of disease-induced neurogenesis and described the emergence of proliferative neuroblasts in the
injured caudate nucleus. Reactivation of the SVZ in demyelinating diseases, such as MS, has not been reported so
far. Our preliminary studies using MS tissues highlight the
detection of PSA-NCAM-expressing progenitors in some
types of lesions (Picard-Riera, unpublished data). Whether
these cells arise from the SVZ is currently under investigation.
Taken together, these different models reveal the
ability of SVZ cells to undergo increased proliferation,
ectopic migration, and multipotential differentiation. This
differentiation is lesion specific, insofar as trauma induces
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astroglial differentiation, a loss of neurons favors neuronal
differentiation, and oligodendrogenesis occurs essentially
in response to demyelination. Thus, it seems that local
cues originating either from the lesion or from the environment in which cells migrate are important to direct
their differentiation into the appropriate cell fate. Although SVZ cells reactivate in response to injury, they do
not display a massive replacement, and newly generated
neurons do not represent a stable population. As previously suggested by Lindvall and colleagues (Arvidsson et
al., 2002), the functional integration and long-term survival of these newly generated cells have to be further
investigated to determine the extent to which SVZ cells
can participate in self-repair.
THE HIPPOCAMPUS
The DG of the hippocampus has also been extensively studied. Stem cells originating from the SGZ of the
DG migrate into the GCL, where they differentiate into
granule neurons that extend axons to the CA3 region
(Altman and Das, 1965; Bayer, 1982; Kaplan and Bell,
1984; Kuhn et al., 1996). Gage and colleagues studied
rodent SGZ cells in vitro and found that their stem cells
retain the potential for self-renewal and the ability to
differentiate into neurons, astrocytes, and oligodendrocytes (Palmer et al., 1997). In mice, the proliferative cells
of the SGZ give rise to neurons, astrocytes, and oligodendrocyte progenitors (van Praag et al., 2002). The newly
generated neurons integrate correctly into the hippocampal circuitry. Neurogenesis also occurs in the SGZ of tree
shrews (Gould et al., 1997), nonhuman primates such as
macaques (Gould et al., 1999b, 2001; Kornack and Rakic,
1999), marmosets (Gould et al., 1998), and humans (Eriksson et al., 1998). Furthermore, an in vivo study performed
in Old World monkeys reported the generation of astrocytes and oligodendrocytes in the DG (Kornack and Rakic, 1999). SGZ cells of the adult human brain were also
studied in vitro, confirming their stem cell features (Kukekov et al., 1999; Roy et al., 2000).
Questions arise about the phenotype of the primordial stem cells of the SGZ. Alvarez-Buylla and colleagues
demonstrated that GFAP-expressing cells of the SGZ can
generate neurons of the GCL (Seri et al., 2001). The same
work also demonstrated that a cell organization similar to
that described for the SVZ exists in the hippocampus. In
the SGZ, a weakly proliferative stem cell expressing GFAP
(type B cell) gives rise to a small, dark, transient cell (type
D cell), specific to the SGZ, that finally generates a GCL
neuron. Several works have underscored the transient
existence of these new neurons in both rodents (Cameron
et al., 1993; Gould et al., 1999a) and Old World monkeys
(Gould et al., 2001). In contrast, a recent study performed
in mice highlighted the long-term persistence of newly
generated neurons in the hippocampus, which were detected as late as 11 months after BrdU labeling (Kempermann et al., 2003).
Animal models of neurological diseases are also used
to investigate the potential for repair of the SGZ. Seizure
induces proliferation in the rodent SGZ, increasing the
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proliferation rate of progenitor cells (Parent et al., 1997,
2002; Bengzon et al., 1997). Ischemia accelerates proliferation in rodents (Liu et al., 1998; Jin et al., 2001;
Nakatomi et al., 2002; Takasawa et al., 2002; Dempsey et
al., 2003) and also in nonhuman primates (Tonchev et al.,
2003). Although SGZ cells normally undergo shortdistance migration to integrate into the GCL, long-
distance migration does not seem to occur in pathological
models. Many studies have highlighted the presence of
lesion-induced neurogenesis in the hippocampus. Sharp
and colleagues induced transient global ischemia in gerbils
and traced proliferative cells of the DG by using BrdU
injections (Liu et al., 1998). The observation of BrdUlabeled cells at different time points allowed the authors to
establish their pattern of migration and differentiation.
Fifteen days after ischemia, most of the BrdU-positive cells
were located in the SGZ but did not express NeuN. From
26 to 40 days after ischemia, traced cells progressively
migrated to the GCL, where finally 61% of them expressed NeuN. Interestingly, the control animals also displayed an increased number of double-labeled NeuN/
BrdU cells between days 26 and 40, confirming that
neurogenesis occurs under normal conditions. Moreover,
SGZ cells also undergo astrogliogenesis. Some SGZ progenitors migrate to the hilus to generate astrocytes,
whereas a proportion of the cells that migrate to the DG
and the dentate hilus remains unidentified. These unlabeled cells could be either undifferentiated progenitors or
oligodendrocytes, the latter cell type having rarely been
investigated. Neurogenesis in the hippocampus has also
been demonstrated in various models of focal ischemia in
the rat (Jin et al., 2001; Arvidsson et al., 2001; Takasawa et
al., 2002; Dempsey et al., 2003) and global ischemia in
macaque monkeys (Tonchev et al., 2003).
All these studies demonstrate that new SGZ-derived
neurons are able to replace lost neurons and to restore
function of the hippocampus. In pathologies, SGZ cells
are reactivated, migrate over a short distance, and undergo
neurogenesis. The long-term persistence of newly generated neurons has been demonstrated in the noninjured
hippocampus, but this property remains to be confirmed
Š
Fig. 1. The adult rodent brain contains areas with mitotic activity.
A: The subventricular zone (SVZ) contains proliferative cells (red dots)
lining the rostral part of the lateral ventricle. In nonpathological situations, these cells migrate along the rostral migratory stream (RMS) to
generate new neurons in the olfactory bulb. In response to injury, these
cells can migrate ectopically into the striatum or the corpus callosum or
caudally toward the CA1 region of the hippocampus. Under these
conditions, SVZ cells retain the capacity to differentiate into astrocytes,
oligodendrocytes, and neurons. Some of them migrate into the cortex
to maintain the existence of resident progenitors. Those progenitors
seem to be glial ones, and whether they can undergo neurogenesis
remains controversial. B: In the hippocampus, stem cells reside in the
subgranular zone (SGZ) of the dentate gyrus (DG). These cells migrate
to the granule cell layer (GCL) to differentiate into neurons, extending
axons to the CA3 area of the hippocampus. They also generate some
astrocytes and oligodendrocytes in the GCL. In response to lesions,
SGZ cells migrate in large numbers to the GCL to add more neurons,
some of them being functional. These cells also undergo gliogenesis in
the hilus (h); they give rise to astrocytes and undetermined cells that
could be oligodendrocytes. C: In the spinal cord, progenitors exist in
the ependymal layer and the parenchyma. Cells generated in response
to a lesion are essentially glia, although a few neurons have been
reported. OB, olfactory bulb; V, ventricle; GM, gray matter; WM,
white matter.
Neural Stem Cells and CNS Repair
in pathological conditions. Moreover, although stem cells
from the hippocampus display some glial differentiation,
their ability to repair traumatic or demyelinating lesions is
still unclear.
THE CORTEX
Unlike the case for the SVZ and the SGZ, few
studies have identified neural stem cells in the rodent
cortex. However, neural stem cells have been isolated
from the human cortex and amygdala (Arsenijevic et al.,
2001). Recently, resident glial precursors were isolated
from human subcortical white matter (Nunes et al., 2003).
These precursors appear to be multipotential cells retaining the ability to undergo both neurogenesis and gliogenesis in vitro and following transplantation. Gross and colleagues report the genesis of new neurons in the neocortex
of adult macaque monkeys (Gould et al., 1999c). These
cells arise from the SVZ and migrate through the white
matter to integrate into the neocortex, where they differentiate into mature neurons. This ventricular-cortical migration may be a remnant of the waves of tangential
migration observed from the lateral and medial ganglionic
eminences to the neocortex during development (Corbin
et al., 2001). However, two studies performed in macaques were not in agreement with these data and, in
contrast, demonstrated that BrdU-positive cells detected
in the neocortex are in fact satellite glial cells closely
apposed to resident neurons (Kornack and Rakic, 2001;
Koketsu et al., 2003). These studies underscore the necessity to perform detailed confocal analysis and threedimensional reconstruction to establish unambiguously the
origin of newly generated neurons and glia in the adult
CNS.
However, in pathological situations, in situ cortical
neurogenesis can occur. The induction of synchronous
apoptotic degeneration of specific neurons of the anterior
cortex in adult mice leads to the replacement of lost
neurons (Magavi et al., 2000). In this study, neurogenesis
was confirmed using three-dimensional reconstruction.
Moreover, some of the newly generated neurons were
mature neurons forming long-distance corticothalamic
connections. Though not investigated, these cells may also
be activated in response to demyelination and participate
in myelin repair.
THE SPINAL CORD AND THE
FOURTH VENTRICLE
Because neurogenesis occurs in the adult SVZ, such
a phenomenon is likely to occur through the entire ventricular neuroaxis. Reynolds and colleagues tested this
hypothesis by evaluating the in vitro characteristics of
different regions of the rodent spinal cord (Weiss et al.,
1996). Cells from various dorsoventral regions of the
spinal cord and the third and the fourth ventricle were
expanded in medium enriched with EGF and FGF-2. All
these regions display self-renewal and multipotential features of stem cells. The lumbosacral segment of the spinal
cord is defined as the area providing the greatest number
of multipotent cells with close similarities to cultures from
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the lateral ventricles. However, the nature of the stem cell
in the ependyma remains to be elucidated. Mitotic activity, though discrete, also exists around the fourth ventricle
(Martens et al., 2002). Further investigations must be
performed to determine the potential for reactivation in
this area.
In vitro, FGF-2 alone is sufficient to give rise to both
neurons and glia in all spinal cord regions (Shihabuddin et
al., 1997). Proliferating cells of the spinal cord reside not
only in the ependymal layer of the central canal but also in
the parenchyma (Horner et al., 2000). In nonpathologic
conditions, these cells are glial progenitors; they generate
essentially astrocytes and oligodendrocytes but not neurons. Ependymal and parenchymal progenitors are activated in response to spinal cord transection (Yamamoto et
al., 2001). They proliferate and constitute approximatively
12% of the BrdU-labeled cells in the parenchyma, and,
when isolated in vitro, they generate astrocytes and oligodendrocytes but few neurons. Questions persist about the
precise nature and origin of these cells. Do they arise from
the ependyma or the parenchyma? Do they have similar
multipotential features? Gage and colleagues hypothesized
two models to explain adult neurogenesis in the spinal
cord (Horner et al., 2000). In the first, both ependymal
and parenchymal proliferative cells are stem cells; in the
second, the ependymal cell is a stem cell whose progeny
migrates to the parenchyma to become a resident progenitor. Strategies should be envisioned to label each of these
populations specifically and to determine their cell fate.
Immature progenitors expressing PSA-NCAM in the absence of other markers and originating from the ependyma
are also observed in response to focal demyelination
(Oumesmar et al., 1995). However, their contribution to
myelin repair remains to be established.
FACTORS STIMULATING ENDOGENOUS
STEM CELLS
In vivo, the fate of SVZ cells is neurogenesis; however, growth factor infusion is able to direct cell differentiation toward astrocytes and oligodendrocytes in addition
to neurons (Craig et al., 1996). SVZ cells retain the
capacity to migrate both rostrally and caudally and to
differentiate into the appropriate phenotype. However, it
appears that this migration is quite limited and that differentiation does not always imply adequate functionality.
The infusion of growth factors in nonpathological conditions can enhance proliferation and trigger the mobilization and differentiation of SVZ cells. The infusion of EGF
increases cell proliferation in the SVZ and the olfactory
tract and favors gliogenesis rather than neurogenesis (Craig
et al., 1996; Kuhn et al., 1997). Whereas EGF enhances
the migration and dispersion of cells in the parenchyma
surrounding the olfactory tract, FGF-2 enhances cell proliferation in the SVZ and neurogenesis in the OB (Kuhn
et al., 1997; Wagner et al., 1999). In aged animals, transforming growth factor-␣ (TGF-␣) and FGF-2 return the
proliferation rate of SVZ cells to that of young adults
(Tropepe et al., 1997; Decker et al., 2002).
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Picard-Riera et al.
Growth factor treatment enhances the contribution
of stem cells to repair mechanisms. The infusion of FGF-2
and EGF induces a 50-fold increase in neurogenesis from
the SVZ in response to ischemia (Nakatomi et al., 2002).
We found that priming SVZ cells by a single injection of
FGF-2 prior to intra-CNS grafting enhances their ability
to form myelin in recipients (Lachapelle et al., 2002).
TGF-␣ treatment induced the migration and differentiation of SVZ progenitors in a Parkinson’s disease model in
the rat (Fallon et al., 2000). Cells migrated to the site of
TGF-␣ infusion, in the striatum, where they differentiated
into neurons. Although the functionality of the newly
generated neurons was not physiologically assessed, the
activation of the SVZ cells and their migration/
differentiation to the site of injury were correlated with
the recovery of functional activity; the treated animals
displayed improvement in behavioral tests. In chemically
demyelinated mice, an intraperitoneal injection of FGF-2
or TGF-␣ increases the number of SVZ cells recruited to
the lesion in young adults but not aged animals (Decker et
al., 2002). Insofar as aged and young adult SVZ cells
possess a similar potential for migration in vitro, these data
highlight the crucial role of the lesioned environment in
the recruitment of SVZ cells. Brain-derived neurotrophic
factor (BDNF) improves the recruitment of SVZ cells to
the OB and stimulates their differentiation into neurons
(Zigova et al., 1998; Pencea et al., 2001b; Benraiss et al.,
2001).
In the hippocampus, growth factors act on proliferation and neurogenesis rather than on migration. Under
normal conditions, IGF-1 is reported to increase hippocampal proliferation and neurogenesis (Aberg et al.,
2000). The same growth factor, as well as glia-derived
neurotrophic factor (GDNF), increases proliferation and
survival time of progenitors in ischemic rats (Dempsey et
al., 2003). Although FGF-2 seems to promote only neurogenesis under nonpathological situation (Kuhn et al.,
1997; Wagner et al., 1999), the effect of FGF-2 was
assessed in homozygous FGF-2-deficient mice subjected
to either seizure or ischemia (Yoshimura et al., 2001).
FGF-2–/– mice displayed reduced BrdU incorporation and
a decreased number of NeuN/BrdU double-labeled cells
compared with wild-type mice. Exogenous FGF-2 allowed this situation to be overcome. Interestingly, no
proliferation differences appeared between FGF-2deficient and wild-type mice under nonpathological conditions, confirming the above-mentioned result showing
no effects of FGF-2 on cell proliferation under normal
conditions. However, intracisternal infusion of FGF-2
promotes proliferation and neurogenesis in the DG of rats
after focal ischemia (Wada et al., 2003). Injury may either
favor FGF-2 uptake by cells or reactivate a population of
cells responsive to this growth factor.
The reduced mitotic activity of the fourth ventricle
can be emphasized by using an infusion of EGF, FGF-2,
and heparin (Martens et al., 2002). These growth factors
promote proliferation in the whole ventricular neuroaxis,
whereas EGF induces the migration of cells from the
fourth ventricle and the ependymal layer of the spinal
cord. The origin of the proliferative cells found in the
spinal cord may be controversial; some of them may be
resident progenitors of the parenchyma. Similarly, in the
fourth ventricle, as in the spinal cord, some cells have
differentiated into astrocytes or oligodendrocytes but not
into neurons. Thyroid hormone has been shown to be a
factor enhancing oligodendrogenesis in EAE rats (Calza et
al., 2002). Whereas EAE promotes the increased proliferation of progenitors in the spinal cord of rats, treatment
with the thyroid hormone T4 leads to reduced mitotic
activity and favors their differentiation into oligodendrocytes. These results suggest that different growth factors
could be administered in different time windows first to
enhance proliferation and migration and subsequently to
stimulate differentiation.
In addition to the growth factors described above,
morphogens, such as bone morphogenic proteins (BMPs),
Shh, and Wnt signalling, regulate the proliferation and
differentiation of SVZ neural stem cells. For instance,
several lines of evidences support a role of Shh in adult
neural stem cell proliferation and maturation (Lai et al.,
2003). Furthermore, it was recently reported that oral
administration of a Shh agonist increased the number of
proliferating cells in the adult SVZ and hippocampal DG.
This effect is mediated by an up-regulation of Gli1 signalling (Machold et al., 2003). However, the nature of the
cells that produce Shh in the SVZ and DG remains unclear. These data suggest that this morphogen may also
play a critical role in the pathological status of the adult
mammalian brain. It may be possible to take advantage of
the continuous expression of Shh in adult germinative
zones to develop new therapeutic drugs for neural disorders. BMPs and their antagonist Noggin also play a critical
role in the proliferation and differentiation of adult SVZ
stem/progenitor cells (Lim et al., 2000). SVZ cells express
BMPs and their cognate receptors. BMPs potently inhibit
neurogenesis both in vitro and in vivo and promote glial
differentiation. In contrast, Noggin promotes neurogenesis in vitro and inhibits glial cell differentiation. Lim et al.
proposed that ependymal Noggin secretion creates a neurogenic niche in the SVZ by blocking BMP signaling.
Insofar as this mechanism is relatively well understood
under normal conditions, it will be of interest to investigate whether the expression profiles of these molecules are
changed following brain damage. In fact, it has recently
been reported that the intravenous administration of
BMP7 has neuroprotective effects and induces neuronal
repair in cerebral stroke in adult rats (Chang et al., 2003).
Other epigenetic factors influence neurogenesis in
both hippocampal and olfactory structures. Mice exposed
to an enriched olfactory environment display increased
neurogenesis and survival time of the new neurons (Rochefort et al., 2002). The absence of changes in hippocampal
proliferation indicates that this neurogenesis is specific for
olfactory function.
However, stress decreases proliferation in the SGZ in
rats (Gould and Cameron, 1996), tree shrews (Gould et al.,
Neural Stem Cells and CNS Repair
1997), and marmosets (Gould et al., 1998), possibly
through an increased concentration of glucocorticoı̈des,
but this remains to be demonstrated (Cameron and Gould,
1994). Gross and colleagues indicate that new neurons
added in the GCL have a transient existence (Gould et al.,
2001). Several studies have demonstrated that an enriched
environment, consisting of the addition of elements to
create a three-dimensional environment, increases neurogenesis and, to a lesser extent, astrogliosis in the hippocampus of rodents (Kempermann et al., 1997a,b; van Praag et
al., 2002). Interestingly, whereas odor enrichment is specific for OB neurogenesis, environmental enrichment induces neurogenesis only in the hippocampus (Brown et
al., 2003). Neurogenesis seems to be intimately linked to
the function of the structures in which it occurs. According to this hypothesis, it would be interesting to investigate
the relative importance of olfactive vs. hippocampal neurogenesis in the human brain in which learning and memory may prevail over olfaction. The impact of an enriched
environment on oligodendrogenesis in pathological and
nonpathological conditions has not been investigated to
date. These results suggest that “laboratory” studies performed in nonenriched environments may underestimate
the extent of the neurogenesis and gliogenesis that would
occur if animals were studied in their natural environment.
CONCLUSIONS
Both the SVZ and the SGZ retain the potential to
increase cell proliferation and neurogenesis in response to
various insults. Although SGZ cell migration seems to be
limited to the DG and the hilus of the hippocampus, even
in pathological situations, SVZ cells, whose fate is to
migrate rostrally to the OB, can alter this migration to
escape prematurely into neighboring areas, such as the
striatum and corpus callosum. Taking advantage of their
caudal migration, SVZ cells can also ectopically invade the
CA1 layer of the hippocampus. Hippocampal and SVZ
stem/progenitor cells generate neurons, some of which are
functional, but also astrocytes and oligodendrocytes in
response to injury. The real involvement of the other
germinative zones under pathological conditions should
be further investigated. Moreover, the long-term effects of
neurogenesis and gliogenesis remain elusive. Do the new
neurons accurately integrate into neuronal circuitry, and
do oligodendrocytes undergo effective remyelination? Because white matter oligodendrocyte progenitors participate in myelin repair, it will be important to determine the
advantages of the new oligodendrocyte progenitors derived from germinative zones over the resident white
matter ones. Because neurogenesis and oligodendrogenesis
from germinative areas remain a restricted phenomenon,
efforts should focus on the cues promoting the long-term
survival and functional differentiation of endogenous
stem/progenitor cells to repair the injured CNS efficiently. The identification of the signals involved in reactivation and of the cell type triggered by the lesion would
help to resolve the contribution of stem cells to repair
mechanisms. Insofar as each disease dictates the genesis of
a particular cell phenotype, it will be of interest to com-
229
pare the nature of the signals involved and to investigate
the relevance of the results described for rodents to human
neurodegenerative and demyelinating diseases of the
CNS.
ACKNOWLEDGMENTS
N.P.-R. was supported by the Fondation pour la
Recherche Médicale.
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