Download Regulation of Stroke-Induced Neurogenesis in Adult Brain—Recent

Cerebral Cortex 2006;16:i162--i167
doi:10.1093/cercor/bhj174
Regulation of Stroke-Induced Neurogenesis
in Adult Brain—Recent Scientific Progress
Zaal Kokaia1,2, Pär Thored2,3, Andreas Arvidsson2,3 and
Olle Lindvall2,3
1
Laboratory of Neural Stem Cell Biology, Section of Restorative
Neurology, Stem Cell Institute, University Hospital, SE-221 84
Lund, Sweden, 2Lund Strategic Research Center for Stem Cell
Biology and Cell Therapy, Lund, Sweden and 3Laboratory of
Neurogenesis and Cell Therapy, Section of Restorative
Neurology, Wallenberg Neuroscience Center, University
Hospital, SE-221 84 Lund, Sweden
Stroke induced by middle cerebral artery occlusion in adult rodents
induces the formation of new neurons in the damaged striatum,
a region that normally does not show neurogenesis. Here we
describe recent findings on the regulation of neurogenesis after
stroke, in particular regarding the duration of the neurogenic
response and the influence of age, as well as the molecular
mechanisms influencing migration and survival of the new neurons.
We also discuss some crucial issues that need to be addressed in
the further exploration of this potential self-repair mechanism after
damage to the adult brain.
Keywords: migration, neural stem cells, neurogenesis, striatum, stroke,
subventricular zone
Introduction
Ischemic stroke induced by middle cerebral artery occlusion
(MCAO), causing infarction in the striatum and cerebral cortex,
gives rise to increased cell proliferation in the adult rat
subventricular zone (SVZ) (Jin and others 2001; Zhang and
others 2001; Zhang R, Zhang Z, Zhang C, and others 2004). The
newly formed neuroblasts migrate from the SVZ into the
damaged striatum (Arvidsson and others 2002; Parent and
others 2002; Jin and others 2003; Zhang R, Zhang Z, Wang,
and others 2004), a region in which neurogenesis does not
occur in the intact brain. After differentiation, a substantial
proportion of the new neurons express markers characteristic
of the mature neurons that died following the insult, that is,
striatal medium spiny neurons (Arvidsson and others 2002;
Parent and others 2002). These findings have raised the
possibility that functional improvement after stroke may be
induced through neuronal replacement from endogenous
neural stem cells (NSCs) in the adult brain.
Here we describe some of our most recent, partly unpublished data with focus on 3 major scientific issues related to
the regulation of neurogenesis after stroke: First, what is the
duration of striatal neurogenesis after the ischemic insult? The
neurogenic response has so far been thought to be acute and
transient, lasting only for a couple of weeks and giving rise to
very few new neurons. Second, can new neurons be formed
from endogenous NSCs also in the aged brain? If striatal
neurogenesis is maintained, it will raise the clinical interest in
this mechanism because stroke mainly affects older people.
Third, which are the molecular mechanisms regulating the
directed migration of the new neurons to the damaged area and
underlying the major loss of the new neuroblasts soon after they
have been formed? Identification of these mechanisms could
lead to new strategies to more efficiently attract the new
neurons to the site of injury as well as increase their long-term
survival.
Ó The Author 2006. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: [email protected]
Materials and Methods
In all studies described here, we used a well-characterized rat model of
stroke induced by MCAO. With respect to both pathology and
symptomatology, this model closely resembles the most common type
of stroke in adult humans. Briefly, under halothane anesthesia, the
middle cerebral artery of artificially ventilated rats was occluded with
a nylon monofilament inserted through the common carotid artery
(Koizumi and others 1986; Zhao and others 1994). After 30 min or 2 h,
the filament was withdrawn. The 30-min insult causes neuronal death
restricted to the striatum, whereas 2 h MCAO leads to damage also to
the overlying parietal cortex. For sham surgery, the filament is advanced
only a few millimeters inside the internal carotid artery. Body temperature, arterial blood pressure, pO2, pCO2, and pH were monitored
during surgery and kept within a predetermined physiological range.
For labeling of new cells, the mitotic marker 5-bromo-29-deoxyuridine
(BrdU) (50 mg/kg intraperitoneal) was given either 3 times with 2-h
interval and animals were killed 2 h thereafter (for assessing proliferation) or twice daily during 2 weeks and rats were then sacrificed up
to 1 year later (for determining survival and differentiation). To
determine the identity of the new cells, double-label immunocytochemistry with antibodies against BrdU and different phenotypical markers
was performed and double staining was confirmed by confocal
microscopy. Numbers of doublecortin+ (Dcx+) and Dcx+/BrdU+ cells
were counted in the striatum at 340 magnification using an epifluorescence microscope with a 0.25-mm quadratic grid, the most medial
column lining the SVZ. Four sections, evenly distributed throughout the
striatum, were sampled from each animal.
Results
Stroke Leads to Long-Lasting Morphological and
Functional Changes in the SVZ
Previous studies have demonstrated that maximum cell proliferation in the ipsilateral SVZ occurs at 1--2 weeks after MCAO
(Arvidsson and others 2002; Zhang R, Zhang Z, Wang, and
others 2004; Zhang R, Zhang Z, Zhang C, and others 2004). We
have now found (Thored and others 2005) increased number
and size of neurospheres isolated from ipsilateral SVZ at 6
weeks post-MCAO and expansion of the size of the ipsilateral
SVZ at both 2 and 6 weeks. When we injected the mitosis
marker BrdU just before sacrifice at 4 days but not at 6 weeks
after MCAO, BrdU labeling was increased in the ipsilateral SVZ.
This observation argues against a long-term increase of the pool
of rapidly dividing progenitors after stroke. Taken together,
our findings provide evidence that stroke leads to long-term
alterations in the stem cell niche in the SVZ.
Stroke Leads to Persistent Production of
New Striatal Neurons
In order to determine the duration of the neurogenic response
after stroke, we studied the occurrence of neuroblasts expressing Dcx in the striatum of adult rats at various time points after
2 h of MCAO. Dcx is a reliable marker of neurogenesis, which
is transiently expressed (during about 2--3 weeks) in newly
formed neuroblasts in both the intact and injured brain (Brown
and others 2003; Couillard-Despres and others 2005). Contralateral to the ischemic lesion, and in sham-operated animals,
Dcx immunoreactivity was confined to the SVZ and a few
striatal cells. In contrast, in the damaged striatum, the number
of Dcx+ cells was elevated already at 1 week and was stable
thereafter up to 16 weeks following the insult. At all time points,
the Dcx+ cells migrated from the SVZ laterally and ventrally
into the damaged area (Fig. 1).
Following a milder stroke, 30 min of MCAO, which gave rise
to a lesion restricted to the striatum, the neurogenic response
was less pronounced. The number of Dcx+ cells correlated
significantly with the volume of the striatal injury. Thus, the size
of the ischemic lesion determines the degree of activation of
the molecular and cellular mechanisms that promote recruitment of new striatal neurons after stroke.
We confirmed that neurogenesis occurs both early and late
after stroke and that neuroblasts formed also months after the
insult differentiate into mature neurons using BrdU injections
(Fig. 2). When BrdU was given during the first 2 weeks postMCAO and animals were killed directly thereafter, many Dcx+
cells were also BrdU+ (45%). Similarly, when BrdU was injected
during weeks 7 and 8 after MCAO, most of the Dcx+ neuroblasts
(71%) were colabeled with BrdU. Four weeks after BrdU
injections, these cells had lost their Dcx expression and
differentiated into BrdU+ cells coexpressing the mature neuronal marker NeuN (Fig. 3).
We have recently extended our findings on the duration of
the neurogenic response after stroke by giving BrdU injections
during 2 weeks in 5 rats subjected to 2 h MCAO 1 year earlier
(Fig. 4). Animals were perfused 4 weeks after the last BrdU
injection. All rats showed Dcx+ cells and fibers in the striatum
ipsilateral to the ischemic damage, whereas no Dcx+ staining
was found in the contralateral striatum. The number of Dcx+
cells corresponded to about one-fourth of that observed during
the first 4 months (106 ± 13 and 428 ± 40 cells). New cells
with a mature neuronal phenotype (NeuN+/BrdU+) were also
found in the ischemic striatum in all animals. Interestingly, the
ratio between NeuN+/BrdU+ cells and Dcx+ cells at 1 year was
similar to that at 6 weeks (10% and 20%, respectively). Taken
together, our findings indicate that striatal neurogenesis after
Figure 2. Numbers of all Dcx+ cells and Dcx+/BrdU+ double-labeled cells in the
damaged striatum following 2 weeks of daily BrdU injections performed either early
(weeks 1 and 2) or late (weeks 6 and 7) after 2 h MCAO. Note the gradual, timedependent decrease of the portion of Dcx+/BrdU+ cells in the total population of Dcx+
cells. Data are means ± standard error of mean.
Figure 1. Distribution of new Dcx+ cells at 2, 6, and 16 weeks after stroke, from SVZ
toward damaged striatum, and involvement of SDF-1a/CXCR4 signaling in the
neuroblast migration. Note that there is no difference in the percentage of Dcx+ cells
(of total number of Dcx+ cells) at different distances from SVZ at the 3 time points.
Also note that after intraventricular infusion of the CXCR4 blocker AMD 3100 during
weeks 5 and 6 after stroke, significantly more cells stay closer to SVZ and fewer cells
migrate toward the damaged striatum. Means ± standard error of mean. *P < 0.05
compared with vehicle, unpaired t-test.
Figure 3. Schematic representation of stroke-induced striatal neurogenesis at early
(A) and late (B) time points after 2 h MCAO. Production of Dcx+ striatal neuroblasts in
the SVZ is maintained at the same level from 1 up to 16 weeks after stroke. Daily BrdU
injections performed either early (weeks 1 and 2, A) or late (weeks 6 and 7, B) after 2 h
MCAO lead to similar events: the number of Dcx+/BrdU+ newly formed neuroblasts,
which is increased, is then gradually decreased with parallel increase of the number of
NeuN+/BrdU+ new striatal mature neurons.
Cerebral Cortex 2006, V 16 Supplement 1 i163
Figure 4. Dcx immunoreactivity in the contralateral ( A) and ipsilateral (B) striatum 1 year after 2 h MCAO. (C) Numbers of all Dcx+ and Dcx+/BrdU+ neuroblasts and NeuN+/BrdU+
new mature neurons in ipsi- and contralateral striatum at 1 year after 2 h MCAO. (D--F) Confocal images of NeuN+/BrdU+ new striatal neurons at 1 year after 2 h MCAO with daily
BrdU injections for 2 weeks and sacrificed 4 weeks thereafter. Orthogonal reconstructions from confocal z-series presented as viewed in x--z (bottom) and y--z (right) plane. Arrow
depicts double-labeled neuron. LV, lateral ventricle.
stroke continues at least for 1 year and that, despite a decline in
the formation of new neuroblasts at this late time point, the
yield of differentiated neurons seems to be rather unchanged.
Directed Migration of New Neurons to Damaged Area
after Stroke Is Regulated by Stromal Cell--Derived
Factor-1a
The chemokine stromal cell--derived factor-1a (SDF-1a) and its
receptor C-X-C chemokine receptor 4 (CXCR4) have been
reported to mediate homing of transplanted bone marrow-derived cells to sites of brain injury (Hill and others 2004; Ji and
others 2004) and migration of grafted NSCs to the infarcted area
after stroke (Imitola and others 2004). During brain development, SDF-1a/CXCR4 signaling plays an important role for
migration of neural progenitors (Lazarini and others 2003).
SDF-1a triggers in vitro migration of cells dissociated from adult
mouse SVZ neurospheres (Tran and others 2004), and CXCR4 is
expressed by mouse SVZ progenitors (Tran and others 2004).
Finally, SDF-1 immunostaining is increased in the injured mouse
striatum at least up to 4 weeks after stroke (Hill and others
2004). We have now (Thored and others 2005) obtained several
lines of evidence that SDF-1a/CXCR4 signaling is involved in the
persistent migration of new striatal neuroblasts from SVZ to the
damaged area after stroke in the adult brain. First, we found that
SDF-1 expression was upregulated in the ischemic rat striatum,
mainly in reactive astrocytes, at both early and late time points
after stroke, that is, up to 16 weeks after 2 h MCAO. Second, we
observed in vitro that SVZ neurosphere cells expressed the
CXCR4 and migrated toward a gradient of SDF-1a. This
migration was completely suppressed by the specific CXCR4
blocker AMD 3100. Finally, we infused AMD 3100 or vehicle
intraventricularly in rats subjected to 2 h MCAO during weeks 5
and 6 after the insult (Fig. 1). The AMD 3100 infusion caused
i164 Stroke-Induced Neurogenesis
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Kokaia and others
a significant suppression of the migration of the newly formed
neurons in the striatal parenchyma. In accordance with these
findings, Robin and others (2005) reported from a parallel study
that cultured SVZ progenitors exhibited increased migration
when overlaid on stroke brain slices as compared with normal
brain slices. Blocking SDF-1a by a neutralizing antibody against
CXCR4 attenuated the stroke-enhanced migration. However, in
our own experiments (Thored and others 2005), AMD 3100
only partially suppressed the migration of the new striatal
neurons in vivo, which may be due to incomplete blockade of
the CXCR4, but probably indicates that other cellular and
molecular mechanisms are also involved in directing the new
neurons to the damaged area.
Many New Neurons Die within Weeks After Stroke Due to
a Caspase-Mediated Apoptotic Mechanism
Only a portion of the stroke-generated striatal neuroblasts forms
mature neurons. We have not obtained any evidence that
the new neuroblasts remain in an undifferentiated state, which
indicates that many of them die. The involvement of caspasemediated apoptotic death in the loss of these neurons is
suggested by 2 main findings: First, that scattered Dcx+ cells
in the ipsilateral striatum coexpressed active caspase-cleaved
poly(adenosine diphosphate-ribose) polymerase (PARP) at both
2 and 8 weeks after MCAO (Thored and others 2005). The PARP
protein is a substrate of active caspases that upon cleavage by
caspases becomes inactivated as apoptotic cell death is initiated
(Herceg and Wang 2001). Second, infusion of a caspase inhibitor
cocktail or vehicle intraventricularly during the first 2 weeks
after 2 h MCAO lead to markedly higher number of Dcx+ cells in
the damaged striatum (Thored and others 2005).
It is conceivable that inflammatory changes accompanying
the ischemic damage contribute to the poor survival of the new
striatal neurons. Inflammation suppresses neurogenesis in the
dentate gyrus (Ekdahl and others 2003; Monje and others 2003)
by compromising the survival of the new neurons. Also, the new
striatal neurons will most likely die if they do not establish
synaptic connections and receive appropriate trophic signals.
Interestingly, we have found that a population of new neurons
survived for 4 months after stroke, which suggests that integration and trophic support can be achieved to some extent
in the stroke-damaged striatum (Thored and others 2005).
Stroke-Induced Neurogenesis Is Maintained in
the Aged Brain
We have explored whether stroke triggers neurogenesis in the
aged brain also and compared young adult (3 months) and
old (15 months) rats (Darsalia and others 2005). There was a
dramatic reduction of cell proliferation in the SVZ under basal
conditions. At 7 weeks after 1 h MCAO, the number of new
Dcx+ neuroblasts and mature NeuN+/BrdU+ neurons was
higher in the ipsilateral as compared with contralateral striatum
in both age groups. Interestingly, there were no significant differences in the numbers of new neuroblasts or mature neurons
in the ischemic striatum between young and old animals.
Thus, despite the low basal cell proliferation in the SVZ, this
potential mechanism of self-repair operates also after stroke in
the aged brain.
Discussion
The data described here demonstrate that a stroke, induced by
MCAO in adult rats, leads to long-term alterations in the
structure and function of the SVZ ipsilateral to the ischemic
damage. At least up to 1 year after the insult, the SVZ continues
to produce new neuroblasts, which migrate into the striatum
and then adopt a mature neuronal phenotype. Thus, NSCs in the
SVZ are a constant source of a cellular raw material, which
could be used for self-repair in the brain during the recovery
phase after stroke. In the following, we will discuss some of the
most important issues to address in order to further explore the
restorative potential of stroke-induced neurogenesis.
Can the New Stroke -Generated Neurons Become
Morphologically and Functionally Integrated
into the Brain?
Striatal neurons that are generated in the intact brain by
overexpressing brain derived neuotrophic factor and noggin
in the ventricular wall can project to their normal target area,
that is, the globus pallidus (Chmielnicki and others 2004).
However, following a stroke, target neurons may also have been
damaged that could interfere with the regenerative process.
Whether the stroke-generated striatal neurons receive afferents
and form efferent connections with mature neurons that
survived the insult is currently unknown.
Cells generated both in the hippocampal subgranular zone
and in the SVZ of the intact brain exhibit the electrophysiological characteristics of functional neurons (van Praag and others
2002; Carleton and others 2003). So far, patch-clamp recordings
have not been possible from the stroke-generated striatal
neurons because of technical problems with very ineffective
transduction using available green fluorescent protein (GFP)labeled viral vectors. Thus, it is not known whether the new
neurons develop the functional properties of striatal neurons
and if they become integrated into existing synaptic and neural
circuitries. Labeling of NSCs in the SVZ and their progeny using
a novel lentiviral-GFP vector (Consiglio and others 2004) may
provide the solution to this problem.
Which Neuronal Phenotypes Can Be Generated from
NSCs in the SVZ?
The most well-established new cell formed from NSCs in the
SVZ and migrating into the striatum after stroke expresses
markers characteristic of medium spiny neurons, that is, the
type of neuron mainly affected by the lesion. Virtually, all newly
generated neuroblasts express Pbx and Meis2 (Arvidsson and
others 2002), which are transcription factors observed in
striatal medium spiny neurons during embryonic development.
After maturation, about 50% of the new neurons express
the specific marker for medium spiny neurons dopamine- and
cyclic AMP-regulated phosphoprotein-32 (DARPP-32). But stroke
also causes degeneration of striatal interneurons. Teramoto and
others (2003) have reported generation of one type of striatal
interneuron, parvalbumin-expressing neurons, in the striatum
of epidermal growth factor--treated mice subjected to stroke. So
far, the formation of cells expressing interneuron markers has
not been shown after stroke in rats. However, using a different
model of striatal injury, that is, intrastriatal injection of the
excitotoxin quinolinic acid, we have demonstrated new neurons in the striatum expressing not only DARPP-32 but also
markers of 2 types of striatal interneurons, parvalbumin and
neuropeptide Y (Collin and others 2005). Our data indicate
that the SVZ can produce both striatal projection neurons and
interneurons in response to damage. These neuron types, which
are damaged both after stroke and after quinolinic acid infusion,
have different origins during embryonic development, that is,
lateral and medial ganglionic eminence, respectively (Marin and
others 2000). Whether the different striatal neuronal phenotypes generated in the adult brain arise from the same precursor
population in the SVZ or if the projection neurons and interneurons maintain separate origins within the SVZ is currently
unknown.
A crucial question is whether new neurons formed in the SVZ
after stroke can migrate also to the damaged cerebral cortex. So
far, this has not been convincingly demonstrated, and it is also
unclear whether neurogenesis can be triggered from local
NSCs in the cortical parenchyma. Interestingly, there is experimental evidence that under certain circumstances, neurogenesis
can be induced in the adult cerebral cortex by cortical injury.
Targeted apoptotic degeneration of cortical neurons in mice,
leaving the tissue architecture intact, has been reported to lead
to the formation of new cortical neurons extending axons to the
thalamus (Magavi and others 2000) and spinal cord (Chen and
others 2004). In contrast, only one report (Jin and others 2003)
has described migration of Dcx+ neuroblasts into the penumbra
of the ischemic cortex after stroke. Similarly, only one group has
observed the presence of BrdU+ cells colabeled with the marker
of mature neurons NeuN in the stroke-damaged cortex ( Jiang
and others 2001). Other studies from several laboratories have
failed to detect migration of the newly formed Dcx+ neuroblasts
from the SVZ to the cerebral cortex or any significant numbers
of mature NeuN+/BrdU+ cortical neurons after stroke (Zhang
and others 2001; Arvidsson and others 2002; Parent and others
2002). Taken together, these data indicate that in the ischemically damaged cortex, the cues necessary to trigger substantial
migration of neuroblasts from the SVZ or neurogenesis from
local parenchymal NSCs are lacking.
Cerebral Cortex 2006, V 16 Supplement 1 i165
Which Are the Functional Consequences of
Stroke-Induced Neurogenesis?
The long-lasting neurogenesis from endogenous NSCs after
stroke occurs concomitantly with the spontaneous recovery of
motor function, which is observed both in experimental animals
and in humans. Similarly, delivery of several growth factors
and other compounds during the first weeks after the insult
promotes both striatal neurogenesis and behavioral improvement. Although these observations suggest a functional role
of stroke-induced neurogenesis, there is at present no direct
evidence of a causal relationship between the formation of
new neurons and the symptomatic relief. It is a major challenge
for this research field to develop strategies to distinguish, in
a conclusive way, the functional consequences of neurogenesis.
This is required in order to efficiently optimize the improvement induced by neurogenesis. One possibility could be to
deliver after the stroke a mitosis inhibitor such as cytosine-b-Darabionfuranoside (Ara-C), which can dramatically suppress cell
proliferation in SVZ. The problem with this approach is that AraC will block proliferation also of other cell types in different
parts of the brain. It will, therefore, be difficult to attribute
observed behavioral changes after Ara-C to the lack of neurogenesis. A more attractive solution could be to generate
conditional transgenic mice in which the new neurons found
after stroke can be selectively ablated.
In conclusion, much work remains in exploring the potential
of the adult brain’s self-repair mechanisms. Hypothetically, this
basic research may lead to clinical applications in the future.
However, before any studies in patients are even considered,
we must know much more about how to control proliferation
of NSCs in the SVZ, migration of the new neuroblasts to the
damaged area, and their differentiation into specific phenotypes. We must also be able to induce functional integration of
the new neurons into existing synaptic and neural circuits and
to stimulate the neurogenesis for optimum functional recovery
in animal models.
Notes
Our own work was supported by the Swedish Research Council;
European Union project LSHBCT-2003-503005 (EUROSTEMCELL); and
The Söderberg, Crafoord, and Kock Foundations. The Lund Stem Cell
Center is supported by a Center of Excellence grant in Life Sciences
from the Swedish Foundation for Strategic Research. Conflict of
Interest : None declared.
Address correspondence to Zaal Kokaia, Laboratory of Neural Stem
Cell Biology, Section of Restorative Neurology, Stem Cell Institute, University Hospital, SE-221 84 Lund, Sweden. Email: [email protected].
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