J Neural Transm (2011) 118:61–74
DOI 10.1007/s00702-010-0478-4
REVIEW ARTICLE
Cell-based therapy for stroke
Yu Luo
Received: 6 August 2010 / Accepted: 23 August 2010 / Published online: 14 October 2010
Ó Springer-Verlag (outside the USA) 2010
Abstract Current treatments for stroke, such as the use of
thrombolytic agents, are often limited by a narrow thera-
peutic time window. However, the regeneration of the
brain after damage is still active days even weeks after
stroke occurs, which might provide a second window for
treatment. Cell-based therapy can be categorized into two
strategies. One is transplantation of exogenous cells into
the injured brain to replace the lost cells or support the
remaining cells. The other strategy is to enhance the pro-
liferation, differentiation, migration of endogenous stem or
progenitor cells. Recent development in adult stem cell
research and advancement in the induction of pluripotent
stem cells from somatic adult cells provide a tremendous
opportunity for transplantation therapy. Understanding the
mechanisms and regulations involved in the endogenous
neurogenesis will also help develop novel therapeutic
interventions to promote neurogenesis and functional
recovery in stroke. This review describes up-to-date pro-
gresses in cell-based therapy for the treatment of stroke.
Keywords Stroke
Cell-based therapy
Stem cells

iPS cells
Introduction
Stroke is one of the leading causes of death and disability
worldwide and has an incidence of approximately 150–200
in 100,000 (Modan and Wagener 1992). There are two
types of stroke: ischemic stroke which is caused by an
Y. Luo (&)
National Institute on Drug Abuse, I.R.P.,
251 Bayview BLVD, Baltimore, MD 21224, USA
e-mail: luoy@mail.nih.gov
occlusion of a blood vessel and hemorrhagic stroke which
is initiated by a rupture of a blood vessel in the brain.
Among these two types of stroke, ischemic stroke consti-
tutes majority of the stroke case (85–90%) and hemor-
rhagic stroke constitutes 10–15% of the stroke cases
(Qureshi et al. 2001). With the development of rehabilita-
tion in stroke patients, there has been significant
improvement in the long-term outcome in stroke patients.
However, there are still many patients suffering from
severe neurological deficits and are dependent on care
weeks and months after stroke onset (Eriksson et al. 2008).
Therefore, stroke places a heavy burden on the economy in
our society.
Current treatment strategies for stroke primarily focus
on reducing the size of ischemic damage and on rescuing
dying cells early after occurrence. Treatments, such as the
use of thrombolytic agents, are often limited by a narrow
therapeutic time window (Gilman 2006; Goldstein 2007).
However, the regeneration of the brain after damage is still
active days even weeks after stroke occurs, which might
provide a second window for treatment (Thored et al.
2006).
Cell-based therapy can be categorized into two strate-
gies. One is transplantation of exogenous cells into the
injured brain to replace the lost cells or support the
remaining cells. The other strategy is to enhance the pro-
liferation, differentiation, migration of endogenous stem or
progenitor cells.
Transplantation of exogenous cells
Depending on the location of the occlusion, various brain
regions are affected differently in stroke. In many cases of
stroke, there is a ‘‘core’’ region which is a central zone of
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necrosis and surrounding it is the ‘‘penumbra’’ region
which is composed of partially injured brain (Hakim 1998;
Rafalowska 2002; Touzani et al. 1995). Different cell types
are all affected by ischemic injury but neurons seem to be
the most vulnerable. In the penumbra area, it is possible
that neurons may be partially or completely lost, whereas
glia, vasculature, and overall architecture are still intact
(Hakim 1998). Given that there is multiple cell type loss in
stroke, ideal regenerative strategies needs to achieve the
replacement of a variety of cells in central nervous system
(CNS). However, since neurons are the most vulnerable
cells to ischemic damage, most of the current strategies in
replacement therapy aim for replacement of neurons.
Another possible intervention is to support the existing
neurons by means of inhibiting apoptosis and promoting
the integrity of neuronal connections. Early work in stroke
transplantation demonstrated that the use of fetal neocor-
tical grafts had beneficial outcome in behavioral
improvement in a rat stroke model (Grabowski et al. 1994;
Mattsson et al. 1997; Sorensen et al. 1996). However,
translating this early success into human studies was dif-
ficult due to both the limitation in source tissue and the
ethical concerns.
Currently, the cell types that have been tested in stroke
model include embryonic stem cells (ESCs), adult-derived
neural stem cells (NSCs), bone marrow or mesenchymal
stem cells (BMSCs), and umbilical cord blood stem cells
(UCBCs). Other than attempting to replace the lost cells in
stroke brain, some other cell types may work by providing
support and recruiting endogenous progenitor cells to the
stroke brain. One example for the latter is the olfactory
ensheathing cells (OECs) and olfactory nerve fibroblasts
(ONFs). Cell types that have been tested in preclinical
transplantation studies are summarized in Table 1. We will
discuss them in detail below.
Embryonic stem cells
Embryonic stem (ES) cells have many characteristics
required for an optimal cell source for cell-replacement
therapy (Bjorklund 2000; Doss et al. 2004). ES cells are
self-renewing and multipotent cells derived from the inner
cell mass of the preimplantation blastocyst (Evans and
Kaufman 1981). It has been shown that transplantation of
undifferentiated ES cells into animals produces teratomas
(Reubinoff et al. 2000) or even highly malignant terato-
carcinomas (Reubinoff et al. 2000; Thomson et al. 1998).
Due to the potential risk, there have not been extensive
reports on transplanting undifferentiated ES cells in stroke
animals (Erdo et al. 2003; Hoehn et al. 2002). However, it
has been reported in a Parkinson’s disease model, when
transplanted at a low single-cell density, undifferentiated
ES cells were able to proliferate and fully differentiate into
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dopaminergic neuons (Bjorklund et al. 2002). The animals
receiving transplants demonstrated functional recovery in
unilateral rotation. Neuroimaging studies also confirmed
recovery in transplanted animals. No tumor formation was
reported in this study. Two factors seem to be important in
determining the tumor formation and the fate of trans-
planted cells. The first is cell density. It is reported that at
high density, undifferentiated ES cells often develop into
cells originating from all germ layers and form large het-
erogenous structures that fail to integrate into the host brain
(Deacon et al. 1998). However, when diluted to low density,
the cell-to-cell contact is decreased among ES cells and the
host–donor interaction is enhanced, which allows differ-
entiation into neurons with proper phenotype (Bjorklund
et al. 2002). The second important factor is the species
barrier between donor and host cells. It has been reported in
stroke models that xenotransplants of murine undifferenti-
ated ES cells into the stroke rat brain result in successful
differentiation and migration towards the injured area
(Hoehn et al. 2002), whereas, homologous transplantation
into mouse brain resulted in highly malignant teratocarci-
nomas without migration away from the transplant
site(Erdo et al. 2003). Interestingly, the reported successful
transplantation in the Parkinson’s disease model is also a
case of cross-species example (mouse undifferentiated ES
cells to rat brain; Bjorklund et al. 2002). Although homol-
ogous transplantation offers less immune response in the
host tissue and smaller chance for rejection, in the case of
undifferentiated ES cells, a tumor-suppressive effect caused
by xenologous transplantation might not be adverse.
Another possible solution is to differentiate ES cells in
vitro first. The tumorigenic potential of ES cells seems to be
greatly reduced when cells are predifferentiated in vitro
before implantation (Erdo et al. 2003). Recent developments
(Takahashi et al. 2007; Takahashi and Yamanaka 2006; Yu
et al. 2007) in the induction of pluripotent stem cells from
somatic adult cells provide a tremendous opportunity for this
field. Stem cells can be derived from an adult animal and
engineered or differentiated in vitro and transplanted back
into the diseased organism. Initial success has been reported
in a Parkinson’s disease model using iPS cells (induced
pluripotent stem cells; Wernig et al. 2008). There have not
been reports of iPS cell transplantation in stroke studies but
if it works, this technique would provide the advantage of
both generating autologous and specifically engineered stem
cells for an individual patient.
Adult stem cells
Adult derived NSCs
Immortalized neuronal precursor cell lines have been
extensively tested and reviewed in other papers (Andres
 Table 1 Summary of preclinical studies investigating cell transplantation in stroke
Cell origin Cell type Stroke model Delivery route Delivery time* Differentiation Functional recovery Reference

Embryonic stem D3 ES cell line Mouse/Rat MCAo IC: contralateral 2 weeks Neurons (NeuN?) in rats ND Erdo et al. (2003)
cellsm expressing GFP cortex/striatum Tumor formation in mouse
ES cell line Rat MCAo 60 min IC: contralateral 2 week ND ND Hoehn et al. (2002)
expressing GFP corpus callosum
and striatum
Cell-based therapy for stroke

Adult NSCs Rat hippocampus Rat TGI IC: bilateral dorsal 2 week Neurons and astrocytes Improvement in water Toda et al. (2001)
NSCs hippocampus maze test
Rat SVZ NSCs Rat Embolic MCAo Cisterna magna 2 days ND Angiogenesis measured Jiang et al. (2005)
by MRI
Rat SVZ NSCs Rat Embolic MCAo Cisterna magna 2 days Neurons (TuJ1?) Angiogenesis measured Li et al. (2006)
by MRI
Rat SVZ NSCs Rat Embolic MCAo Cisterna magna 2 days Neuronal morphology and Recovery on foot fault Zhang et al. (2003)
connection with adjacent and adhesive removal
neurons test
Rat SVZ NSCs Rat MCAo IC: right ischemic 3h Neurons (nestin?/PSA- Recovery in limb Kameda et al. (2007)
overexpressing boundary zone NCAM? but not placing test and
GDNF MAP2?/astrocytes cylinder test
Mouse GFP positive Rat MCAo IC: ipsilateral cortex 7 days Neuorns (DCX?) and Recovery in cylinder Hicks et al. (2007)
SVZ NSCs and striatum astocytes (GFAP?) test only in enriched
environment
Bone marrow MSCs Rat MCAo 2 h Intravenous 1 or 7 days Neurons (NueN? and Recovery in Chen et al. (2001b)
derived stem cells MAP-2?) and astocyte somatosensory
(GFAP?) behavior and NSS
MSCs Rat MCAo 2 h Intracarotid 1 day Neurons and astrocytes Recovery on adhesive- Li et al. (2001)
removal test and NSS
MSCs Rat MCAo 2 h Intravenous 1 day Neurons and astrocytes Recovery on sticky tape Li et al. (2002)
test
MSCs Rat MCAo 2 h Intracerebral 1 day Neurons and astrocytes Recovery in Chen et al. (2001a)
somatosensory
behavior and NSS
MAPCs Rat MCAo IC: ipsilateral cortex 1 week Neurons, astrocytes and Recovery on limb Zhao et al. (2002)
oligodendrocytes placement and sticky
tape test
Adult olfactory bulb HOECs Rat MCAo Intracerebral 1 day Neurons and astrocytes Recovery on behavioral Shyu et al. (2008)
tests
ES embryonic stem cells; IC intracerebral; MCAo middle cerebral artery occlusion; NSCs neural stem cells; GFP green fluorescent protein; ND not determined; TGI transient global ischemia;
SVZ subventricular zone; SGZ subgranular zone; MRI magnetic resonance imaging; GDNF glial-derived nerve growth factor; PSA-NCAM poly-sialated neural cell adhesion molecule; MAP2
microtubule-associated protein 2; DCX doublecortin; GFAP glial fibrillary acidic protein; MSCs marrow stromal cells; MAPCs multipotent adult progenitor cells; hOECs human olfactory
ensheathing cells; NSS neurological severity score
* Delivery time after stroke onset
63

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et al. 2008a). We will focus here on primary cultured cells
derived from adult CNS as a source for cell transplants.
Neural stem/progenitor cells can be found in tissues of
fetus, neonate, young, and adult animals. They are repre-
sentative of cells that retain the capacity to renew them-
selves and to differentiate into variety types of cells in the
CNS (Doetsch et al. 1999; Eriksson et al. 1998; McKay
1997; Reynolds and Weiss 1992; Richards et al. 1992).
These cells can be found in many regions in the brain
(McKay 1997). Whether there are neuronal stem cells in
the cortex or midbrain is still under unclear (Gould 2007).
Subventricular zone (SVZ; Doetsch et al. 1999; Reynolds
and Weiss 1992) and Subgranular zone (SGZ; Eriksson
et al. 1998), however, have been clearly established to
contain self-renewable stem/progenitor cells (Fig. 1). Iso-
lated neuronal stem cells are able to proliferate in response
to different growth factors, such as basic fibroblast growth
factor (bFGF) or epidermal growth factor (EGF), and can
be differentiated into both neuronal and glial cells (Rey-
nolds and Weiss 1992, 1996). NSCs from both SVZ and
SGZ have been transplanted into animal models of stroke
with beneficial outcomes. When transplanted into a rat
stroke model at 2 weeks after transient global ischemia, rat
hippocampal NSCs were able to integrate and differenti-
ated into both neurons and astrocytes in hippocampus,
which led to a significant recovery in learning and memory
Fig. 1 Areas of the adult brain where neurogenesis persists. a The
parasagittal section of a mouse brain shows the brain regions involved
in rodent adult neurogenesis. Neruoblasts generated at the subven-
tricular zone (SVZ) migrate through the rostral migratory stream
(RMS) to reach the olfactory bulb (OB). Subgranular zone (SGZ)
resides in the hippocampus. b Coronal section depicts the SVZ region
(red). c Coronal section depicts the SGZ region (red)
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function (Toda et al. 2001). Several other studies explored
the possibility of transplanting SVZ cells in animal stroke
models (Jiang et al. 2005; Li et al. 2006; Zhang et al.
2003). In these studies, SVZ NSCs could successfully
differentiate into different neurons and glial cell types,
exhibit robust migration to the ischemic area, and produce
improvement in functional behavioral tests. It should be
noted that NSCs cells isolated from adult brain can be
genetically modified to express certain genes which may
facilitate the regeneration process (Kameda et al. 2007).
Gene modification can also push these progenitor cells to
differentiate towards a non-default phenotype (Shim et al.
2007). For example, Nurr1-engineered adult SVZ NSC
cells survived, integrated, and differentiated into mature
dopaminergic (DA) neurons in vivo that could reverse the
behavioral deficits when placed in the host striatum of
parkinsonian rats (Shim et al. 2007). This opens up the
possibility of using these cells in the treatment of other
neurodegenerative diseases. In stroke animal models, it has
also been noted that an enriched environment (Hicks et al.
2007) appears to improve NSCs migration and functional
recovery, emphasizing the importance of combinatory
therapy with transplantation and rehabilitation.
BMSCs
When stem/progenitor cells are introduced into an allo-
genic host, the acute and chronic graft-versus-host inter-
action/rejection might interfere with the survival of donor
cells (Battler and Leor 2006). Adult autologous stem cells
derived from bone marrow (BMSCs) are promising alter-
native sources for cell replacement therapies for stroke.
In addition to hematopoietic stem cells, bone marrow
contains mesenchymal stem cells (MSCs) that are multi-
potent and can differentiate into osteoblasts, chondroblasts,
adpocytes, and skeletal muscle (Tang et al. 2007). Animal
study demonstrated that injection of MSCs in the infarct
border zone leads to regeneration of neurons with
improved survival rate and brain function in a stroke model
(Chen et al. 2001a). Injection of MSCs cells into the carotid
artery (Li et al. 2001) or intravenous administration of
MSCs (Chen et al. 2001b; Li et al. 2002) are also beneficial
in a stroke model. The introduced cells appear to have the
ability to penetrate the blood brain barrier (BBB) and
migrate to the ischemic area, and improve neurological
recovery in stroke animal models.
There are several bone marrow derived cell types that
have greater potential than normal BMSCs, such as mul-
tipotent adult progenitor cells (MAPCs; Jiang et al. 2002),
marrow isolated adult multilineage inducible (MIAMI)
cells (Dar et al. 2006), human bone marrow-derived mul-
tipotent stem cells (hBMSCs; Yoon et al. 2005), and very
small embryonic-like stem cells (VSEL; Kucia et al. 2006).
Cell-based therapy for stroke
These cells are pluripotent and can differentiate into cell
types originated from mesodermal, endodermal, and ecto-
dermal layers (Tang et al. 2007). As an example, MAPCs
have been shown to be able to generate functional cell
types from all three embryonic layers, including mature
functional neurons in vitro. When tested in an in vivo
stroke model, MAPCs could significantly enhance func-
tional recovery in stroke animals (Zhao et al. 2002).
hBMSCs have been tested in myocardial infarction (MI)
animal model with beneficial outcome (Yoon et al. 2005).
To our knowledge, the other bone marrow-derived plurip-
otent cell types have not been tested in models of ischemic
brain injury.
The underlying mechanisms of the beneficial effect of
bone marrow-derived stem cells are not clear. Given the
fact that there is only very few cells found at the ischemic
region and the low percentage of cells expressing a neu-
ronal marker, it is not likely that BMSCs work by replacing
the lost cells (Coyne et al. 2006). It is more probable that
they enhance the functional outcome by indirectly sup-
porting repair mechanisms. Nevertheless, BMSCs are very
attractive source for cell transplantation. They generate no
ethical concerns; they are also easily obtainable, and are
highly expandable. Since adult stem cells can be trans-
planted autologously, these cells have the advantage of
been tolerated by host without eliciting immune response
and without the need to apply immunosuppressive agents.
Olfactory ensheathing cells
Olfactory ensheathing cells (OECs) are the cells en-
sheathing the axons of neurons in olfactory bulb. These
cells share the features of both Schwann cells and astro-
cytes (Doucette 1984). When transplanted in a spinal cord
injury model, OECs promote central nervous system axo-
nal regeneration (Doucette 1995). Recently, OECs have
been tested in a stroke animal model in which they secreted
trophic factors including stromal cell-derived factor-1
alpha (SDF-1a). Rats implanted with OECs showed
improvement in both behavioral measurements and func-
tional neuroimaging (Shyu et al. 2008). Clinical trials of
OEC transplantation have also generated positive results in
multiple neurological diseases (Feron et al. 2005; Lima
et al. 2006).
Potential mechanisms of cell transplantation-mediated
recovery
Understanding how transplanted cells improve the recovery
in stroke animals is critical in improving treatment and
translating findings into clinical trials. Multiple mecha-
nisms have been proposed that may account for the bene-
ficial outcome observed in cell transplantation studies.
65
Cell replacement. In many studies on cell transplanta-
tion therapy for stroke, it has been repeatedly reported that
transplanted cells are able to migrate to the ischemic brain
area and differentiate into neuronal and glial phenotypes
(Andres et al. 2008b; Bliss et al. 2007). Furthermore,
synaptogenesis and intergration into host neuronal circuits
have been demonstrated in host brain (Englund et al. 2002;
Wernig et al. 2004). All this evidence suggests that cell
replacement could contribute to the reconstitution of host
neuronal circuits. However, it has been documented in the
past decade that neural differentiation is not necessary for
the beneficial outcome observed in cell transplantation-
based therapy. In fact, increasing evidence suggests that it
might not be the major mechanism in transplantation
therapy. First, the beneficial effect observed after trans-
plantation appears too early for the differentiation and
integration of cells into local circuits. Second, in some
studies, although neuronal differentiation is seen, the
degree of differentiation and intergration of the trans-
planted cells do not correlate with functional outcome
(Lindvall et al. 2004; Shyu et al. 2006). Furthermore, a
recent reported has found that peripherally transplanted
cells do not have to cross the BBB at all to induce neu-
roprotective effects (Borlongan et al. 2004). It is likely that
there are other mechanisms contributing to the therapeutic
benefit of cell transplantation in stroke.
Transplanted cells may produce trophic factors that
will support the survival of existing neurons in the pen-
umbra. Examples of such trophic factors include vascular
endothelial growth factor (VEGF), fibrobalst growth fac-
tor (FGF), glial cell-derived neurotrophic factor (GDNF),
and brain-derived neurotrophic factor (BDNF; Borlongan
et al. 2004; Johnston et al. 2001; Kurozumi et al. 2005;
Llado et al. 2004). These factors have also been shown to
enhance restoration of local synaptic activity by syna-
ptogenesis. In one study, human cord blood cells in
ischemic brain increased sprouting of nerve fibers from
the contralateral to the ischemic hemisphere (Xiao et al.
2005). A recent study using olfactory ensheathing cells in
transplantation therapy demonstrated increased neurite
regeneration in stroke animals, possibly mediated by
coregulation of PrPC and CXCR4 expression (Shyu et al.
2008).
Evidence also points to the possibility that transplanted
cells may play an important role in enhancing the neo-
vasculariztion in stroke animals. Some of the transplanted
cells, BMSCs, for example, are capable of differentiating
into endothelial cells, which can contribute to the neovas-
cularization in damaged brain (Chen et al. 2001b). Cell
transplantation-induced neovascularization have been
reported with bone marrow stromal cells, neural stem cells,
and cells from human blood origin (Chen et al. 2003; Jiang
et al. 2005; Shen et al. 2006; Taguchi et al. 2004).
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Facilitating the recruitment of endogenous stem cells.
Endogenous neurogenesis can be enhanced by injury such
as ischemic injury, which we will discuss more in detail in
the following section. Transplanted cells could also facil-
itate the endogenous repair process. Stromal cell-derived
factor-1 (SDF-1) and its receptor, CXC-chemokine recep-
tor-4 (CXCR4) are important molecules in stem cell
mobilization and migration (Aiuti et al. 1997; Hattori et al.
2003; Petit et al. 2002). A recent study has demonstrated
that implanted cells can secret SDF-1, which sequentially
helped the recruitment and homing of endogenous stem
cells into the ischemic region (Stumm et al. 2002). Once
the cells arrive at the damaged area, transplanted cells may
also support the survival of newly generated neurons and
glial cell by inhibiting apoptosis at the injury sites (John-
ston et al. 2001).
Use of exogenous stem cells in restorative therapy for
stroke has made significant progress in the past recent years
and has resulted in some early phase clinical trials sug-
gesting beneficial effect of this strategy [for review see
(Bliss et al. 2007)]. However, there are still many issues to
consider before this can be optimized for further clinical
applications. For example, transplanted stem/progenitor
cells could lead to the formation of tumors. A recent case
of an Israel Ataxia Telangiectasia patient who developed a
donor-derived brain tumor following neural stem cell
transplantation raises concerns on the safety of using
neuronal progenitor cells (NPCs) transplantation (Amari-
glio et al. 2009). Although there is evidence that adult stem
cells have a lower oncogenic potential and greater stability
in maintaining a differentiated state (Grompe 2002), cau-
tion is still needed when considering it as an option for
treatment in man. Other factors needed to be optimized
include the time for transplantation, the route of cell
delivery, and the need for combinatory strategies such as
co-delivery of trophic factors in combination with reha-
bilitation therapy.
Modulating endogenous stem cells
An alternative strategy is to modulate endogenous neuro-
genesis. Understanding how endogenous stem cells are
activated, differentiate, migrate, integrate, and restore
neuronal circuitry will help us develop less invasive ther-
apeutic interventions, avoiding the need for transplanting
exogenous cells.
Despite the long existing dogma established in the late
nineteenth century that there is no regereration in adult
CNS (Cajal 1928), in phe last decade, rapid progress in
stem cell biology have clearly documented that there is
persistent neurogenesis in both healthy and diseased adult
brain (Alvarez-Buylla and Lim 2004; Gould 2007; Zhao
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et al. 2008). It is well established that constitutive neuro-
genesis occurs in the subventricular and the subgranular
zones (Fig. 1) of the hippocampla dentate gyrus (Jordan
et al. 2006; Ming and Song 2005). NSCs cells can be
isolated from these two areas and can be cultured in vitro as
self-renewable neurospheres in EGF and bFGF containing
media (Reynolds and Weiss 1992; Reynolds and Weiss
1996). Upon withdrawn of the growth factors, they can
differentiate into neurons, astrocytes, and oligodendrocytes
(Reynolds and Weiss 1996).
Self-renewing NSCs in the SVZ are Glial fibrillary
acidic protein (GFAP) positive, slowly dividing astrocytes,
also called type B cells. Type B cells proliferate and pro-
duce transit-amplifying cells (type C cells). Type C cells
proliferate rapidly and differentiate into neuroblasts (type
A cells). Type A neuoblasts then migrate into target
regions and terminal differentiate into various cell types
(Alvarez-Buylla and Lim 2004). Under physiological
conditions, SVZ NSCs proliferate and migrate along the
rostral migratory stream (RMS) to the olfactory bulb and
differentiate into granular interneurons (Grote and Hannan
2007). A recent study suggests that human brain also har-
bors NSCs in the SVZ and has an analogous RMS (Curtis
et al. 2007). Many studies have demonstrated that stroke
can activate neurogenesis in the SVZ and SGZ. Further-
more, newly generated neurons migrate toward ischemic
boundary regions and differentiate into neurons (Arvidsson
et al. 2002; Parent et al. 2002; Zhang et al. 2001). There are
multiple steps involved in neurogenesis for damage-
induced repair. These include the proliferation of NSCs,
migration of neuroblasts to the damaged area, differentia-
tion into neuronal and glial cell types, and survival and
integration of the newly born cells into local circuitry. It is
now accepted that, although stroke stimulates these pro-
cesses, the endogenous response is not enough for recovery
of brain function (Chopp and Li 2008). Enhancement of
one or several of the above processes may be required to
observe a meaningful recovery in function. A variety of
endogenous and exogenous factors have been shown to be
able to interfere with one or more of these processes; we
will briefly summarize them in this review. Understanding
the mechanisms and regulations involved in these steps
will help develop novel therapeutic interventions to pro-
mote endogenous neurogenesis and functional recovery in
stroke. Factors that modulate the endogenous neurogenesis
in animal studies are summarized in Table 2.
Proliferation and survival of NSCs
Liu et al. (1998) first demonstrated that global ischemia can
increase the neurogenesis in hippocampus. They reported a
maximum of 12-fold increases in Bromodeoxyuridine
(BrdU)-labeled cells in SGZ in hippocampus at 11 days
Cell-based therapy for stroke 67

Table 2 Factors modulate the proliferation, survival and differentiation of endogenous NSCs in animal studies
Animal Route of Time of Possible Effect on Functional Reference
model delivery treatment mechanisms neurogenesis recovery

BDNF Non-stroke Viral-delivery Adult ND : BrdU? neurons ND Benraiss

animal into lateral in olfactory bulb et al.
ventricle and striatum (2001)
GDNF Rat stroke Infusion into Days 13–26 Proliferation/ Increase in % of DCX?/ ND Kobayashi
striatum post stroke Survival/Neuronal BrdU? cells et al.
differentiation (2006)
VEGF Non-stroke i.c.v infusion Adult for Proliferation : BrdU? cells in SVZ ND Jin et al.
animal 3 days and SGZ (2002)
EGF Non-stroke IC Adult for Proliferation : proliferation and ND Craig et al.
animal 6 days migration into adjacent (1996)
parenchyma
Mouse IC Days 5–12 Proliferation : transit-amplify cells ND Ninomiya
MCAo post stroke : neuroblasts 6 days after et al.
treatment stops (2006)
FGF-2 Non-stroke i.c.v infusion Adult for Proliferation : BrdU? cells at SVZ, OB ND Kuhn et al.
animal 14 days and striatum (1997)
TGF-a MCAo IC (striatum) Week 5–8 post Proliferation : cell migration to injury Recovery in Guerra-
90 min stroke site and differentiation behavioral Crespo
into neurons tests et al.
(2009)
EPO Non-stroke i.c.v infusion Adult for Proliferation of ; multipotent stem cells in ND Shingo et al.
animal 6 days neural progenitor SVZ : new neurons at OB (2001)
cells
IGF-1 Rat MCAo i.c.v infusion Days 0–7 after Proliferation/survival : BrdU? cells in DG at 1wk ND Dempsey
(1 h) stroke and 3 wks after stroke et al.
(2003)
Eph Non-stroke i.c.v infusion Adult for 13 h Proliferation : number of NSCs at SVZ ND Conover
animal or 3.5 days ; migration of neuroblasts et al.
(2000)
cGMP Aged rat i.p. Days 7–14 Proliferation : number of proliferating Recovery Zhang et al.
MCAo after stroke neuronal cells at SVZ (Ki67?) behavioral (2006a)
differentiation : % of DCX? cells in test
newborn cells
Wnt Non-stroke LV-wnt3 Adult Proliferation neuronal : number of proliferating ND Lie et al.
animal injection into differentiation cells (2005)
DG : % of DCX?/BrdU? cells
Dopamine DA L-DOPA Week 4–6 post Proliferation ; proliferating NSCs in ND Hoglinger
depletion delivered s.c. 6-OHDA SVZ which can be et al.
model lesion reversed by L-DOPA (2004)
treatment
p53 Rat MCAo i. c. v/i.p. Days 6–9 after Proliferation/survival : proliferating cells at SVZ Recovery in Luo et al.
inhibitor stroke ; apoptosis locomotor (2009)
(PFT-a) activity
: new born neurons
at injury site
BDNF brain-derived neurotrophic factor; GDNF glial-derived nerve growth factor; VEGF vascular endothelial growth factor; EGF epidermal
growth factor; FGF-2 basic fibroblast growth factor; TGF-a transforming growth factor alpha; EPO erythropoietin; IGF-1 insulin-like growth
factor-1; Eph elk-related tyrosine kinase; cGMP cyclic guanosine monophosphate; PFT-a Pifithrin-alpha, a p53 specific inhibitor; ND not
determined; BrdU Bromodeoxyuridine (5-bromo-2-deoxyuridine, BrdU), a synthetic nucleoside that is an analog of thymidine; SVZ subven-
tricular zone; SGZ subgranular zone; MCAo middle cerebral artery occlusion; NSCs neural stem cells; MAP2 microtubule-associated protein 2;
DCX doublecortin; OB olfactory bulb; IC intracerebral; DG denta gyrus; LV lentiviral; i.c.v. intracerebral ventricular; i.p. intraperitoneal;
s.c. subcutaneous; 6-OHDA 6-Hydroxydopamine; L-DOPA levodopa

after ischemia. Increased NSCs have also been reported in increased numbers of BrdU-labeled cells in the ischemic
the SVZ following ischemia (Arvidsson et al. 2002). Many area. This, however, by itself dose not illustrate whether
studies reported that after certain treatments there are the treatments have an effect on the proliferation of NSCs

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or on enhanced survival of daughter cells derived from
NSCs. Many of the newly generated cells do not survive
the ‘‘hostile’’ environment after ischemia (Chang et al.
2007). Increased BrdU-positive cells in the ischemic region
could be a result of both mechanisms. Recently, several
studies closely examined the proliferation and division of
SVZ NSCs. Adult SVZ contains both asymmetric and
symmetric terminal cell division, as well as symmetric
non-terminal cell division (Zhang et al. 2004, 2006b). The
authors reported that as a response to stroke, an increased
neurogenesis might result from transiently switching neural
progenitors division from asymmetric to symmetric and
from a reduction of the length of cell cycle (Zhang et al.
2004, 2006b). Their recent study suggests that stroke
triggers early expansion of the progenitor cell pool by
shortening the cell-cycle length and retaining daughter
cells within the cell cycle at an early stage after stroke. At a
later stage, lengthening the cell cycle and the G1 phase
leads to the daughter cells exiting the cell cycle and dif-
ferentiating into neurons (Zhang et al. 2008). We will
summarize some of the known factors that can modulate
the proliferation/survival of adult NSCs together in this
review. A careful re-examination of the precise mecha-
nisms of these factors on cell proliferation or survival
would be critical for further advancing them into possible
clinical trials in stroke patients.
Mitogen/growth factors
BDNF Both virally delivered BDNF expression in ven-
tricle lining cells (Benraiss et al. 2001) and direct infusion
of BDNF (Pencea et al. 2001) into the lateral ventricle
showed similar effects in increasing BrdU-labeled new
neurons in olfactory bulb, striatum, and other regions in the
brain. It was, however, not examined in these studies
whether the increase in newly generated neurons is an
effect due to increased proliferation or to the trophic effect
of BDNF on the new born neurons.
GDNF GDNF (Kobayashi et al. 2006) infusion into
striatum after stroke in rats increased cell proliferation in
the ipsilateral SVZ, which was confirmed by a second
endogenous cell marker for proliferating cells (Ki67).
GDNF also promoted the survival of newborn cells that
were pre-labeled 1 week before infusion of GDNF. Fur-
thermore, GDNF may also promote the neuronal differen-
tiation, given the fact that percentage of doublecortin
(DCX)/BrdU positive cells increased in GDNF treated
animals (Kobayashi et al. 2006).
VEGF Intracerebroventricular administration of VEGF
(Jin et al. 2002; Schanzer et al. 2004) into rat brain
increased BrdU labeling of cells in the subventricular zone
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Y. Luo
(SVZ) and the subgranular zone (SGZ) of the hippocampal
dentate gyrus (DG). The increase in BrdU labeled cells is
likely due to an increase in cell proliferation, rather than a
decrease in cell death, because VEGF did not reduce cas-
pase-3 cleavage in the SVZ or SGZ.
EGF and FGF-2 Early studies demonstrated that In vivo
infusion of epidermal growth factor (EGF) into adult
mouse forebrain for 6 consecutive days resulted in a
dramatic increase in the proliferation and total number of
subependymal cells and induced their migration away
from the lateral ventricle walls into adjacent parenchyma
(Craig et al. 1996). Studies also have shown that exoge-
nous basic fibroblast growth factor (FGF-2) and epidermal
growth factor (EGF) have differential and site-specific
effects on progenitor cells in vivo (Kuhn et al. 1997).
Both growth factors expanded the SVZ progenitor popu-
lation after 2 weeks of intracerebroventricular adminis-
tration, but only FGF-2 induced an increase in the number
of newborn cells, most prominently neurons, in the
olfactory bulb. Another study (Ninomiya et al. 2006)
demonstrated that cerebral ischemia resulted in an
increase in the number of EGF receptor (EGFR)-positive
transit-amplifying cells (type C cells) in the SVZ. EGF
infusion into the ischemic brain caused the number of
transit-amplifying cells to increase and the number of
neuroblasts to decrease. On the other hand, 6 days after
the discontinuation of EGF infusion, a significant increase
in the number of neuroblasts was found, both in the
striatum and the SVZ, suggesting a possible delayed
therapeutic effect (Ninomiya et al. 2006).
TGF-a The primary endogenous ligand for the EGF
receptor TGF-a, has been demonstrated to be required for
the NSCs proliferation in vivo (Fallon et al. 2000; Tropepe
et al. 1997). TGF- a knockout animals exhibit reduced
proliferation in the anterior portion of SVZ and a reduced
number of neuroblasts migrating to the OB. Interestingly, a
recent study (Guerra-Crespo et al. 2009) has demonstrated
that even after 4 weeks post-stroke, TGF-a is able to
induce a massive proliferative response in SVZ NSCs.
These newly generated cells migrate preferentially along,
and ventral to, the corpus callosum (CC), and external
capsule to the site of the injury where many of them dif-
ferentiate into several site-appropriate neuronal phenotypes
in association with near complete (99%) behavioral
recovery. The prolonged time window for TGF-a efficacy
offers a unique treatment opportunity for clinical applica-
tion. Another recent study demonstrated that intranasally
delivered TGF-a in mice after stroke reduced infarct vol-
ume and increased neurogenesis in SVZ, suggesting a
noninvasive convenient way to delivery TGF-a that
bypasses the BBB (Ma et al. 2007).
Cell-based therapy for stroke
EPO Erythropoietin (EPO), a cytokine induced in hypoxia,
and the epo receptor are both expressed in adult SVZ. Both in
vitro and in vivo treatment of epo lead to increase in neuronal
progenitors at the expense of multipotent progenitors
(Shingo et al. 2001). EPO infusion into the adult lateral
ventricles resulted in a decrease in the numbers of NSCs in
the subventricular zone, an increase in newly generated cells
migrating to the olfactory bulb, and an increase in new
olfactory bulb interneurons. Infusion of anti-EPO antibodies
had the opposite effect (Shingo et al. 2001). It is possible that
Epo might affect the number of daughter cells that stay in cell
cycle and the cells that exit cell cycle and undergo terminal
neuronal differentiation. This hypothesis is supported by the
application of epo infusion for 7 days after 7 days of EGF
treatment (Kolb et al. 2007). Substantial regeneration of the
damaged cerebral cortex and reversal of impairments in
spontaneous and skilled motor tasks, in a rat model of stroke,
is observed with combined EGF/Epo treatment. Cortical
regeneration and functional recovery occurred even when
growth factors administration was delayed for up to 7 days
after the stroke-induced lesion (Kolb et al. 2007).
IGF-1 Infusion of IGF-1 increased the number of BrdU-
positive cells in both DG and SVZ. This may be explained by
enhancement of the survival of NSCs, especially for SVZ
NSCs, whose life span is increased from 1 to 3 weeks in this
study (Dempsey et al. 2003). The endogenous IGF-1 path-
way may be critical in the adaptive response to ischemic
damage as well. One study (Yan et al. 2006) identified 15
diffusible, mitogenic factors whose expressions are upreg-
ulated in the ischemic cortex. It was hypothesized that since
both the DG and SVZ are distant from the damaged cortex,
the stimulation of NSCs might be mediated through diffus-
ible factors. IGF-1 is among the identified factors (Yan et al.
2006). In addition, the progenitors in both the SVZ and DG
showed IGF-1 receptor expression. Inhibiting IGF-1 activity
by intracerebroventricular infusion of IGF-1 antibody sig-
nificantly blocked the ischemia-induced neural progenitor
proliferation (Yan et al. 2006). These results suggest that
IGF-1 formed in the ischemic penumbra might be one of the
endogenous diffusible factors that mediate post-ischemic
neural progenitor proliferation.
Factors in signaling pathway
Eph Eph family of receptor tyrosine kinases and their
transmembrane-associated ephrin ligands are also involved
in neurogenesis of SVZ NSCs (Conover et al. 2000). EphB1-
3 and EphA4 and their transmembrane ligands, ephrins-B2/
3, are expressed by cells of the SVZ. The ephrin-B ligands
are associated with type B cells. Infusion of EphB2 or
ephrin-Bw into the lateral ventricle leads to increased cell
proliferation but disrupts the migration of neuroblasts
69
(Conover et al. 2000). This suggests that Eph and their
ligands can expand the self-renewable multi-potent cell pool
at the expense of neuronal differentiation and migration. For
therapeutic purposes, a sequential and combined treatment
with other neural differentiation factor might be required.
cGMP pathway Phosphodiesterase type 5 (PDE5) is
highly specific for hydrolysis of cGMP (Corbin and Francis
1999). Administration of sildenafil, a specific inhibitor of
PDE5, substantially increases cGMP levels in the brain and
enhances neurogenesis in the SVZ of rats after focal
cerebral ischemia. Treatment with Sildenafil significantly
increased the proliferating cells in both young and old
stroke rats (Zhang et al. 2002). Furthermore, aged rats
exhibit decreased basal levels of cGMP (Chalimoniuk and
Strosznajder 1998) and Sildenafil treatment enhances the
functional recovery in aged rats after stroke (Zhang et al.
2006a). Because in man, stroke happens primarily in aging,
this study might have important clinical implications.
Wnt signaling pathway Wnt signaling can regulate the
proliferation of NSCs in SGZ (Lie et al. 2005). Wnt3 is
expressed in the hippocampal neurogenic niche and the
Wnt/-catenin pathway is active in this region. It was dem-
onstrated that overexpression of Wnt3 is sufficient to
increase neurogenesis from adult hippocampal progenitor
cells (AHPs) in vitro and in vivo. Furthermore, blockade of
Wnt signaling reduces neurogenesis from AHPs in vitro and
abolishes neurogenesis almost completely in vivo. This
study also demonstrated that Wnt signaling enhances the
proliferation of NSCs but does not affect their survival. In
addition, Wnt signaling specifically enhances the differen-
tiation of NSCs into a neuronal phenotype (Lie et al. 2005).
Dopamine Dopamine (DA) can also modulate neuro-
genesis (Hoglinger et al. 2004). There is ultrastructural
evidence showing that highly proliferative precursors in the
adult subependymal zone express dopamine receptors and
receive dopaminergic afferents. Depletion of dopamine in
rodents decreases precursor cell proliferation in both the
subependymal zone and the subgranular zone. Proliferation
is restored completely by a selective agonist of D2-like
(D2L) receptors (Hoglinger et al. 2004). Since cerebral
dopamine depletion is found in Parkinson’s disease, this
study suggests that neuroregeneration might be compro-
mised and lead to further compromise of other brain
functions in Parkinson’s disease patients.
Combinatory therapy or factors that have combinatory
effects
Although proliferation of NSCs cells can be enhanced by
many factors, due to the hostile environment in the
123
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ischemic damaged brain area, many new born cells die
within 1 week after birth (Dempsey et al. 2003). Arvidsson
et al. (2002) found that the percentage of neurons that
traveled to the striatum and were able to mature accounted
for only 0.2% of the neurons that had been lost in a MCAo
model. This suggests the need for therapeutic treatments
that combine multiple factors or factors that can both
promote the proliferation and enhance the survival of
newly born cells. Combined therapy utilizing multiple
factors such as bFGF and notch (Androutsellis-Theotokis
et al. 2006) or 7 days of EGF followed by 7 days of EPO
treatment (Kolb et al. 2007) have been demonstrated to be
effective. A recent study indicated that p53 protein is
highly expressed in the NPC area in SVZ, compared with
surrounding brain regions. Neurospheres from the lateral
ventricle wall of adult p53 null animals proliferated faster
and incorporated more BrdU than wild-type controls
(Meletis et al. 2006). These data suggest that the survival/
proliferation of adult NPCs from the SVZ is influenced by
p53. It is also possible that inhibition of P53 may augment
the proliferation and survival of endogenous NPCs and
alter the biological outcomes days after stroke. Given the
dual function of p53 in both cell cycle regulation and
apoptosis, our group has recently tested a synthetic com-
pound that effectively inhibits p53 in a MCAo model in
rats (Luo et al. 2009). Delivery of PFT-alpha, a synthetic
p53 inhibitor, 7 days after stroke is able to enhance the
proliferation of NSCs, inhibit the apoptosis of newly born
cells, and promote the behavioral recovery in animals.
PFT-alpha increased the number of surviving newly born
cells at the penumbra, probably due to the dual effect in
both promoting proliferation and improving survival.
Treatment did not start until 7 days after stroke and still
demonstrated to be effective. This gives us a valuable
therapeutic window, which is critical in the clinical treat-
ment of stroke (Luo et al. 2009).
Migration of neuroblast cells
In the intact adult brain, SVZ neuroblasts migrate along the
RMS to the olfactory bulb. Lateral migration into the
striatum and parenchyma is not observed in intact brain
(Alvarez-Buylla and Lim 2004). In the ischemic damaged
brain, however, neuroblasts will migrate laterally into the
damaged area (Arvidsson et al. 2002), in some cases
forming the chain-like structures (Yamashita et al. 2006).
Interestingly, this directional migration is closely associ-
ated with thin astrocytic processes and blood vessel, sug-
gesting that blood vessels may act as a scaffold for
neuroblast migration (Yamashita et al. 2006). It has also
been reported that SVZ-derived neuroblasts primarily
migrate into a neurovascular niche in the stroke penumbra
(Ohab et al. 2006), suggesting that besides its role as a
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Y. Luo
scaffold, blood vessel might also provide a diffusible
chemoattractant. Multiple factors have been demonstrated
to be involved in the directed migration of neuroblasts.
Stromal cell-derived factor 1 (SDF-1) and CXC Chemokine
receptor-4 (CXR-4)
SDF-1 (CXCL12) is a member of the alpha (CXC) che-
mokine family which are small chemoattractant molecules
that are involved in inflammatory responses (Matthys et al.
2001). SDF-1 and its receptor CXCR4 have been demon-
strated to play an important role in the mobilization and
homing of stem cells to bone marrow (Aiuti et al. 1997;
Hattori et al. 2003, 2001; Petit et al. 2002). They have also
been shown to play a role in the directional migration of
neuroblasts in CNS as well (Imitola et al. 2004; Shyu et al.
2004). Studies show that NSCs express CXC chemokine
receptor 4 (CXCR4) and human NSCs migrate in vivo
(including from the contralateral hemisphere) toward an
infarcted area where local astrocytes and endothelium up-
regulate the inflammatory chemoattractant stromal cell-
derived factor 1alpha (SDF-1alpha). In contrast, CXCR4
blockade blocks this pathology-directed chain migration
(Imitola et al. 2004). Other studies have confirmed the
endogenous role of SDF-1/CXCR4 in directing the
migration of neuroblasts toward injury site (Shyu et al.
2004). Furthermore, it has been suggested that secreting
SDF-1 might be one of the mechanisms whereby trans-
planted cells facilitate the recovery of injured brain (Shyu
et al. 2008).
Other chemokines and factors
Other factors that direct migration of neuroblasts include
monocyte chemoattractant protein-1 (MCP-1), infusion of
which into the normal striatum induced neuroblast migra-
tion to the infusion site (Yan et al. 2007). In knockout mice
that lacked either MCP-1 or its receptor CCR2, there was a
significant decrease in the number of migrating neuroblasts
from the ipsilateral SVZ to the ischemic striatum (Yan
et al. 2007). Angiopoitin (ANg)-1 and its receptor Tie 2,
and Slit and its receptor (ROBO) also promote post-stroke
neuroblast migration and behavioral recovery (Ohab et al.
2006; Sawamoto et al. 2006).
Differentiation and integration into local circuitry
Factors that facilitate neuronal differentiation include
GDNF (Kobayashi et al. 2006) and Wnt (Lie et al. 2005)
signaling pathway. Caution is needed when trying to
differentiate proliferative effect from neuronal differenti-
ation effect. For example, in our p53 inhibitor study (Luo
et al. 2009), we observed an increase in total number of
Cell-based therapy for stroke
newborn neurons in penumbra but this was not due to an
enhancement in differentiation because the percentage of
neuronal cells in the population of new born cells did not
change. Rather, it was due to increased proliferation of
SVZ NSCs which resulted in an increase in the total
number of newly generated cells. Similarly, an agent
could enhance differentiation but at the expense of
decrease the proliferation of NSCs. In this case, a
sequential and combined therapeutic treatment would be
required where first a proliferative agent would be applied
followed by a differentiating factor. Compared with
extensive research focusing on the proliferation of NSCs,
more research effort is needed in this area.
Future directions
The findings reported from preclinical and clinical studies
demonstrate that stem-cell-based therapies have the
potential to improve the clinical outcome in stroke patients
(Bjorklund 2000; Bliss et al. 2007). Recent advances in
stem cell research offers the possibility to harvest adult
terminally differentiated cells and reprogram them into
stem cells (Takahashi and Yamanaka 2006; Yu et al. 2007).
These iPS cells can be expanded in vitro and genetically
modified to suit specific therapeutic requirement. Trans-
lating of this technology in possible clinical usage would
offer the advantage of generating unlimited and autolo-
gous, patient-specific stem cells. Small pharmaceutical
molecules that can modulate endogenous neurogenesis are
also a promising area for developing therapy for neurode-
generative and injury-related disease. Although still in
controversial (Manganas et al. 2007; Ramm et al. 2008),
advances in technology that enables non-invasive tracking
and monitoring of NSCs in vivo, such as fMRI (Manganas
et al. 2007), would greatly facilitate the research in this
area.
Acknowledgments The author thanks Dr. Barry Hoffer for helpful
discussion and critical comments.
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