Neural stem cell,differentiation,developmental biology,regenerative medicine.
1.1 Stem cell in regenerative medicine
Stem cells have self-renewing potential and the
ability to produce differentiated derivatives de novo.
These unique properties make them an ideal
resource for regenerative medicine applications
aiming to repair damaged tissues by supplying
different types of cells,organs or tissues . NSCs
self-renew and give rise to neurons,astrocytes and
oligodendrocytes [2,3]. Stem cell-based
approaches to tissue repair are in development for a
number of therapeutic applications,in particular for
orthopaedic treatment . Studies carried out over
the last decade have established the presence of
neural stem cells in postnatal and adult stages,and
highlighted the characteristics and differentiation
potential of these neural progenitors. Neural stem
cells (NSCs) represent potentials candidates for
neural repair by replacement of lost or damaged
CNS cells,and recent advances have opened new
prospects for stem cell-based approaches to CNS
1.2 Evidence of NSCs in the adult brain
Early work from Altman in the 60s presented
autoradiographic and histological evidence of neurogenesis in the dentate gyrus (DG) of the
hippocampus,neocortex and olfactory bulb of the
adult rodents [4-6]. Many subsequent studies
confirmed this observation [7,8],and the use of
techniques labelling dividing cells such as
bromodeoxyuridine (BrdU) confirmed the
occurrence of neurogenesis not only in adult rodent
brains,but also in primates [9,10]. Lois and
Alvarez-Buylla showed that dividing cells labelled
with [3H] thymidine in the SVZ can differentiate into
neurons and glia in vitro,identifying the SVZ as a
source of neural precursors in adult mammalian
brain . Using a similar approach,Corotto also
found new cells are generated in the subependymal
layer (SVZ),and migrate to the olfactory bulb,where
the majority of the newly generated cells persist at
least 16 weeks . In adult primates,Kornack and
Rakic reported new neuronal cells generated in the
DG of hippocampus and the SVZ of adult macaque
monkeys [10,13] and in humans,Erisson presented
the first evidence of neurogenesis in DG of the adult
human brain and further indicated that the human
hippocampus retains the ability to generate neurons
throughout life . More recently,Sanai found a
group of SVZ astrocytes in the lateral ventricles of
the adult human that proliferate in vivo and possess
stem cell properties in vitro. Also,the study showed
no evidence of neuronal migratory stream to the
olfactory bulb in human brain,which is still in debate
The persistence of neurogenic activity in the
adult brain suggests the existence of NSCs .
Experiments have been developed to identify and
characterise NSCs using the 2 criteria defining stem
cells: - multipotency,i.e. the ability to generate both
glial and neuronal cell types from a single cell,- selfrenewal,i.e. the maintenance of stem cell
characteristics over serial passages.
Neural progenitor cells have first been isolated
from adult mouse brain tissue including SVZ. When
isolated in vitro,these cells were shown to grow as
floating colonies of progenitor cells,known as
neurospheres  (Figure 1A). In 1995,Gage et al.
isolated and characterisized progenitors from adult
rat hippocampus,which also formed neurospheres
and retained the capacity to generate mature glia and neurons when transplanted into the adult rat
brain . Based on previous findings,Reynolds
and Weiss developed a method to test the selfrenewal
potential of these progenitor populations by
performing a clonal analysis. In this procedure,neurospheres are dissociated into single cells and
plated in individual wells. Formation of clonally
derived spheres maintaining the differentiation
potential of the original culture over serial passages
is used to assess the stem cell characteristics of the
1.3 Nature of NSCs
Doetsch et al. have shown that SVZ astrocytes
labeled in vivo give rise to multipotent neurospheres in vitro ,suggesting a model in which dividing
SVZ astrocytes give rise to immature precursors,which themselves divide to form tight clusters that
generate migrating neuroblasts. This model has
been strongly supported by other studies [23,24].
Using similar approach,Seri identified SGL
astrocytes as NSCs in the adult hippocampus .
These hippocampal NSCs also share astrocytic
characteristics including GFAP expression,and are
able to divide and generate neurons under normal
conditions or after treatment. Filippov et al. used the
nestin-GFP transgenic mouse model to confirm that
the putative NSCs in the adult hippocampus share
astrocytic features . Although some studies
have reported the presence of NSCs among the
non-GFAP expressing population of the adult SVZ
based on flow cytometry [27,28],the glial origin of
NSCs appears largely accepted [9,29].
1.4 NSCs present in other areas
Apart from the SVZ and the DG,other regions of the
postnatal brain have been reported to contain NSClike
cells. Putative NSCs have been identified in the
7-day old mouse cerebellum of mice,where the
cells were mainly located in the white matter .
Klein et al. reported the existence of putative NSCs
from the adult cerebellum (P>42 days) using the
neurosphere assay ,although there is still a
debate about the distribution and function of NSCs
in the adult cerebellum [32,33]. Putative NSCs
have also been isolated from adult spinal cord,and
throughout the entire ventricle neuroaxis of mice
. Clonal analysis demonstrated that these cell
populations proliferate in response to EGF+bFGF,and share the ability to self-renew,expand and
maintain their multipotency shown for SVZ NSCs
. NSCs isolated from the lateral,3rd and 4th
ventricle,as well as from the thoracic and
lumbar/sacral segment of spinal cord were
compared in vitro. The lumbar/sacral spinal cord
presented the strongest neurosphere-forming ability,compared with the lateral,the third and fourth
ventricles. However,only cells in the lateral
ventricles could proliferate and expand in response
of EGF alone .
Outside of the brain,Ahmad et al. reported a
population of mitotically quiescent cells in the
pigmented ciliary body of the adult rats with chronic
BrdU injection. These cells also proliferated in the
presence of FGF2,formed self-renewing
neurospheres,and were able to differentiate into
neurons and glia .
1.5 Markers for NSC characterisation
There isn’t to date a single marker uniquely specific
for the adult NSC. NSCs have been reported to
express a range of markers such as those listed
below,which,when detected in combination,are
routinely used to identify this stem cell population
Nestin is widely used to characterise NSCs [37,38] (Figure 1B). This intermediate filament protein
was found to be expressed predominantly in
neuroepithelial stem cells during embryogenesis
. In differentiated cells,Nestin expression is
sharply reduced and is replaced by tissue-specific
intermediate filament protein [37,39]. The use of the
Nestin-GFP transgenic mouse,where GFP (green
fluorescent protein) expression is controlled by the
regulatory sequence of nestin,allows NSC isolation
by FACS (fluorescent-activated cell sorting) based
on GFP expression .
Figure 1.Neurosphere isolated from mouse SVZ tissue.
(A) Phase contrast view of a single neurosphere. (B)
Nestin immunostaining of SVZ neurosphere. Bar: 100µm.
Musashi1 is a member of neural RNA-binding
family used as a marker for neuroprogenitors [37,41,42]. In the developing rodent brain,Musashi1 is
expressed predominantly in proliferating multipotent
neural stem cells; however Musashi1 expression is
reduced during neurogenesis and lost in newly
generated post-mitotic neurons. Musashi1 is
reported to have a role of maintaining the selfrenewing
ability of NSCs by positively regulating the
Notch signaling pathway .
Sox1 and Sox2 are members of the SoxB1
subfamily of transcription factors expressed in early
embryonic neuroepithelium . Sox1 expression is
observed in proliferating neural precursors
throughout embryogenesis and into adulthood .
Sox1 expression is down-regulated as progenitors
exit from mitosis and differentiate into neurons or
glia,suggesting a role in the maintenance of the
undifferentiated state . Sox2 is expressed in ES
cells,in embryonic neuroepithelium stem cells and
in neurogenic regions of the CNS throughout
adulthood . Sox2-positive neuroprogenitors
express nestin,and SVZ-derived neurospheres lose
Sox2 expression upon neuronal differentiation .
Sox2 is required for the maintenance of NSCs,as
inhibition of Sox2 signaling is associated with
neuronal differentiation whereas constitutive
expression inhibits progenitor differentiation .
ABCG2 is a member of the ATP-binding
cassette (ABC) family of transporter proteins
present in many normal and malignant tissues.
Cultured human neuroprogenitors express ABCG2,and the proportion of ABCG2-positive cells in
neurospheres is similar to that of Nestin-positive cells . ABCG2 and Nestin have often been
shown to co-localize in the same cells,and ABCG2
expression is sharply down regulated during
Prominin-1 (also named CD133) is a
transmembrane protein originally identified on
hematopoietic stem cells [51,52] before being used
to isolate neuroprogenitors [52,53]. FACS analysis
has shown that CD133-positive cells from human
fetal brain can form neurospheres,self-renew and
show multipotency at the single-cell level . Very
recently,CD133 has been used to identify and
isolate neuroprogenitors from embryonic and adult
mouse brain and was found to be co-expressed with
other NSC markers including Sox1,Sox2,Nestin
and Musashi .
Integrins are cell surface receptors mediating
interactions between cells and the extracellular
matrix . 1 integrin was found to be as effective
as CD133 for NSCs isolation,and cells with high
levels of 1 integrin expression also show increased
expression of NSC markers such as CD133,nestin,sox2,and musashi1 .
2. Stem cell research for applications in
Because of their proliferative and differentiation
properties,NSCs represent a promising resource
for future approaches aiming to repair damaged or
lost brain cells in a range of pathologies. However,one of the main unresolved issues precluding such
developments remains the availability of human
NSCs suitable for cell therapy.
2.1 Human NSCs:
Human NSCs have been isolated from fetal and
adult postmortem brains [57-59],mostly from SVZ
tissue and other regions including hippocampus,white matter,olfactory bulb,cortex and spinal cord
[60-65]. The dissected tissue is mechanically
disaggregated,and the dissociated cells grow as
neurospheres in a serum-free defined medium
containing bFGF,leukemia inhibitory factor (LIF),and EGF. These cultures were shown to allow a 107
fold increase in the number of cells while retaining
their differentiation potential towards neurons and
glia [66-68]. Fetal and adult NSCs present many
advantages for therapy purposes. NSCs are known
to efficiently generate differentiated lineages ,and to have the ability to migrate towards injury sites
 where they may secrete factors  promoting
proliferation and repair [72-74].
2.2 Embryonic stem (ES) cell-derived NSCs
Pluripotent ES cells can differentiate into multiple
neural phenotypes in the presence of neurotrophic
factor [75-81]. Several approaches have been taken
to promote neuronal differentiation in ES cultures,including exposure to retinoic acid,low-density
culture,growth factors treatment,co-culture with
other cell types,and forced expression of lineagespecific
genes [82-85]. Neural progenitors
generated in vitro from both ES cells can be sorted
from ES cultures using surface antigens .
Human ES cell-derived neuroprogenitors can
integrate into the ventricles of newborn mice and
differentiate . ES cells are amenable to large
scale culture and permissive to genetic modification
enabling expression of therapeutic agents [69,87].
However,ES cells have the ability to produce
teratoma-like growths when injected into mice,thus
presenting an inherent safety issue for any ESderived
therapeutic approach [80,88].
2.3 NSCs from non-neural cells
Other adult stem cell populations have been
reported to exhibit some neural potential in vitro and
sometimes in vivo. Mesenchymal stem cells (MSCs)
represent a bone marrow cell population able to
differentiate into bone and cartilage derivatives [87,89,90]. It has also been suggested that bone
marrow-derived stem cells can give rise to extramesodermal
lineages including neural cells both in
vitro and when transplanted into rodent models [91,92]. Doubts remain on whether these observation
may arise from transdifferentiation (direct change
into neurons) [91-94],transdetermination (change
into stem cells of different origin),or cell fusion
(integration of assimilated cells into existing neurons)
MSCs present many advantages for cellular
therapy,since they are easily accessible for
collection  and allow autologous transplants
without immunosupression issues [96-98]. MSCs
can survive after implantation in the brain and
migrate broadly [96,99-101],however,it is still unclear whether neural-like cells derived from such
non-neural tissues would be able to respond
appropriately to signals within the brain [87,92,102].
3. NSC applications
3.1 Targeted pathologies
The discovery of NSCs opens the possibility to
develop future therapies to replace neurons
damaged due to injury or neurodegenerative
diseases through two approaches: exogenous
NSCs transplantation,and endogenous NSC
activation [103,104]. NSCs-based application are
envisaged around 2 main strategies: (i) cell
replacement,as NSCs are delivered intracerebrally
or intravenously and reach the target organ to
generate appropriate cell types; (ii) neuroprotection,using NSCs as vehicles to provide neuroprotective
molecules such as glial cell line-derived
neurotrophic factor (GDNF) to the injury site .
Rodents provide critical in vivo models for studies
evaluating the feasibility and efficiency of NSCbased
applications for a range of conditions such as
those highlighted below.
-Alzheimer’s disease (AD) is characterized by
progressive impairment of memory and cognitive
functions  due to neuronal degeneration and
synaptic loss throughout the hippocampus,neocortex,amygdale,thalamus and substantia
nigra . Cognitive decline caused by the
progressive loss of differentiated cells could in
theory be restored through transplantation of NSCs
or NSC-derivatives . As genetically modified
NSCs have shown migration capacity after
transplantation,they could serve as vehicles to
deliver therapeutic molecules [108,109].
-Huntington’s disease (HD) is a fatal disorder
characterized by degeneration of projection neurons
in the striatum due to mutation of huntingtin gene
. The potential of a stem cell-based approach
would be to preserve of brain function by replacing
neurons in the striatum. In rat and monkey models
of HD,the transplantation of fetal striatal tissue
containing projection neurons has shown
improvement in motor and cognitive functions [110- 112]. Furthermore,clinical trials involving HD
patients have demonstrated that human fetal striatal
grafts can survive and integrate without typical
pathology at least for 18 months . It is therefore
conceivable that NSC transplantation may similarly
provide a possible alternative. Adult neural
progenitors isolated from the SVZ and transplanted
into striatum of a HD rat model were also shown to
promote motor function recovery .
-Multiple sclerosis (MS) is an inflammatory and
demyelinating disease characterized by the loss of
the myelin sheath surrounding axons,resulting in
signal conduction deficits and severe neurological
symptoms . Oligodendrocyte progenitors
present are capable of producing myelin but do not
remyelinate the axons affected . One possible approach could be the transplantation of
oligodendrocyte progenitors able to mature and
myelinate in situ [116,117]. One study reported that
adult mouse NSCs isolated from the periventricular
region forebrain transplanted into a mouse model of
MS caused an increase in oligodendrocyte
progenitors,some of which were found to actively
remyelinate axons .
-Parkinson disease (PD) is characterized by a
progressive degeneration of dopaminergic neurons
in the substantia nigra,causing tremor and impairing
movement [108,109]. Early trials based on
intrastriatal transplantation of human fetal
mesencephalic tissue provided promising results in
treated patients [119,120],thus suggesting possible
benefits for cell replacement strategies. In addition,using human stem cell for the delivery of
neuroprotective molecules may help to hinder
disease progression. Engineered human neural
progenitor containing GDNF were transplanted into
of rat and monkey striatum,and achieved cytokine
release,which increased the survival and function of
dopamine neurons .
-Spinal cord injures lead to loss of motor function,and stem cell transplantation into injured spinal cord
has shown benefits in rats [122,123]. Human NSCs
isolated from fetal brain tissue using surface
antigens  were transplanted into injured mouse
spinal cord and gave rise to new neurons and
oligodendrocytes,which promote locomotor
recovery . However,the differentiation of NSCs
needs to be controlled to avoid abnormal axon
sprouting leading to severe side-effects . Using
NSCs to improve remylination might represent a
feasible approach ,since there appears to be a
correlation between the number of newly born
oligodendrocytes from NSCs implants and the
extent of locomotor function recovery in rats .
In another study,transplantation of human ES cellderived
oligodendrocyte progenitors into the injured
rat spinal cord caused enhanced myelination and
motor function improvement ,thus highlighting
the potential of stem cell-based approaches.
-Stroke results from interruption of cerebral blood
flow producing ischemia,cell degeneration and
long-term damages [108,109]. One study
describing the transplantation of human fetal NSCs
into a rat model reported survival of the implanted
NSCs and migration of newly formed cells towards
ischemic sites . Transplantation of primate ES
cell-derived cells into a mouse model of stroke
showed generation of neuronal and glial cells,restoration of connections and motor function
recovery [128,129]. A recent study in adult rats
reported that SVZ NSCs could similarly contribute to
generate neuroblasts which could differentiate into
mature neurons able to migrate towards the
ischemic damage .
Present in the CNS throughout postnatal life,endogenous NSCs represent a promising resource
for brain repair. However,the number and
regenerative capacity of endogenous precursors
may represent limited therapeutic potential without
some form of activation,particularly in cases of
neurological disease . In order to efficiently
manipulate endogenous NSCs for therapy,the
mechanisms regulating NSCs fate choice and
proliferation need to be elucidated.
Activation of endogenous progenitors has been
tested by intracerebroventricular infusion of EGF
and bFGF into the lateral ventricle of a rat model,leading to the increased neurogenesis after bFGF
treatment,and increased astrocyte production after
EGF treatment . In a rat model of PD,infusion
of transforming growth factor- lead to proliferation
toward injection sites . Other exogenous
molecules may also support activation of
endogenous NSCs,such as Sonic hedgehog (Shh),which is promotes cell proliferation in the SVZ and
SGZ [59,133-135]. Such approaches thus
represent important avenues for fundamental
research,and may identify new targets for
Over the last decades,research on NSCs has
made rapid progress,providing tools for the
identification and isolation of NSCs from both in
embryos and discrete regions of the adult brain.
Their therapeutic potential is under investigation
using experimental models of CNS disease,and
early results obtained in animal models suggest
NSC-based treatments may provide functional
benefit. However,many issues remain to be
clarified: the ideal cell source for therapy,appropriate procedures for the in vitro manipulation
to obtain the number of cells required for transplant,and cell delivery strategies. Moreover,a better
understanding of the regulation of endogenous
NSCs proliferation and differentiation in both
pathological conditions and normal conditions could
provide new means of non-invasive NSCs therapy,through directed recruitment and differentiation of
the desired cell type in situ in order to replace cells
lost by injury or disease.
The authors are grateful to Dr H. Priddle and
Hassan Rashidi for critical reading of the manuscript.
V.S. is indebted to the Anne McLaren fellowship
scheme (Univ. of Nottingham) and to the
Alzheimer’s Society for their support,past and
- Gardner R.L. (2007) Stem cells and regenerative
medicine: principles,prospects and problems. C R
Biol. 330(6-7): p. 465-73.
- Gritti A.,Parati E.A.,Cova L.,et al. (1996)
Multipotential stem cells from the adult mouse brain
proliferate and self-renew in response to basic
fibroblast growth factor. J Neurosci. 16(3): p. 1091-
- Reynolds B.A.,Weiss S. (1992) Generation of neurons
and astrocytes from isolated cells of the adult
mammalian central nervous system. Science.
255(5052): p. 1707-10.
- Altman J. (1969) Autoradiographic and histological
studies of postnatal neurogenesis. IV. Cell
proliferation and migration in the anterior forebrain,with special reference to persisting neurogenesis in
the olfactory bulb. J Comp Neurol. 137(4): p. 433-57.
- Altman J.,Das G.D. (1965) Autoradiographic and
histological evidence of postnatal hippocampal
neurogenesis in rats. J Comp Neurol. 124(3): p. 319-
- Altman J.,Das G.D. (1966) Autoradiographic and
histological studies of postnatal neurogenesis. I. A
longitudinal investigation of the kinetics,migration
and transformation of cells incorporating tritiated
thymidine in neonate rats,with special reference to
postnatal neurogenesis in some brain regions. J
Comp Neurol. 126(3): p. 337-89.
- Bayer S.A. (1982) Changes in the total number of
dentate granule cells in juvenile and adult rats: a
correlated volumetric and 3H-thymidine
autoradiographic study. Exp Brain Res. 46(3): p. 315-
- Kaplan M.S.,Hinds J.W. (1977) Neurogenesis in the
adult rat: electron microscopic analysis of light
radioautographs. Science. 197(4308): p. 1092-4.
- Taupin P. (2006) Neural progenitor and stem cells in
the adult central nervous system. Ann Acad Med
Singapore. 35(11): p. 814-20.
- Kornack D.R.,Rakic P. (1999) Continuation of
neurogenesis in the hippocampus of the adult
macaque monkey. Proc Natl Acad Sci U S A. 96(10):
- Lois C.,Alvarez-Buylla A. (1994) Long-distance
neuronal migration in the adult mammalian brain.
Science. 264(5162): p. 1145-8.
- Corotto F.S.,Henegar J.A.,Maruniak J.A. (1993)
Neurogenesis persists in the subependymal layer of
the adult mouse brain. Neurosci Lett. 149(2): p. 111-4.
- Kornack D.R.,Rakic P. (2001) The generation,migration,and differentiation of olfactory neurons in
the adult primate brain. Proc Natl Acad Sci U S A.
98(8): p. 4752-7.
- Eriksson P.S.,Perfilieva E.,Bjork-Eriksson T.,et al.
(1998) Neurogenesis in the adult human
hippocampus. Nat Med. 4(11): p. 1313-7.
- Sanai N.,Tramontin A.D.,Quinones-Hinojosa A.,et al.
(2004) Unique astrocyte ribbon in adult human brain
contains neural stem cells but lacks chain migration.
Nature. 427(6976): p. 740-4.
- Sanai N.,Berger M.S.,Garcia-Verdugo J.M.,et al.
(2007) Comment on "Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension".
Science. 318(5849): p. 393; author reply 393.
- Curtis M.A.,Kam M.,Nannmark U.,et al. (2007)
Human neuroblasts migrate to the olfactory bulb via a
lateral ventricular extension. Science. 315(5816): p.
- Gage F.H. (2000) Mammalian neural stem cells.
Science. 287(5457): p. 1433-8.
- Gage F.H.,Ray J.,Fisher L.J. (1995) Isolation,characterization,and use of stem cells from the CNS.
Annu Rev Neurosci. 18: p. 159-92.
- Reynolds B.A.,Weiss S. (1996) Clonal and population
analyses demonstrate that an EGF-responsive
mammalian embryonic CNS precursor is a stem cell.
Dev Biol. 175(1): p. 1-13.
- Reynolds B.A.,Rietze R.L. (2005) Neural stem cells
and neurospheres--re-evaluating the relationship. Nat
Methods. 2(5): p. 333-6.
- Doetsch F.,Caille I.,Lim D.A.,et al. (1999)
Subventricular zone astrocytes are neural stem cells
in the adult mammalian brain. Cell. 97(6): p. 703-16.
- Chiasson B.J.,Tropepe V.,Morshead C.M.,et al.
(1999) Adult mammalian forebrain ependymal and
subependymal cells demonstrate proliferative
potential,but only subependymal cells have neural
stem cell characteristics. J Neurosci. 19(11): p. 4462-
- Laywell E.D.,Rakic P.,Kukekov V.G.,et al. (2000)
Identification of a multipotent astrocytic stem cell in
the immature and adult mouse brain. Proc Natl Acad
Sci U S A. 97(25): p. 13883-8.
- Seri B.,Garcia-Verdugo J.M.,McEwen B.S.,et al.
(2001) Astrocytes give rise to new neurons in the
adult mammalian hippocampus. J Neurosci. 21(18): p.
- Filippov V.,Kronenberg G.,Pivneva T.,et al. (2003)
Subpopulation of nestin-expressing progenitor cells
in the adult murine hippocampus shows
electrophysiological and morphological
characteristics of astrocytes. Mol Cell Neurosci. 23(3):
- Rietze R.L.,Valcanis H.,Brooker G.F.,et al. (2001)
Purification of a pluripotent neural stem cell from the
adult mouse brain. Nature. 412(6848): p. 736-9.
- Capela A.,Temple S. (2002) LeX/ssea-1 is expressed
by adult mouse CNS stem cells,identifying them as
nonependymal. Neuron. 35(5): p. 865-75.
- Ihrie R.A.,Alvarez-Buylla A. (2008) Cells in the
astroglial lineage are neural stem cells. Cell Tissue
Res. 331(1): p. 179-91.
- Lee A.,Kessler J.D.,Read T.A.,et al. (2005)
Isolation of neural stem cells from the postnatal
cerebellum. Nat Neurosci. 8(6): p. 723-9.
- Klein C.,Butt S.J.,Machold R.P.,et al. (2005)
Cerebellum- and forebrain-derived stem cells
possess intrinsic regional character. Development.
132(20): p. 4497-508.
- Sottile V.,Li M.,Scotting P.J. (2006) Stem cell marker
expression in the Bergmann glia population of the
adult mouse brain. Brain Res. 1099(1): p. 8-17.
- Alcock J.,Scotting P.,Sottile V. (2007) Bergmann glia
as putative stem cells of the mature cerebellum. Med
Hypotheses. 69(2): p. 341-5.
- Weiss S.,Dunne C.,Hewson J.,et al. (1996)
Multipotent CNS stem cells are present in the adult
mammalian spinal cord and ventricular neuroaxis. J
Neurosci. 16(23): p. 7599-609.
- Ahmad I.,Das A.V.,James J.,et al. (2004) Neural
stem cells in the mammalian eye: types and
regulation. Semin Cell Dev Biol. 15(1): p. 53-62.
- Zipori D. (2004) The nature of stem cells: state rather
than entity. Nat Rev Genet. 5(11): p. 873-8.
- Bauer H.C.,Tempfer H.,Bernroider G.,et al. (2006)
Neuronal stem cells in adults. Exp Gerontol. 41(2): p.
- Lendahl U.,Zimmerman L.B.,McKay R.D. (1990)
CNS stem cells express a new class of intermediate
filament protein. Cell. 60(4): p. 585-95.
- Frederiksen K.,McKay R.D. (1988) Proliferation and
differentiation of rat neuroepithelial precursor cells in
vivo. J Neurosci. 8(4): p. 1144-51.
- Mignone J.L.,Kukekov V.,Chiang A.S.,et al. (2004)
Neural stem and progenitor cells in nestin-GFP
transgenic mice. J Comp Neurol. 469(3): p. 311-24.
- Kaneko Y.,Sakakibara S.,Imai T.,et al. (2000)
Musashi1: an evolutionally conserved marker for CNS
progenitor cells including neural stem cells. Dev
Neurosci. 22(1-2): p. 139-53.
- Toda M.,Iizuka Y.,Yu W.,et al. (2001) Expression of
the neural RNA-binding protein Musashi1 in human
gliomas. Glia. 34(1): p. 1-7.
- Sakakibara S.,Okano H. (1997) Expression of neural
RNA-binding proteins in the postnatal CNS:
implications of their roles in neuronal and glial cell
development. J Neurosci. 17(21): p. 8300-12.
- Collignon J.,Sockanathan S.,Hacker A.,et al. (1996)
A comparison of the properties of Sox-3 with Sry and
two related genes,Sox-1 and Sox-2. Development.
122(2): p. 509-20.
- Pevny L.,Rao M.S. (2003) The stem-cell menagerie.
Trends Neurosci. 26(7): p. 351-9.
- Pevny L.H.,Sockanathan S.,Placzek M.,et al. (1998)
A role for SOX1 in neural determination.
Development. 125(10): p. 1967-78.
- Brazel C.Y.,Limke T.L.,Osborne J.K.,et al. (2005)
Sox2 expression defines a heterogeneous population
of neurosphere-forming cells in the adult murine brain.
Aging Cell. 4(4): p. 197-207.
- Ellis P.,Fagan B.M.,Magness S.T.,et al. (2004)
SOX2,a persistent marker for multipotential neural
stem cells derived from embryonic stem cells,the
embryo or the adult. Dev Neurosci. 26(2-4): p. 148-65.
- Graham V.,Khudyakov J.,Ellis P.,et al. (2003) SOX2
functions to maintain neural progenitor identity.
Neuron. 39(5): p. 749-65.
- Islam M.O.,Kanemura Y.,Tajria J.,et al. (2005)
Functional expression of ABCG2 transporter in
human neural stem/progenitor cells. Neurosci Res.
52(1): p. 75-82.
- Weigmann A.,Corbeil D.,Hellwig A.,et al. (1997)
Prominin,a novel microvilli-specific polytopic
membrane protein of the apical surface of epithelial
cells,is targeted to plasmalemmal protrusions of nonepithelial
cells. Proc Natl Acad Sci U S A. 94(23): p.
- Corbeil D.,Roper K.,Hellwig A.,et al. (2000) The
human AC133 hematopoietic stem cell antigen is
also expressed in epithelial cells and targeted to
plasma membrane protrusions. J Biol Chem. 275(8):
- Uchida N.,Buck D.W.,He D.,et al. (2000) Direct
isolation of human central nervous system stem cells.
Proc Natl Acad Sci U S A. 97(26): p. 14720-5.
- Corti S.,Nizzardo M.,Nardini M.,et al. (2007)
Isolation and characterization of murine neural
stem/progenitor cells based on Prominin-1
expression. Exp Neurol. 205(2): p. 547-62.
- Hynes R.O. (2002) Integrins: bidirectional,allosteric
signaling machines. Cell. 110(6): p. 673-87.
- Hall P.E.,Lathia J.D.,Miller N.G.,et al. (2006)
Integrins are markers of human neural stem cells.
Stem Cells. 24(9): p. 2078-84.
- Rubio F.J.,Bueno C.,Villa A.,et al. (2000)
Genetically perpetuated human neural stem cells
engraft and differentiate into the adult mammalian
brain. Mol Cell Neurosci. 16(1): p. 1-13.
- Vescovi A.L.,Parati E.A.,Gritti A.,et al. (1999)
Isolation and cloning of multipotential stem cells from
the embryonic human CNS and establishment of
transplantable human neural stem cell lines by
epigenetic stimulation. Exp Neurol. 156(1): p. 71-83.
- Palma V.,Lim D.A.,Dahmane N.,et al. (2005) Sonic
hedgehog controls stem cell behavior in the postnatal
and adult brain. Development. 132(2): p. 335-44.
- Roy N.S.,Wang S.,Jiang L.,et al. (2000) In vitro
neurogenesis by progenitor cells isolated from the
adult human hippocampus. Nat Med. 6(3): p. 271-7.
- Nunes M.C.,Roy N.S.,Keyoung H.M.,et al. (2003)
Identification and isolation of multipotential neural
progenitor cells from the subcortical white matter of
the adult human brain. Nat Med. 9(4): p. 439-47.
- Pagano S.F.,Impagnatiello F.,Girelli M.,et al. (2000)
Isolation and characterization of neural stem cells
from the adult human olfactory bulb. Stem Cells.
18(4): p. 295-300.
- Arsenijevic Y.,Villemure J.G.,Brunet J.F.,et al.
(2001) Isolation of multipotent neural precursors
residing in the cortex of the adult human brain. Exp
Neurol. 170(1): p. 48-62.
- Schwartz P.H.,Bryant P.J.,Fuja T.J.,et al. (2003)
Isolation and characterization of neural progenitor
cells from post-mortem human cortex. J Neurosci
Res. 74(6): p. 838-51.
- Liu X.,Zhu Y.,Gao W. (2006) Isolation of neural stem
cells from the spinal cords of low temperature
preserved abortuses. J Neurosci Methods. 157(1): p.
- Carpenter M.K.,Cui X.,Hu Z.Y.,et al. (1999) In vitro
expansion of a multipotent population of human
neural progenitor cells. Exp Neurol. 158(2): p. 265-78.
- Svendsen C.N.,Caldwell M.A.,Ostenfeld T. (1999)
Human neural stem cells: isolation,expansion and
transplantation. Brain Pathol. 9(3): p. 499-513.
- Kuhn H.G.,Svendsen C.N. (1999) Origins,functions,and potential of adult neural stem cells. Bioessays.
21(8): p. 625-30.
- Micci M.A.,Pasricha P.J. (2007) Neural stem cells for
the treatment of disorders of the enteric nervous
system: strategies and challenges. Dev Dyn. 236(1):
- Aboody K.S.,Brown A.,Rainov N.G.,et al. (2000)
Neural stem cells display extensive tropism for
pathology in adult brain: evidence from intracranial
gliomas. Proc Natl Acad Sci U S A. 97(23): p. 12846-
- Noble M. (2000) Can neural stem cells be used to
track down and destroy migratory brain tumor cells
while also providing a means of repairing tumorassociated
damage? Proc Natl Acad Sci U S A.
97(23): p. 12393-5.
- Ourednik J.,Ourednik V. (2004) Graft-induced
plasticity in the mammalian host CNS. Cell Transplant.
13(3): p. 307-18.
- Ourednik V.,Ourednik J. (2005) Graft/host
relationships in the developing and regenerating CNS
of mammals. Ann N Y Acad Sci. 1049: p. 172-84.
- Martino G.,Pluchino S. (2006) The therapeutic
potential of neural stem cells. Nat Rev Neurosci. 7(5):
- Bain G.,Kitchens D.,Yao M.,et al. (1995) Embryonic
stem cells express neuronal properties in vitro. Dev
Biol. 168(2): p. 342-57.
- Finley M.F.,Kulkarni N.,Huettner J.E. (1996) Synapse
formation and establishment of neuronal polarity by
P19 embryonic carcinoma cells and embryonic stem
cells. J Neurosci. 16(3): p. 1056-65.
- Fraichard A.,Chassande O.,Bilbaut G.,et al. (1995)
In vitro differentiation of embryonic stem cells into
glial cells and functional neurons. J Cell Sci. 108 ( Pt
10): p. 3181-8.
- Kawasaki H.,Mizuseki K.,Nishikawa S.,et al. (2000)
Induction of midbrain dopaminergic neurons from ES
cells by stromal cell-derived inducing activity. Neuron.
28(1): p. 31-40.
- Liu S.,Qu Y.,Stewart T.J.,et al. (2000) Embryonic
stem cells differentiate into oligodendrocytes and
myelinate in culture and after spinal cord
transplantation. Proc Natl Acad Sci U S A. 97(11): p.
- Reubinoff B.E.,Itsykson P.,Turetsky T.,et al. (2001)
Neural progenitors from human embryonic stem cells.
Nat Biotechnol. 19(12): p. 1134-40.
- Zhang S.C.,Wernig M.,Duncan I.D.,et al. (2001) In
vitro differentiation of transplantable neural
precursors from human embryonic stem cells. Nat
Biotechnol. 19(12): p. 1129-33.
- Tropepe V.,Hitoshi S.,Sirard C.,et al. (2001) Direct
neural fate specification from embryonic stem cells: a
primitive mammalian neural stem cell stage acquired
through a default mechanism. Neuron. 30(1): p. 65-
- O'Shea K.S. (2001) Directed differentiation of
embryonic stem cells: genetic and epigenetic
methods. Wound Repair Regen. 9(6): p. 443-59.
- O'Shea K.S. (2002) Neural differentiation of
embryonic stem cells. Methods Mol Biol. 198: p. 3-14.
- Kitajima H.,Yoshimura S.,Kokuzawa J.,et al. (2005)
Culture method for the induction of neurospheres
from mouse embryonic stem cells by coculture with
PA6 stromal cells. J Neurosci Res. 80(4): p. 467-74.
- Carpenter M.K.,Inokuma M.S.,Denham J.,et al.
(2001) Enrichment of neurons and neural precursors
from human embryonic stem cells. Exp Neurol.
172(2): p. 383-97.
- Vawda R.,Woodbury J.,Covey M.,et al. (2007)
Stem cell therapies for perinatal brain injuries. Semin
Fetal Neonatal Med. 12(4): p. 259-72.
- Reubinoff B.E.,Pera M.F.,Fong C.Y.,et al. (2000)
Embryonic stem cell lines from human blastocysts:
somatic differentiation in vitro. Nat Biotechnol. 18(4):
- Howell J.C.,Lee W.H.,Morrison P.,et al. (2003)
Pluripotent stem cells identified in multiple murine
tissues. Ann N Y Acad Sci. 996: p. 158-73.
- Meletis K.,Frisen J. (2003) Blood on the tracks: a
simple twist of fate? Trends Neurosci. 26(6): p. 292-6.
- Mezey E.,Chandross K.J.,Harta G.,et al. (2000)
Turning blood into brain: cells bearing neuronal
antigens generated in vivo from bone marrow.
Science. 290(5497): p. 1779-82.
- Mezey E.,Key S.,Vogelsang G.,et al. (2003)
Transplanted bone marrow generates new neurons
in human brains. Proc Natl Acad Sci U S A. 100(3): p.
- Wei G.,Schubiger G.,Harder F.,et al. (2000) Stem
cell plasticity in mammals and transdetermination in
Drosophila: common themes? Stem Cells. 18(6): p.
- Weimann J.M.,Charlton C.A.,Brazelton T.R.,et al.
(2003) Contribution of transplanted bone marrow
cells to Purkinje neurons in human adult brains. Proc
Natl Acad Sci U S A. 100(4): p. 2088-93.
- Alvarez-Dolado M.,Pardal R.,Garcia-Verdugo J.M.,et al. (2003) Fusion of bone-marrow-derived cells
with Purkinje neurons,cardiomyocytes and
hepatocytes. Nature. 425(6961): p. 968-73.
- Black I.B.,Woodbury D. (2001) Adult rat and human
bone marrow stromal stem cells differentiate into
neurons. Blood Cells Mol Dis. 27(3): p. 632-6.
- Weiss M.L.,Mitchell K.E.,Hix J.E.,et al. (2003)
Transplantation of porcine umbilical cord matrix cells
into the rat brain. Exp Neurol. 182(2): p. 288-99.
- Sanchez-Ramos J.R. (2002) Neural cells derived
from adult bone marrow and umbilical cord blood. J
Neurosci Res. 69(6): p. 880-93.
- Clarke D.L.,Johansson C.B.,Wilbertz J.,et al. (2000)
Generalized potential of adult neural stem cells.
Science. 288(5471): p. 1660-3.
- Lu P.,Blesch A.,Tuszynski M.H. (2004) Induction of
bone marrow stromal cells to neurons: differentiation,transdifferentiation,or artifact? J Neurosci Res. 77(2):
- Miller R.H. (2006) The promise of stem cells for
neural repair. Brain Res. 1091(1): p. 258-64.
- Keene C.D.,Ortiz-Gonzalez X.R.,Jiang Y.,et al.
(2003) Neural differentiation and incorporation of
bone marrow-derived multipotent adult progenitor
cells after single cell transplantation into blastocyst
stage mouse embryos. Cell Transplant. 12(3): p. 201-
- Pluchino S.,Zanotti L.,Deleidi M.,et al. (2005)
Neural stem cells and their use as therapeutic tool in
neurological disorders. Brain Res Brain Res Rev.
48(2): p. 211-9.
- Berninger B.,Hack M.A.,Gotz M. (2006) Neural stem
cells: on where they hide,in which disguise,and how
we may lure them out. Handb Exp Pharmacol. (174):
- Hess D.C.,Borlongan C.V. (2008) Stem cells and
neurological diseases. Cell Prolif. 41 Suppl 1: p. 94-
- Tuszynski M.H.,Thal L.,Pay M.,et al. (2005) A
phase 1 clinical trial of nerve growth factor gene
therapy for Alzheimer disease. Nat Med. 11(5): p.
- Braak H.,Braak E. (1991) Demonstration of amyloid
deposits and neurofibrillary changes in whole brain
sections. Brain Pathol. 1(3): p. 213-6.
- Lindvall O.,Kokaia Z. (2006) Stem cells for the
treatment of neurological disorders. Nature.
441(7097): p. 1094-6.
- Kim S.U. (2007) Genetically engineered human
neural stem cells for brain repair in neurological
diseases. Brain Dev. 29(4): p. 193-201.
- Dunnett S.B. (2000) Functional analysis of frontostriatal
reconstruction by striatal grafts. Novartis
Found Symp. 231: p. 21-41; discussion 41-52.
- Kendall A.L.,Rayment F.D.,Torres E.M.,et al.
(1998) Functional integration of striatal allografts in a
primate model of Huntington's disease. Nat Med. 4(6):
- Palfi S.,Conde F.,Riche D.,et al. (1998) Fetal
striatal allografts reverse cognitive deficits in a
primate model of Huntington disease. Nat Med. 4(8):
- Freeman T.B.,Cicchetti F.,Hauser R.A.,et al. (2000)
Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. Proc
Natl Acad Sci U S A. 97(25): p. 13877-82.
- Vazey E.M.,Chen K.,Hughes S.M.,et al. (2006)
Transplanted adult neural progenitor cells survive,differentiate and reduce motor function impairment in
a rodent model of Huntington's disease. Exp Neurol.
199(2): p. 384-96.
- Back S.A.,Tuohy T.M.,Chen H.,et al. (2005)
Hyaluronan accumulates in demyelinated lesions and
inhibits oligodendrocyte progenitor maturation. Nat
Med. 11(9): p. 966-72.
- Windrem M.S.,Nunes M.C.,Rashbaum W.K.,et al.
(2004) Fetal and adult human oligodendrocyte
progenitor cell isolates myelinate the congenitally
dysmyelinated brain. Nat Med. 10(1): p. 93-7.
- Nistor G.I.,Totoiu M.O.,Haque N.,et al. (2005)
Human embryonic stem cells differentiate into
oligodendrocytes in high purity and myelinate after
spinal cord transplantation. Glia. 49(3): p. 385-96.
- Pluchino S.,Quattrini A.,Brambilla E.,et al. (2003)
Injection of adult neurospheres induces recovery in a
chronic model of multiple sclerosis. Nature.
422(6933): p. 688-94.
- Kordower J.H.,Freeman T.B.,Snow B.J.,et al.
(1995) Neuropathological evidence of graft survival
and striatal reinnervation after the transplantation of
fetal mesencephalic tissue in a patient with
Parkinson's disease. N Engl J Med. 332(17): p. 1118-
- Piccini P.,Brooks D.J.,Bjorklund A.,et al. (1999)
Dopamine release from nigral transplants visualized
in vivo in a Parkinson's patient. Nat Neurosci. 2(12):
- Behrstock S.,Ebert A.,McHugh J.,et al. (2006)
Human neural progenitors deliver glial cell linederived
neurotrophic factor to parkinsonian rodents
and aged primates. Gene Ther. 13(5): p. 379-88.
- McDonald J.W.,Liu X.Z.,Qu Y.,et al. (1999)
Transplanted embryonic stem cells survive,differentiate and promote recovery in injured rat
spinal cord. Nat Med. 5(12): p. 1410-2.
- Ogawa Y.,Sawamoto K.,Miyata T.,et al. (2002)
Transplantation of in vitro-expanded fetal neural
progenitor cells results in neurogenesis and
functional recovery after spinal cord contusion injury
in adult rats. J Neurosci Res. 69(6): p. 925-33.
- Cummings B.J.,Uchida N.,Tamaki S.J.,et al. (2005)
Human neural stem cells differentiate and promote
locomotor recovery in spinal cord-injured mice. Proc
Natl Acad Sci U S A. 102(39): p. 14069-74.
- Hofstetter C.P.,Holmstrom N.A.,Lilja J.A.,et al.
(2005) Allodynia limits the usefulness of intraspinal
neural stem cell grafts; directed differentiation
improves outcome. Nat Neurosci. 8(3): p. 346-53.
- Keirstead H.S.,Nistor G.,Bernal G.,et al. (2005)
Human embryonic stem cell-derived oligodendrocyte
progenitor cell transplants remyelinate and restore
locomotion after spinal cord injury. J Neurosci. 25(19):
- Kelly S.,Bliss T.M.,Shah A.K.,et al. (2004)
Transplanted human fetal neural stem cells survive,migrate,and differentiate in ischemic rat cerebral
cortex. Proc Natl Acad Sci U S A. 101(32): p. 11839-
- Hayashi J.,Takagi Y.,Fukuda H.,et al. (2006)
Primate embryonic stem cell-derived neuronal
progenitors transplanted into ischemic brain. J Cereb
Blood Flow Metab. 26(7): p. 906-14.
- Ikeda R.,Kurokawa M.S.,Chiba S.,et al. (2005)
Transplantation of neural cells derived from retinoic
acid-treated cynomolgus monkey embryonic stem
cells successfully improved motor function of
hemiplegic mice with experimental brain injury.
Neurobiol Dis. 20(1): p. 38-48.
- Thored P.,Arvidsson A.,Cacci E.,et al. (2006)
Persistent production of neurons from adult brain
stem cells during recovery after stroke. Stem Cells.
24(3): p. 739-47.
- Kuhn H.G.,Winkler J.,Kempermann G.,et al. (1997)
Epidermal growth factor and fibroblast growth factor-2
have different effects on neural progenitors in the
adult rat brain. J Neurosci. 17(15): p. 5820-9.
- Fallon J.,Reid S.,Kinyamu R.,et al. (2000) In vivo
induction of massive proliferation,directed migration,and differentiation of neural cells in the adult
mammalian brain. Proc Natl Acad Sci U S A. 97(26):
- Lai K.,Kaspar B.K.,Gage F.H.,et al. (2003) Sonic
hedgehog regulates adult neural progenitor
proliferation in vitro and in vivo. Nat Neurosci. 6(1): p.
- Machold R.,Hayashi S.,Rutlin M.,et al. (2003)
Sonic hedgehog is required for progenitor cell
maintenance in telencephalic stem cell niches.
Neuron. 39(6): p. 937-50.
- Ahn S.,Joyner A.L. (2005) In vivo analysis of
quiescent adult neural stem cells responding to Sonic
hedgehog. Nature. 437(7060): p. 894-7.