Download Genetic programs and responses of neural stem/progenitor cells

Physiol Genomics 14: 171–197, 2003;
10.1152/physiolgenomics.00021.2002.
invited review
Genetic programs and responses of neural stem/progenitor
cells during demyelination: potential insights
into repair mechanisms in multiple sclerosis
Jaime Imitola,1 Evan Y. Snyder,2 and Samia J. Khoury1
1
Center for Neurologic Diseases, Partners MS Center, Department of Neurology, Brigham and
Women’s Hospital, and 2Department of Neurology, Harvard Institutes of Medicine, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston Massachusetts 02115
neural stem cells; experimental autoimmune encephalomyelitis; neuroregeneration; cytokines; neural transplantation; neurodegeneration
MULTIPLE SCLEROSIS (MS) is the most commonly diagnosed neurological disease in young adults (201). This
chronic debilitating disease represents a high cost to
society in terms of both productivity and chronic health
care resources (45). The current treatment of MS relies
on immunologic manipulation. However, it is becoming
clear that repair should be considered as a goal for
treatment. Demyelination, axonal degeneration, neuronal dysfunction, and apoptosis (57, 157) are key
features in MS pathology, and current evidence suggests that remyelination to some extent also occurs
spontaneously (236, 238). As these “self-repair” mechanisms begin to be better understood, optimization and
permanence of neural repair may become a target for
new therapies. Here we review what is known about
the role of neural stem cells (NSCs) and progenitor
cells in demyelinating diseases. We will first discuss
basic concepts of NSC and progenitor biology, especially oligodendrocyte progenitor cells (OPCs). We will
then review the genetic programs involved in NSC and
OPC proliferation, differentiation, and apoptosis, then
discuss the responses of endogenous and exogenous
NSCs and OPCs to the demyelinating environment
Article published online before print. See web site for date of
publication (http://physiolgenomics.physiology.org).
Address for reprint requests and other correspondence: S. J.
Khoury, 77 Ave. Louis Pasteur R710, Harvard Institutes of Medicine, Boston, MA 02115 (E-mail: [email protected]).
and the emerging evidence of molecules that may be
involved in such responses. Finally, we will analyze the
therapeutic potential of these findings.
GLOSSARY
For the aid of the reader, here we briefly provide
some definitions and descriptions of relevant concepts.
Self-renewing capacity. This is the ability of a stem
cell in vivo and in vitro to generate new stem cells with
the same characteristics.
Multipotency. Multipotency is the ability of a stem
cell to give rise to a lineage-specific committed progenitor cell that will terminally differentiate in mature
progeny.
Symmetric vs. asymmetric division. Symmetric division is the generation of two clonally derived stem cells,
whereas asymmetric division is the generation of a
stem cell and a committed progenitor.
NG2. NG2 is a proteoglycan, i.e., a marker for oligodendrocyte progenitor cells.
O4. O4 is an antibody that has recognized a developmental regulated epitope, which signals the first
step into terminal oligodendrocyte differentiation.
Th1 cytokines. Th1 cytokines are secreted preferentially by T cells that have differentiated along a T
helper 1 phenotype, including IFN-␥, lymphotoxin, and
interleukin-2.
Th2 cytokines. Th2 cytokines are secreted preferentially by T cells that have differentiated along a T
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Imitola, Jaime, Evan Y. Snyder, and Samia J. Khoury. Genetic
programs and responses of neural stem/progenitor cells during demyelination: potential insights into repair mechanisms in multiple sclerosis. Physiol
Genomics 14: 171–197, 2003; 10.1152/physiolgenomics.00021.2002.—In recent years, it has become evident that the adult mammalian CNS contains
a population of neural stem cells (NSCs) described as immature, undifferentiated, multipotent cells, that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells. This article reviews recent progress in elucidating the genetic programs and dynamics of
NSC and OPC proliferation, differentiation, and apoptosis, including the
response to demyelination. Emerging knowledge of the molecules that may
be involved in such responses may help in the design of future stem
cell-based treatment of demyelinating diseases such as multiple sclerosis.
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BASIC CONCEPTS OF NEURAL STEM AND
PROGENITORS CELLS
Neural Stem and Progenitor Cells
The current definition of a NSC relies upon “operational” criteria rather than on a set of molecular markers alone. NSCs are cells from the central nervous
system (CNS) and peripheral nervous system (PNS)
that are multipotent and self-renewing (76) (Fig. 1A).
Multipotency is the ability of a single cell clone to give
rise to the three major types of cells in the CNS (e.g.,
neurons, oligodendrocytes, and astrocytes) throughout
the nervous system at all stages of life, as well as to
repopulate those regions when depleted of cells. The
term “self-renewal” is used to define the capacity of a
clone to generate new stem cells with identical properties from generation to generation. NSCs seem to have
a proliferative response to certain cytokines such as
epidermal growth factor (EGF) and basic fibroblast
growth factor (bFGF), although the number of such
factors seems to be growing (76).
“Progenitor cells” are a step further along than NSCs
in the differentiation process; they have committed to a
particular lineage (neuronal or glial) and have begun to
express lineage-specific markers. How irreversible or
invariant such commitment is remains an area of active speculation and investigation. Progenitor cells
such as OPCs may, under certain circumstances in
vitro, exhibit “stemness” in that they can be induced to
generate neurons, astrocytes, and oligodendrocytes
(18, 134, 166). Even “end”-differentiated cells have
been observed to evince this property; adult ependymal
cells, for example, when cultured in vitro or when
monitored in vivo are reported to give rise to both
neurons and glia; in vivo they yield neurons that migrate to the olfactory bulb and astrocytes that respond
to injury (122), although controversy exists about the
real stemness of ependymal cells. Other investigators
suggest that subventricular zone (SVZ) astrocytes
rather than ependymal cells are the true stem cells in
that periventricular region. This finding has been clarified recently by Rietze et al. (228), who found nestinpositive pluripotent stem cells in both the subventricular and the ependymal area; interestingly, these cells
were negative for glial fibrillary acidic protein (GFAP),
suggesting heterogeneity of NSCs (59, 139, 228), a
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phenomenon that has recently been observed in human NSCs at the molecular level (259). Other investigators have found stem-like cells within a supposedly
committed “glial” population extracted from the postnatal and adult cortex, adult substantia nigra, as well
as the adult optic nerve; such immature “glia” give rise
to neurons as well as mature oligodendrocytes and
astrocytes (139, 147, 206). It remains unclear what this
heterogeneity of progenitor populations implies: a true
biological phenomenon or a limitation in our ability to
provide cell-specific unambiguous defining markers.
There are specific germinative zones in the embryonic and adult mammalian CNS (5) that can be considered as sources of NSCs. These zones include the
ventricular zone, the SVZ, the external germinal layer
of the cerebellum, the subgranular zone of the dentate
gyrus, and the ependymal layer of the spinal cord (77).
During the earliest stages of cerebrogenesis, neurons
and glia are born in the ventricular zone from NSCs
that become progenitors and migrate out using the
radial glia as a scaffold to reach the cortex. In addition,
radial glia themselves may be multipotent neural precursors with stem cell properties (86, 111, 143, 187).
These same NSCs give rise to secondary germinal
zones, including the SVZ, that contain a reservoir of
undifferentiated, uncommitted NSCs that persist into
adulthood (205). In the adult mammalian CNS, NSCs
can be isolated from the SVZ, striatum, cortex, and the
rostral extension of the olfactory bulb (92). Adult neurogenesis from hippocampus has been observed in humans and rodents during normal and abnormal conditions (64, 194), but the exact cells giving rise to new
neurons are still under investigation. Previous studies
have suggested that neurogenesis in the adult hippocampus arises from NSCs (64, 276) and that astrocytes from hippocampus are capable of regulating neurogenesis by instructing the stem cells to adopt a neuronal fate (253). These adult hippocampal NSCs are
able to generate functional neurons (254). However,
these findings have been challenged by recent work;
Seaberg et al. (239) showed that the dentate gyrus
contains multipotent NSCs during development and
until birth, but these cells become restricted neuronal
progenitors during adulthood. These results would
suggest that what were thought to be adult NSCs from
hippocampus were actually contaminating cells from
the periventricular region that persist near the adult
dentate gyrus and that neuronal restricted progenitors
and not NSCs are the source of newly generated dentate gyrus neurons throughout adulthood.
The adult SVZ (153) is a heterogeneous complex of
several layers of cells adjacent to the ependyma, surrounding the lateral ventricles. So far, four different
types of cells have been identified in the SVZ (Fig. 1, B
and C): type A migrating neuronal precursors that
migrate to the olfactory bulb; type B nestin-positive,
GFAP-positive astrocytes that exhibit NSC properties;
type C nestin-positive multipotent progenitors cells
(61); and ependymal cells that line the ventricles and
the spinal cord and that may have stem-like qualities
as well (60, 122, 144). Current evidence suggests that
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helper 2 phenotype, including interleukin-4 and interleukin-5.
Lysolecithin Lysolecithin is an analog of lysophosphatidylcholine that cause destruction of oligodendrocytes and is used in a model of chemically induced
demyelination.
Cuprizone. Cuprizone is a toxin that targets oligodendrocytes and causes destruction of oligodendrocytes
and is used in model of chemically induced demyelination.
Experimental autoimmune encephalomyelitis (EAE).
EAE is a model for the human disease, MS, that is
achieved by immunizing a susceptible strain of rodents
and primates with myelin antigens.
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173
in the adult SVZ, NSCs express GFAP (115). The
developmental origin of these cells is unclear; it is
suggested that these cells may evolve directly from
radial glia, which are multipotent precursor cells that
participate in neurogenesis as an anchor for tangential
chain migration of neuroblasts (59, 60, 139, 259). Another possibility is that adult NSCs are indeed radial
glia that adopt an adult developmental expression of
GFAP (115).
In the adult CNS, NSCs of the SVZ divide symmetrically, yielding two NSCs, one of which dies by apoptosis leaving the other to maintain the NSC pool during
the life span of the individual (188). During developPhysiol Genomics • VOL
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ment or when external triggering occurs (such as injury), NSCs proliferate either by symmetric division,
where each cell divides into two new NSCs, or by
asymmetric division, where the NSC gives rise to one
new NSC and a progenitor cell. When asymmetric
division predominates, a great number of rapidly proliferating progenitors are generated that migrate out to
their final destination. In the songbird (131), NSCs in
the adult participate in the neurogenesis that is responsible for seasonal changes of the song. Although
neurogenesis has been found to exist in adult mammalian brain, including humans, it is unclear what role
NSCs play there, although they do seem to become
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Fig. 1. Operational definition of a neural
stem cell (NSC). A: adult stem cells can be
isolated by dissection of the subventricular
zone (SVZ). A single cell suspension generates multipotent cells in epidermal
growth factor (EGF) and fibroblast growth
factor (FGF); these cells give rise to a “primary neurosphere” that contains NSC and
progenitor cells. When dissociated at the
single cell level, these cells give rise to
cells with identical multipotentiality (in
this case, defined as a “secondary neurosphere”) to be deemed as “self-renewing.”
NSCs exhibit multipotency when cultured
in medium containing serum; these give
rise to neuronal and glial progenitors and
subsequently more mature and terminally
differentiated cells. B: confocal laser microscopy of bromodeoxyuridine (BrdU) incorporation by cells in the SVZ of adult
mice demonstrating proliferation of SVZ
precursor cells. Bar ⫽ 100 ␮m. CC, corpus
callosum. C: representation of the types of
cellular architecture in the SVZ. The
ependymal cell layer (EP) lines the ventricles; these cells have been postulated to be
NSCs. The SVZ is composed of a heterogeneous population of cells: neuronal precursors (“A”), astrocytes or type B cells that
may also be stem-like NSCs (“B”), type C
multipotent precursor cells that exhibit
NSC properties in vivo and in vitro (“C”),
and adult oligodendrocyte progenitor cells
(OPCs, in red).
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integrated into neuronal circuitry of the hippocampus,
possibly participating in neural plasticity (64, 274, 275)
and learning. Impairing the proliferation of endogenous dentate precursors has been shown to affect behavioral learning in the mouse (245, 246).
Characterization and Pluripotency of NSCs
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NSCs will proliferate in response to EGF and/or
bFGF. This proliferative response can be used to isolate and expand stem-like cells from the CNS. Any
proliferative cell grown in serum-free medium without
a substrate will form a floating cluster of cells. When
such clusters are obtained from primary dissociated
neural cultures (e.g., from the SVZ or embryonic forebrain), they may contain and help select for cells with
stem-like features. Some investigators who employ
this technique have termed this a “neurosphere” assay.
When plated on an adherent substrate with serumcontaining medium, neurons, astrocytes, oligodendrocytes, as well as undifferentiated cells may appear. It
should be emphasized that a single cluster does not
equal a clone unless it has been proven to derive from
a single isolated cell in an isolated well (1, 53, 55, 59,
122, 171, 188, 280). Self-renewal can be implied if a
single cell can give rise to differentiated cells as well as
to other undifferentiated cells that can be similarly
placed into an isolated well and give rise to all differentiated and undifferentiated progeny.
The above-mentioned maneuvers constitute an “operational” definition of a stem cell and remain today
the only valid way of discerning a self-renewing and
multipotent NSC. However, surrogate biological markers are constantly being investigated and tested for
sensitivity and specificity. Nestin, an intermediate filament protein, has been useful in the study of NSCs
(141, 280). Nestin, however, while sensitive, is not
specific; it is expressed by a variety of cells that include
reactive astrocytes, endothelial cells, SVZ neuronal
progenitor cells, and ependymal cells (149, 175), as well
as NSCs. It can also be expressed by non-NSCs, such as
embryonic stem (ES) cells (151, 158) and pancreatic
stem cells (310).
Some investigators have used the low expression of
peanut agglutinin (PNA)-binding and heat stable antigen (HSA) to identify a nestin-positive pluripotent
NSC from the adult SVZ in mice with the phenotype
nestin⫹ PNAlo HSAlo (228). Multipotent neural progenitor cells from the SVZ may also express the intermediate filament vimentin, the polysialic form of neural
cell adhesion molecule (PS-NCAM), and the transcription factor mushashi (242, 304). Another proposed
marker is the carbohydrated Lewis X expressed on
embryonic pluripotent stem cells and found in 4% of
the adult SVZ, but not in the ependymal region. These
Lex-positive populations showed stem cells characteristics (41).
Some studies have identified and isolated populations of NSCs based on flow cytometric characteristics
in response to uptake of the DNA dye Hoechst: both red
and blue wavelengths, similar to studies done in other
stem cells (88, 89). The isolation is based on the differential efflux of the dye by a multidrug transporter. The
population isolated in this way is called “the side population” or “SP” fraction because the cells segregate to
a tiny bin that looks like a small “hook” of cells branching off from the main accumulation of cells after fluorescence-activated cell sorting (FACS). Floating clusters of cells in serum-free medium from dissociated
neural cultures may segregate to this SP population
(108). Furthermore, the novel hematopoietic stem cell
marker CD133 has been used to define a population of
human neural precursors cells that exhibit a CD133⫹
CD34⫺ CD45⫺ phenotype and fulfill all the criteria for
human NSCs. However, it is not clear whether these
cells are a distinct population of NSCs or simply express distinct markers (273). Other NSCs such as neural crest stem cells (NCSCs), have been prospectively
isolated from fetal mouse sciatic nerve using cell surface antigens such as p75, the low-affinity neurotrophin receptor, and P0, a peripheral myelin protein:
these cells exhibit phenotype p75⫹P0⫺ and are capable
of self-renewal and the generation of neurons and glia
(185). It is most likely that a battery of markers will be
needed to define a genuine stem cell. Future work will
involve defining the molecular profile or fingerprint of
a NSC, much as has been derived for the hematopoietic
stem cell.
The term pluripotency refers to the capacity of stem
cells to give rise to the full range of cells and tissues in
an organism. This most extensive potential was
thought to be a specific property of ES cells alone.
However, several controversial observations over the
past 2 yr have suggested that other stem cells, including NSCs, may have such potential under extraordinary nonphysiological circumstances. NSCs have been
reported to give rise to mature nonneural cells (251).
Adult murine NSCs may become hematopoietic cells
after injection into an irradiated host and express such
T cell markers as CD3 (22). Others have shown that,
when injected into early stage mice and chick embryos,
adult NSCs may differentiate into cells of the gastrointestinal tract, heart, and kidney, expressing markers
typically found in these tissues in a nontumorogenic
manner (55). NSCs can also produce skeletal myotubes
both in vitro and in vivo (79). This behavior is also
observed in other stem cells, such as bone-marrowderived stem cells that after intravenous injection in
mice travel to the CNS, express neuronal markers, and
generate an astroglial phenotype (27, 178). The purity
of the NSC populations used in these experiments as
well as the specificity of the markers used to define
specific neural and nonneural cell types remain issues
of ongoing investigation and inquiry in such experiments. Other groups have failed to reproduce these
findings; recently, Morshead et al. (186) transplanted
128 host animals with NSCs, and they could not confirm a contribution to hematopoiesis. An alternative
explanation to the Bjornson experiment (22) is that
fusion rather than true transdifferentiation may explain some of the extraordinary claims of pluripotency
of NSCs (264, 299). In support of this explanation is the
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Oligodendrocyte Progenitor Cells
In the mature CNS, oligodendrocytes are terminally differentiated cells, yet new oligodendrocytes
seem to originate from OPCs (probably by way of
NSCs) (99) since there is production of new oligodendrocytes in the adult forebrain (293) and spinal cord
(107). OPCs can be identified by several markers: the
ganglioside GD3; the cell surface marker A2B5; the
O4 antigen; 14F7 monoclonal antibody (301); the
glycoprotein AN2 (196); the spliced form of 2⬘,3⬘cyclic nucleotide 3⬘-phosphohydrolase (CNPase)
(302); the transcription factors Olig-1, Olig-2,
Nkx2.2, Dlx2 (155, 222); and the integral membrane
proteoglycan NG2 (142, 197). Although NG2 may be
expressed by macrophages and endothelial cells, the
pattern of staining and the complex morphology of
OPCs helps to make the distinction (124, 215) (Fig. 2,
A and B). Using these markers, researchers have
detected OPCs in the adult CNS (226).
Fig. 2. Oligodendrocytes developmental lineage and morphology. NG2-positive (stained red) adult OPCs from the
corpus callosum can exhibit multipolar
(A) and bipolar morphology (B). C: symmetrical cell division is shown in two
young OPCs (red) with incorporated
BrdU (green) indicative of cell division
and showing typical morphology with
radially oriented processes in the adult
mice spinal cord. Arrows in A and B
point to OPC processes and in C to
BRDU-positive nucleus. Scale bar ⫽ 10
␮m. D: developmental stages of oligodendrocytes from a NSC. PDGF, plateletderived growth factor; Gal-C, galactocerebrosidase; PLP, proteolipid protein;
CNPase, 2⬘,3⬘-cyclic nucleotide 3⬘-phosphohydrolase; MBP, myelin basic protein; MOG, myelin oligodendrocyte
glycoprotein.
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recent observation of bone-marrow-derived cells fused
to human Purkinje neurons after bone marrow transplantation (284).
Regardless of how confirmatory experiments for the
above-cited studies turn out, the differentiation potential of stem cells, including NSCs, remains quite extraordinary. Their ability to differentiate in response
to specific environmental clues, both physiological and
nonphysiological, suggests a critical role for cytokines
and cell-to-cell contact signals and the relative levels of
transcription factors on stem cells. For example, the
oct-4 gene defines pluripotency and self-renewal of ES
cells (198); however, it is downregulated when ES cells
change to nestin-positive stem cells (158), suggesting
that different “master” transcription factors may regulate pluripotency of NSCs. Terminal differentiation
likely depends upon the spatiotemporal expression and
interactions of multiple cytokines with their receptors
on the NSC surface that activate specific transcriptional programs (235, 271).
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adult OPCs in vivo; Horner et al. (107) found that less
than 1% of OPCs divide and exhibit a prolonged cell
cycle (Fig. 2C). It is possible that environmental cues
absent in the adult brain but present in the myelinating brain or molecules enriched in the adult brain may
influence this behavior; molecules like Notch and
Jagged have been shown to inhibit OPC differentiation
(282). Moreover, OPCs are regionally heterogeneous in
their ability to differentiate; for example, cortical OPCs
isolated from postnatal day 7 rats exhibit a slow differentiation behavior when compared with optic nervederived cells (216). Despite the biological difference,
adult OPCs also share many of the characteristics of
the perinatal OPCs, such as response to growth factors,
the triiodothyronine (T3)-dependent timing for differentiation, and maintenance of their self-renewing capacity (Table 1). Adult OPCs, which can yield mature
oligodendrocytes in the adult brain, express NG2, the
PDGF␣ receptor, O4, and the FGF receptor (145). They
also express c-kit, a marker for hematopoietic stem
cells that is lost when they differentiate into postmitotic oligodendrocyte (112).
Adult OPCs are maintained in a quiescent state by
a mechanism that involves ␣-amino-3-hydroxy-5methyl-4-isoxazole propionate (AMPA) receptor (208),
the cell cycle inhibitor p27Kip1 (44), and Notch. Activation of the Notch receptor on OPCs blocks their
oligodendrocyte differentiation in the developing optic
nerve (282). Because of their abundance in the CNS
and the fact that their processes contact the nodes of
Ranvier (19), it has been suggested that OPCs subserve synaptic remodeling and plasticity in the adult
CNS (199, 291). Recent data, however, point to a
broader differentiation potential and replication capacity of OPC; depending on the cytokine milieu, they may
exhibit actual neural stem-like characteristics (134,
206, 261).
OPCs express several functional cytokine receptors
such as FGF-2R (176) and the PDGF␣ receptor (225);
in fact, as noted above, such receptors have been used
as markers for OPCs (218). OPCs have been isolated
from brains of healthy humans and of MS patients, and
these express the p75NTR (neurotrophin receptor) that
is implicated in oligodendrocyte survival and apoptosis
(300). In vitro oligodendroglial development can be
recapitulated from NSCs; Zhang et al. (306) demon-
Table 1. Characteristics of perinatal vs. adult OPCs
Characteristics
Perinatal
Adult
Proliferation
Differentiation
Levels of cyclin E
Levels of CDK2
Levels of p27Kip1
Response to growth factors
T3 dependence for
differentiation
Self-renewing capacity
NG2 expression
high
high
high
high
low
yes
low
low
low
low
high
yes
yes
yes
yes
yes
yes
yes
OPC, oligodendrocyte progenitor cell.
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Around embryonic day E15, oligodendrocytes arise
from a subpopulation of precursor cells within the
ventral ventricular zone of the spinal cord and the SVZ
(143, 200). These populations are characterized by the
coexpression of the transcription factors Olig-2 and
Nkx2.2, both of which are involved in OPCs differentiation and myelination (155). Reynolds and colleagues
(99, 227) characterized the time course of oligodendrocyte marker expression and differentiation using the
anti-ganglioside GD3 antibody; these cells arise from
subependymal layers, migrate out, and subsequently
express galactocerebrosidase-C (Gal-C) and the myelin-associated protein CNPase. Myelin basic protein
(MBP) is expressed 2–3 days later, prior to myelin
formation (99, 227).
During oligodendrocyte development, OPCs undergo
several maturational stages determined by specific antigenic expression and developmental potential (Fig.
2D). The OPCs isolated from the neonatal optic nerve
were initially termed “O2A progenitor cells” (221) because they were determined to give rise in vitro to
oligodendrocytes (“O”) as well as type 2 (fibrous) astrocytes (“2A”) depending on the concentration of serum
and platelet-derived growth factor (PDGF) in the
growth medium. In serum-free medium they differentiate into oligodendrocytes, whereas in serum-containing medium they become astrocytes (65). These proliferative, self-renewing, bipotent glial precursors were
immunoreactive to antibodies against GD3, vimentin,
A2B5, and NG2. Adult optic nerve also contains a
similar type of cell that conserves some properties of its
perinatal counterpart (290).
In the initial stages of development, OPCs exhibit
the NG2⫹ PDGFR-␣⫹ O4⫺ phenotype. These cells give
rise to more advanced progenitors expressing O4,
which, in turn, generate premyelinating oligodendrocytes that lose the expression of NG2 and gain the
expression of proteolipid protein (PLP), and, finally, to
mature oligodendrocytes expressing MBP and CNPase
(65). Expression of O4 is a first step into terminal
oligodendrocyte differentiation (83) and indicates a
more committed stage with less proliferative potential
(283). Gal-C expression is associated with terminal
differentiation and is followed by MBP, PLP, and myelin/oligodendrocyte glycoprotein (MOG) expression
(237).
Some of the above-described precursors persist as
adult OPCs. These OPCs differ from their perinatal
counterparts in several respects: they divide, migrate,
and differentiate 3–4 times more slowly than perinatal
OPCs. These differences are likely to be cell intrinsic,
but the exact mechanism of the progressive change of
potential from perinatal OPCs to adult OPCs is unknown. The cell cycle inhibitor p27Kip1 accumulates
as these cells divide and has been proposed as one of
the mechanisms leading to the change in proliferation
potential (240). Additionally, the levels of cdk2 and
cyclin are diminished in adult OPCs compared with
perinatal cells; this may account for the proliferative
state of adult OPCs (16). However, cell intrinsic mechanisms are not sufficient to explain the dormancy of
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MOLECULAR PROGRAMS THAT CONTROL NSC AND
OPC FUNCTION
Genes Involved in NSC Proliferation
The signals responsible for controlling proliferation
and differentiation of precursor cells in the CNS are
starting to be elucidated. Among these molecules, the
cytokines EGF and bFGF (also called “FGF-2”) and
their receptors are critical for the proliferation of NSCs
(93, 132, 280). But many other molecules are involved
(Table 2). EGF and FGF-2 signal through ERK kinases
and induce the proliferation of NSCs and progenitors
(242). NSC expresses both receptors at varying levels
in individual cells. Furthermore, there are specific FGF
or EGF-responsive NSCs. FGF-responsive NSCs are
present early, and EGF-responsive NSCs emerge later
in development. Both FGF-responsive and EGF-responsive NSCs retain their self-renewal and multipotency (168, 269). The activity of FGF is mediated by
FGFR1, which allows the cells to undergo self-renewal
mediated through a calcium-dependent mechanism
(163). The acquisition of a primitive NSC identity from
ES cells is mediated by leukemia inhibitory factor
(LIF) (268) and is enhanced by FGF-2. LIF is involved
in the maintenance of NSCs of the adult SVZ. Several
cytokines [LIF, ciliary neurotrophic factor (CNTF), interleukin-6 (IL-6)] act on the common receptor gp130,
and LIFR⫺/⫺ mice exhibit a decrease in number of stem
cells, whereas administration of CNTF intraventricularly enhances self-renewal of NSCs in vivo (243).
Transforming growth factor-␣ (TGF-␣) is also relevant to SVZ precursor cell fate. The tgf-␣⫺/⫺ mice
exhibit decreased proliferation of SVZ cells, resulting
in a decreased number of progenitors in the SVZ and a
reduced number of neuronal progenitors migrating to
the olfactory bulb. However, their stem cell number
Table 2. Summary of genes related to neural stem and progenitor function
Functional Categories
Gene Name(s)
Factors involved in NSCs proliferation
Factors involved in self-renewing capacity
Factors involved in NSCs neurogenic differentiation
Factors involved in NSCs astrocytic differentiation
Factors involved in OPCs proliferation
Factors involved in OPCs differentiation
Factors involved in OPCs apoptosis and survival
Factors involved in OPCs migration
EGF, FGF-2, LIF, IL-6, PTEN, ␤-catenin, neuregulin, EPO, TGF-␣,
IL-6, CNTF, ephrin-B2, Sonic hedgehog, Emx-2, reelin
P21, N-COR
PS-1, Hes-1, cystatin-C, ephrins, BDNF, IL-11, IL-5, IL-7, IL-9, FGF2, neurogenin-1, SOCS-2
BMP2-4, gp130, CNTF, STAT3 and 5, Notch, PDFG-␣, neuregulin,
N-COR
neuregulin, PDGF-␣, IGF-I, IL-1, GGF-2
gp130, CNTF, Notch, neuregulin, PDGF-␣, Olig-1, Olig-2, Sox-10,
FGF3, histone deacetylases, thyroid hormone, Id4
Fas, TNF-␣, IL-10, PPAR, glutamate, Jagged
CXCR2, Sema-3A, netrin-1, semaphorin F
NSC, neural stem cell.
Physiol Genomics • VOL
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does not change (267). Conversely, intraventricular
infusion of TGF-␣ increases cell proliferation in the
SVZ (67).
In vivo, EGF and FGF exhibit different effects on
NSC. FGF-2 increases the rate of newborn cells, especially neurons, whereas EGF increases the numbers of
glia in the hippocampus (136). Additionally, EGF has
the capacity to convert type C progenitors (see Neural
Stem and Progenitor Cells, above, under BASIC CONCEPTS. . .) cells form the SVZ into multipotent stem cells
(61). FGF is also mitogenic for oligodendrocytes and
OPCs (225). The importance of FGF-2 is revealed by
the observation that introduction of a dominant-negative version of FGFR1 into OPCs results in cells that
are not responsive to FGF-2 and that fail to migrate in
vivo (203).
Some members of the ephrin (Eph) family of tyrosine
kinase receptors are expressed by cells of the SVZ and
have been shown to be involved in the migration of
neuronal progenitors in the adult SVZ. The infusion of
a truncated version of ephrin-B2 into the lateral ventricle increases proliferation of NSCs and disrupts migration of neuronal progenitors (56). Other developmental molecules involved are the Sonic hedgehog,
working through its receptor patched, which regulates
proliferation of NSCs from the hippocampus (138); the
homeobox transcription factor Emx2, which participates in symmetric division of adult SVZ stem cells
(80); and reelin, which facilitates the proliferation of
hippocampal NSCs (130).
Hypoxia-induced cytokines such as erythropoietin
(EPO) regulate the numbers of NSCs in the SVZ, promoting the production of neuronal progenitors and new
olfactory bulb interneurons (244). Other molecules can
act as negative regulators of NSC proliferation; pten⫺/⫺
neurospheres exhibit a greater proliferation, decreased
cell death, and enlarged cell and brain size, which may
suggest a role for pten in the control of neural progenitors proliferation (95). ␤-Catenin transgenic mice
show an increase in the proliferation of neural precursors and increase cerebral cortical and brain size, suggesting that this molecule plays a role in the decision of
precursors to proliferate or differentiate during mammalian neuronal development (52).
strated that human oligodendrocytes appear from neurospheres and express PDGF␣ receptor. The proliferation of these human OPCs was augmented by coculture
with neurons and astrocytes (306). Furthermore, human neurospheres increase their yield of oligodendrocyte production when cultured with T3 (190). Finally,
control of the timing of OPC differentiation requires
extracellular signals such as PDGF␣ and T3 (63).
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CNS development but also for their vulnerability during neurodegenerative processes.
Genes That Control Neuronal Differentiation
Of NSCs
Physiol Genomics • VOL
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Genes That Regulate Glial Differentiation
There are several specific molecules that mediate
glial differentiation; these include cytokines and transcription factors (Table 2). For example, OPCs express
receptors for bone morphogenetic protein (BMP). BMP
actually inhibits oligodendrocyte differentiation by
OPCs and promotes their differentiation into astrocytes (94, 160). Transgenic overexpression of BMP-4
leads to increased numbers of astrocytes and reduced
numbers of oligodendrocytes (87). Insulin-like growth
factor I (IGF-I), neurotrophin-3 (NT-3), and gp130 receptor subunit-related ligands induce the proliferation
of OPCs and postmitotic oligodendrocytes (14). In addition, different gp130-associated neuropoietic cytokines [CNTF, LIF, oncostatin-M, and hematopoietic
cytokines IL-6, IL-11, IL-12, and granulocyte colonystimulating factor (GCSF)] have differential trophic
effects on oligodendroglial lineage (172). Furthermore,
the terminal maturation of OPCs and glial differentiation are dependent on factors that activate gp130/
LIF-␤ receptors, such as CNTF (165). CNTF enhances
the proliferation of OPC as well as the generation of
oligodendrocytes in vivo (12). These effects appear to be
mediated by phosphorylation of the nuclear corepressor N-Cor with its redistribution out of the nucleus into
the cytoplasm. N-Cor⫺/⫺ NSCs exhibit lack self-renewing capacity and spontaneous astrocytic differentiation, establishing N-Cor as a downstream target of
CNTF (102). The downstream signaling pathways responsible for differentiation after gp130 engagement
involve the STAT family of transcription factors (182).
IL-6 and LIF (both of which signal through gp130)
modulate the growth of NSCs and progenitors in vitro
via a STAT3-dependent mechanism that requires the
transcriptional coactivator p300 (193). STAT5 also
plays a role in the proliferation of progenitor cells after
cytokine receptor stimulation (46). Additionally, IL-1
promotes mitotic arrest and oligodendrocyte differentiation of OPCs (278).
The Notch family of proteins is critical for NSC and
progenitor biology. Notch1 has been used to isolate
ependymal stem cells (122). NSCs are depleted in both
Notch⫺/⫺ and preselinin-1⫺/⫺ mice (a key regulator of
Notch signaling). These mice exhibit alteration of both
neuronal and glial differentiation (278). This work contrasts with many reports suggesting an involvement of
Notch in the inhibition of neuronal fate while promoting glial fate or favoring astrocytic differentiation at
the expense of neurogenesis (90). Notch inhibits NCSC
differentiation into neurons; even a transient exposure
to Notch ligands causes an irreversible change from
neurogenesis to gliogenesis (184). Chambers et al. (48)
studied the effects of Notch in vivo and found that an
excess of activated Notch markedly inhibits the generation of neurons from precursors and increases the
generation of astroglial progeny. Notch can also inhibit
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FGF regulates the differentiation of NSCs. At low
concentrations, FGF-2 induces neurogenic differentiation, whereas it induces oligodendroglial differentiation at high doses (220). FGF-2 requires a novel autocrine cofactor, a glycosylated form of cystatin C that
synergizes with FGF-2, to stimulate neuronal differentiation of NSCs in vitro (263).
Presenilin-1 (PS1) is involved in neuronal progenitors fate. PS1 cleaves Notch and induces an activated
form that maintains the neuronal progenitors pool.
PS1⫺/⫺ mice exhibit premature neuronal differentiation associated with aberrant neuronal migration and
disorganization of architecture of the cerebral hemisphere, due to alteration of the notch pathway (98).
Blocking of HES-1, another member of the Notch pathway, results in upregulation of p21, suppression of
NSCs proliferation, and generation of GABAergic neurons (125).
Other cytokines are involved in the lineage commitment of NSCs. Brain-derived neurotrophic factor
(BDNF) increases the morphological and antigenic differentiation of neuronal progenitors derived from
NSCs (2). Other molecules, such as basic helix loop
helix (bHLH) transcription factors, are related to the
differentiation of NSCs to glia and to neurons. Neurogenin promotes neurogenesis by functioning as a transcriptional activator and inhibits the differentiation of
NSCs into astrocytes by inhibiting the STAT signal
transduction associated with astrocytic differentiation
(258). Suppressor of cytokine signaling-2 (SOCS-2), an
intracellular regulator of cytokine signaling, regulates
neurogenesis. SOCS-2⫺/⫺ mice generated fewer neurons and more astrocytes, and the lack of neurons was
related to a decrease of the bHLH neurogenin-1. Overexpression of SOCS-2 increased neurogenesis by blocking growth hormone-mediated downregulation of neurogenin-1 (272).
Hematopoietic cytokines also regulate NSC differentiation. Using immortalized hippocampal stem cells,
Mehler et al. (173) showed that cytokines that participate in T cell maturation, immunoglobulin synthesis,
and hematopoiesis induce progressive neuronal differentiation. The cytokine IL-11 induces the differentiation of NSCs to immature neurons. However, IL-5,
IL-7, and IL-9 induce differentiation of NSCs into more
mature neurons when combined with TGF-␣ after pretreatment with FGF-2. These findings may be of relevance in the context of the potential interaction between immune cell-derived cytokines and precursor
cells during immune-mediated demyelination and injury (Table 2).
Thus several immune-related cytokines play a role in
the proliferation of NSC and progenitor cells. These
molecules may be involved during CNS inflammatory
pathological states such as brain and spinal cord injury
and MS (15). Therefore, these cytokines and chemokines and their receptors may not only be critical for
INVITED REVIEW
Physiol Genomics • VOL
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Genome-wide Screening of Neural Stem and
Progenitor Cells
The functional genetic programs of NSC and OPC
generation, proliferation, and differentiation are being
defined. The introduction of global genomic analysis
and gene profiling is helping to define novel genes.
Geschwind et al. (85), using microarrays derived from
subtractive hybridization between undifferentiated
and differentiated progenitors, found novel and known
genes differentially expressed in the germinative zone
and the NSC clone C17-2 (249). Some of the known
genes with differential expression in the germinative
zone could provide potential markers for NSCs such as
PGAM1 (phosphoglycerate mutase); CAL1H (calpactin
1 heavy chain); Hcyclin D2; cyclin D1; MELK (maternal embryonic leucine zipper kinase) (32). There are
genes that appear to be also enriched in hematopoietic
stem cells, suggesting overlapping genetic programs
between neural and hematopoietic stem cells. Among
such genes is Cyt28, a novel transmembrane protein
member of the secretin subfamily of seven transmembrane receptors (7TM), found in the SVZ and also
expressed in fetal liver stem cells. Other genes such as
Ku80, and cyclin D1 are part of a common genetic
program of hematopoietic and NSCs (265). Although
this approach may yield data about novel genes critical
for stem cell function, it is possible that known genes
that are important for other stem cell populations,
such as cytokine and chemokine receptors, may also be
functionally expressed in these cells. Recently, two
groups have independently defined the transcriptional
profile of several stem cells trying to define the “stemness” by enrichment of genes expressed on several
stem cells compared with their mature progeny using
Affymetrix microarrays. Compared with differentiated
cell types, stem cells expressed a significantly higher
number of genes (represented by expressed sequence
tags) whose functions are unknown. Murine and human hematopoietic stem cells were found to share a
number of expressed gene products, which define key
conserved regulatory pathways in this developmental
system. This overlapping set of gene products represents a molecular signature of stem cells. The molecular attributes include 1) active JAK/STAT (Janus
kinase/signal transducers and activators of transcription), TGF-␤, Yes (Yamaguchi sarcoma) kinase, and
Notch signaling; 2) capacity to sense growth hormone
and thrombin; 3) interaction with the extracellular
matrix via integrin 6/1, Adam 9, and bystin; 4) engagement in the cell cycle, either arrested in G1 or cycling;
5) high resistance to stress, with upregulated DNA
repair, protein folding, ubiquitin system, and detoxifier
systems; 6) a remodeled chromatin, acted upon by DNA
helicases, DNA methylases, and histone deacetylases;
and 7) translation regulated by RNA helicases (120,
223). In embryonic neuroepithelial stem cells (NEP)
and progenitors microarrays a few genes appeared to
be present exclusively in NEP and not in progenitor
cells, e.g., Frizzled 9, Sox-2. The following genes appeared to be enriched in neuronal (e.g., CDK5, neurowww.physiolgenomics.org
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duces the generation of radial glia that become
periventricular astrocytes in the adult (78). Notch receptor activation inhibits OPC maturation and myelination in the CNS (282) and may underlie the lack of
neurogenic differentiation of progenitors after injury
(296).
Neuregulins are cytokines present in the ventral
ventricular zone where they exert their influence on
early OPCs. The neuregulin, glial growth factor-2
(GGF2), is mitogenic for OPCs and is able to maintain
OPC plasticity by reverting their phenotype to nestinexpressing precursor cells (39, 40). Neuregulins, as
well as their specific receptors ErbB2 and ErbB4, are
expressed in multipotent neural precursors from the
striatum. They can control the growth of neurospheres.
Blocking neuregulin activity in these precursors was
associated with decreased mitosis and increased apoptosis. During differentiation of these precursors, neuregulin was required for oligodendrocyte development
(32). Vartanian et al. (277) demonstrated that neuregulin is necessary to obtain mature oligodendrocytes from
OPCs in the spinal cord. Finally, Sonic hedgehog induces oligodendrocyte development and OPC proliferation from subventricular precursor cells (189).
PDGF␣ is involved in generating (225) and is the
principal mitogen for OPCs (262). It can also induce
chemotaxis of NSCs (73) and inhibit their further terminal differentiation into oligodendrocytes (262).
PDGF␣-induced chemotaxis and oligodendrocyte precursor migration of OPCs can be blocked through the
chemokine CXCL1 and its CXCR2 receptor (270).
Other molecules that affect migration of OPCs are
semaphorins and netrins; sema 3A exerts a repulsive
effect, whereas netrin-1 has migratory effect, and
sema-F appears to have a dual effect (256).
During development, bHLH proteins regulate formation of neurons from multipotent progenitor cells. The
bHLH protein Id4 stimulates cell proliferation and
blocks OPC differentiation, whereas downregulation of
this molecule is required in order for OPCs to exit the
cell cycle and differentiate (133). The transcription
factor genes olig-1 and olig-2 that encode for bHLH
proteins are associated with the development of OPCs,
and olig-2 is required for oligodendrocyte and motor
neuron differentiation in the spinal cord (155) (308).
Furthermore, the onset of terminal differentiation of
OPC into myelin-forming cells requires the expression
of transcription factor Sox10 (257). FGFR3 has also
been implicated in this process; in FGFR3⫺/⫺ mice
OPCs proliferation is preserved, but terminal differentiation and myelination of OPCs is impaired (202).
Hormones and histone deacetylase are important in
oligodendroglial development: treatment of rodent and
human neurospheres with T3 increases the number of
oligodendrocytes observed (190). In contrast, treatment with the histone deacetylase inhibitor trichostatin-A decreases the differentiation of oligodendrocytes
resulting in lack of progression of progenitors into
mature oligodendrocytes (164)(Table 2).
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pilin, EphB2, FGF11) or glial (e.g., CXCR4, RhoC,
CD44, tenascin C) precursors (159). These results open
a number of potential discoveries in neural stem biology; the potential of these findings is illustrated by the
recent observations that the protein tyrosine phosphatase receptor type Z (PTPRZ), an enriched gene in
adult NSCs data set (223), is critical for MS and EAE
pathology. Harroch et al. (101), using PTPRZ⫺/⫺ mice,
demonstrated that these animals show impaired recovery from EAE and increased apoptosis of mature oligodendrocytes. More importantly in MS, this gene is
expressed in remyelinating oligodendrocytes, suggesting a link with remyelinating progenitors cells (101).
Endogenous Progenitor Responses During
Experimental Injury
There is increasing evidence for the existence of
regions in the CNS (including in the adult) that can be
considered niches for NSCs and pools for different
progenitors (206). Recently, it has been shown that,
during cerebrogenesis, even exogenous NSCs (used as
“reporter” NSCs) segregate into two distinct pools: one
that migrates and participates in cerebrogenesis and
one that establishes a “dormant” pool of immature cells
in secondary germinal zones both surrounding the ventricles and even within the cortical parenchyma (205).
These pools may be engaged in repair mechanisms
during CNS disease states, for instance.
It was demonstrated some time ago that exogenous
NSCs in the adult neocortex will give rise solely to glia
(the developmentally appropriate response), unless
there is a site of neuronal apoptotic death, in which
case they will then switch their differentiation fate to
yield the missing neurons (252), a program usually
played out only during fetal corticogenesis. Furthermore, an incremental response in the form of proliferation and migration of SVZ cells toward lesions was
reported (121, 260, 295). Nestin immunoreactivity in
the SVZ is increased after injury, and these nestinpositive cells differentiate into astrocytes (105) and
possibly into neurons in an experimental model of
dopaminergic neurodegeneration (127). Ependymal
stem cells migrate out of the central canal and differentiate into astrocytes in response to longitudinal fasciculus injury (75); whereas experimental cortical lesions increase the proliferation and induce expression
of PS-NCAM in the SVZ (260). Finally, Magavi et al.
(161) found that experimental targeted neuronal apoptosis induced a small degree of de novo cortical neurogenesis, possibly from SVZ precursors, in adult mice
CNS. Others found that after injury in the hippocampus, there is increased generation of functional neurons from precursor cells (194) that participate in behavioral learning response (245). Hence, the microenvironment after injury may control the fate of adult
stem cells by reinvoking developmental programs and
generating new cells that may actively participate in
neural circuitry (254).
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Several models of experimental demyelination have
been used: X-irradiation, chemical induced (lysolecithin, ethidium bromide, cuprizone), viral-induced demyelination, mutant myelin strains and immune mediate demyelination (74, 104). In the study of repair
mechanism, the use of a reductionist focused model has
the advantage of separating the components of the
disease; however, to study progenitors and repair during MS will require the use of a model that closely
resemble several aspects of the disease in humans.
EAE, an animal model of MS, is characterized by an
infiltration in the CNS of autoreactive T cells and
macrophages, accompanied by the production of proinflammatory Th1 cytokines (118) and oxidative injury
mediators (106). Similar to MS, EAE is an inflammatory, demyelinating disorder in which several pathological and clinical aspects are reproduced, namely,
axonal damage, neuronal dysfunction and apoptosis,
disruption of the blood-brain barrier (BBB), astrocytosis, prominent inflammatory infiltrate, demyelinating
lesions, and remitting relapsing course of the disease
(135, 294). These pathological aspects should be investigated in the context of endogenous and exogenous
repair and cannot be replicated with more restricted
models, such as chemically induced demyelination or
with X-irradiation in which there is a limited inflammatory response. In addition, EAE, due to the close
correlation of the clinical course of the disease with the
subjacent pathology, has served as a screening tool for
potential therapies that are now clinically useful (309).
In fact NSCs injections have been shown to have an
impact in the clinical score of EAE (213). Another
beneficial aspect of EAE as a model for studying repair
is the existence of several types of induction protocols
that have different clinical and pathological severity
but yet preserve the inflammatory demyelinating nature of the disease.
During the course of EAE, there is increased proliferation of cells in the SVZ, suggesting that stem or
progenitor cells in this area may proliferate in response
to inflammation/demyelination (34). Picard-Riera et al.
(211) extended these observations to a chronic model of
EAE, where they demonstrated proliferation of cells
from the SVZ, migration to the corpus callosum, and
differentiation to astrocytes and a small number of
oligodendrocytes. Furthermore, using a model of EAE
combined with either injection of MOG antibodies to
induce inflammatory demyelination or nonspecific
mouse immunoglobulins to induce an inflammatory
response without demyelination, Di Bello et al. (58)
suggested that remyelination by OPCs appears to be
associated more closely with demyelination than with
inflammation. However, the greater increase in OPC in
inflammatory demyelinating lesions compared with
those induced by anti-Gal-C antibodies suggests a mitogenic role for cytokines and growth factors released
during inflammation (128). It is possible that the inflammatory environment is an important component of
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RESPONSES OF PROGENITORS CELLS
DURING DEMYELINATION
Endogenous Progenitor Responses
During Demyelination
INVITED REVIEW
Exogenous Progenitor Responses To Demyelination
The prospect of using transplants of NSCs and progenitors during demyelination requires an understanding of the behavior of these cells in experimental
models. This would provide information about the interaction between the damaged host and the NSCs
(205, 252). Several groups have used this approach to
show that NSCs and OPCs can differentiate into mature oligodendrocytes. For instance, injection of murine NSC in the neonatal SVZ of dysmyelinated shiverer (shi) mice results in widespread oligodendrocyte
differentiation with myelination of 40% of the host
neuronal process in regions of engraftment with evident clinical improvement (297). EGF-responsive
NSCs also have shown efficacy and oligodendrocyte
differentiation when transplanted into the thoracolumbar region of md rats (96) and the shaking (Sh) pup
canine myelin mutant (96, 179). Nestin-positive human neural precursor cells removed from surgical specimens have been used to induce repair in rat spinal
cord with extensive remyelination (4). Even ES cells
differentiate into oligodendrocytes and myelinate in
culture and after spinal cord transplantation in shi
mice (151) and md rat (28).
Transplanted OPCs were able to repair focal demyelinated areas in the neonatal and adult canine mutant
(8). In the md mutant rat, carrying a mutation in PLP,
injection of OPCs results in myelin formation in a wide
distribution in the host parenchyma (66), and these
cells can be isolated from the rat SVZ as well and
produce robust myelin after transplantation (305).
Some progenitors isolated from the SVZ require in
vitro pre-induction to an oligodendroglial lineage to
achieve myelination in vivo (247). Other cells such as
olfactory ensheathing cells (OECs) and Schwann cells
have been proposed as useful cells for myelin repair.
Purified populations of human OECs have extremely
Physiol Genomics • VOL
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high viability in tissue culture and are capable of
remyelinating persistently demyelinated CNS axons
and of induction of axonal regeneration (113), following
transplantation into experimentally induced demyelinating lesions in the rat spinal cord (11, 126). In
addition, Schwann cells have been used for transplantation into demyelinated areas; Schwann cells derived
from human sural nerve were transplanted into the
X-irradiation/ethidium bromide-lesioned dorsal columns of rats showing extensive remyelination, engraftment, and improved conduction velocity by electrophysiology analysis several weeks postransplantation (11, 113). These results indicate that several types
of progenitors and even Schwann cell may be used for
therapy and that they receive environmental cues that
drive their migration and differentiation toward oligodendrocyte lineage (74). However, the selection of a
particular cell type will require extensive experimentation and careful consideration of other factors such
as source of isolation, in vitro manipulation, and ethical issues. Finally, the use of immature multipotent
progenitors may be more beneficial considering that
NSCs cannot only replace neurons and oligodendrocytes, but serve as modulators of the microenvironment by their ability to release growth factors even
without transgenic manipulation (213).
These results suggest that demyelinating microenvironment may be able to engage exogenous and endogenous progenitor cells to become effectively myelinating cells. However, more information on the behavior
the exogenous NSCs and OPCs in a deleterious environment like EAE is needed.
MOLECULAR MEDIATORS INVOLVED IN NEURAL
PROGENITOR RESPONSES DURING DEMYELINATION
Previous studies suggest that, during demyelinating
insults induced by gliotoxic agents and in EAE and MS,
there is hypertrophy and proliferation of OPCs (50, 58)
(Fig. 3, A and B). There is also proliferation of the SVZ
where putative NSCs reside, reaching a maximum
number at the peak of remyelination, suggesting a
response to the local environment (34, 191). Direct
evidence of the formation of (remyelinating) oligodendrocytes from OPCs in EAE is lacking (58, 224). However, studies of demyelination induced by the injection
of anti-galactocerebroside antibodies and serum complement into the rat spinal cord suggest that remyelination is carried out by OPCs rather than by surviving
oligodendrocytes; repeated insults may lead to chronic
depletion of the OPC pool in the CNS (26). Therefore
the fate and dynamics of NSCs and neural progenitors
may be different from those observed in models with a
monophasic disease. The chronic nature of human disease (e.g., MS) is likely to influence the dynamics of the
pool in a different way: that is, repeated episodes of
myelin destruction may eventually result in the formation of chronic demyelinated lesions that fail to remyelinate as observed in MS (50, 289). There are several
hypotheses linked to a “nonpermissive” molecular milieu to explain the potential fate of neural precursors
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the engagement of the endogenous and exogenous progenitors (34, 58).
Several models of experimental demyelination have
shown that spontaneous remyelination by precursor
cells occurs (24). In a lysolecithin-induced demyelination model, progenitor cells of the adult mouse SVZ
proliferate, migrate, and differentiate into oligodendrocytes (191, 204). Other groups have confirmed these
results with retrovirus labeling of proliferating cells,
demonstrating that endogenous progenitors in the subcortical white matter migrate and engage in repair of
the lesion (42, 43, 84). Recently, Calza et al. (33),
demonstrated that the SVZ cells can be redirected
toward oligodendroglial differentiation with the administration of thyroid hormone (T4). T4 administration reduces cell proliferation and nestin expression in
the SVZ and upregulates the expression of markers for
oligodendrocyte progenitors O4, A2B5, and mature oligodendrocytes in the spinal cord, olfactory bulb, and
SVZ. These findings provide a potential molecular target to influence the differentiation of stem cells and
oligodendrocyte progenitors into myelinating cells.
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during sustained demyelinating insults: 1) the destruction of OPCs and exhaustion of the OPC or NSC pools
by apoptosis; 2) the inability of adult OPCs to fully
differentiate into myelinating oligodendrocytes due to
an ongoing humoral and cellular immune reaction; 3)
The inability of adult OPCs to fully differentiate into
myelinating oligodendrocytes due to the lack of appropriate molecular signals or the existence of negative
molecular signals for OPC differentiation because of
destroyed axons and neurons; and 4) the inhibitory
release of molecules during astrogliosis. The following
paragraphs outline the experimental evidence and molecular mechanism that may support these hypotheses.
Evidence for Precursor Cell Death by Immune
Mediators of Demyelination
There is evidence that precursor cells might be susceptible to cytokine-induced apoptosis (35, 181) (Fig.
3). For instance, pro-inflammatory cytokines can induce cell death of precursors cells via Fas-FasL interPhysiol Genomics • VOL
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actions (62, 233). Oligodendrocytes as well as OPCs are
vulnerable to apoptosis by a Fas-mediated mechanism
(6, 214). TNF-␣ is upregulated during EAE and MS
(219) and can mediate OPC apoptosis in vitro (35).
TNF-␣ also potentiates the apoptotic effects of IFN-␥
on OPC cells, and this effect is partially reversible by
caspase inhibitors (6). TNF-␣ reduces the expression of
transcriptional regulators of survival and differentiation, namely peroxisome proliferator activator receptors (PPARs), especially PPAR␦ (54). The effects of
TNF-␣ in vivo may be more complex; mice that lack
TNF-␣ or the TNF-␣ receptor-2 (TNFR2) exhibit less
remyelination than mice lacking TNF-␣ receptor 1
(TNFR1) in a model of cuprizone-induced demyelination, suggesting a long-term requirement of TNF-␣ in
the proliferation of OPCs (9). Thus there may be a dual
role for TNF-␣, where an increase in TNF-␣ during the
acute phase may be deleterious as observed in experimental brain injury (234). IFN-␥ and lipopolysaccharide induce apoptosis of mature oligodendrocytes and
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Fig. 3. Changes in OPCs during demyelination and postulated mediators of apoptosis of OPCs. A: a typical NG2 multipolar
OPCs is shown in normal spinal cord. B:
during the acute phase of experimental demyelination there is an increase in reactivity of NG2 with changes in morphology.
The arrows point to OPC processes. C: cytokines and other inflammatory mediators
induce cell death of OPCs and other precursor cells by multiple pathways that involve
Th1 cytokines, oxidative stress, neurotransmitters, and antibodies (anti-Alu,
anti-AN2) that react with specific molecules
expressed on OPCs. Surviving precursors
can arrest their differentiation through Nmethyl-D-aspartate (NMDA)-mediated signaling. TNF-␣, tumor necrosis factor-␣;
IFN-␥, interferon-␥; MHC-I, class I major
histocompatibility complex molecule.
INVITED REVIEW
Inability of Adult OPCs To Fully Differentiate Into
Myelinating Oligodendrocytes
Data from MS pathology support a role for NSCs and
progenitor cells in the pathogenesis of MS (217) (Fig.
4). The analysis of demyelinating lesions in MS during
the chronic phase shows that a limited amount of
remyelination occurs (229) and appears to be provided
by migrating OPCs or NSCs that reside near the lesions. Some authors have shown that MS lesions contain a significant number of quiescent OPCs (286, 287).
Using PDGF␣ receptor as a marker, Scolding et al.
(236) have identified OPCs in the CNS of normal adults
and of MS patients. Others have identified a relatively
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quiescent population of OPCs expressing NG2. These
OPCs have been observed in lesions of patients with all
the clinical subtypes of MS (50). In the chronic stages of
the disease, most immature oligodendrocytes did not
appear to be engaged in myelination (50), suggesting
that oligodendrocyte differentiation of precursor cells
is impaired in chronic MS, which is consistent with the
general failure of myelin repair observed during the
later stages of this disease (289).
The lack of remyelination in MS may be due to factors
that induce OPC cell death before they can fully mature
into myelinating oligodendrocytes, leading to the exhaustion of the progenitor pool. Archelos et al. (7) demonstrated that serum and cerebrospinal fluid (CSF) from
44% of patients with relapsing remitting MS react with
protein bearing Alu peptides sequences only found on
OPCs, suggesting that there is an ongoing immune response to the OPC in MS. Similarly, CSF from patients
with relapsing-remitting active MS, but not from stable
MS, contains antibodies against the AN2 molecule, a
glycoprotein critical for myelination and expressed only
by OPC (195). In vitro experiments confirmed the importance of AN2 in myelination (196). In myelinating cultures, anti-AN2 antibody suppressed the synthesis of
myelin protein, supporting the hypothesis that an immunologic attack on AN2-positive OPCs may be responsible
for the impaired remyelination capacity (195). Rat OPCs
coexpress MOG and NG2 in normal adult spinal cord,
raising the possibility that they may be targets of MOGspecific antibodies in this model (146).
Lack of Appropriate Molecular Signals from
Destroyed Axons and Neurons
Normal axons and neurons produce signals that induce oligodendroglial differentiation (31, 156). Neurons, oligodendrocytes and astrocytes not only form an
anatomical unit that maintains the nerve transmission, they also maintain a reciprocal paracrine loop
between axons, myelin, and oligodendrocyte (174).
However, immunologic attacks severely affect the integrity of this unit (174) (Fig. 4). OPCs are influenced
by the axonal and neuronal environment through both
diffusible and contact-mediated signals such as the
neuregulins, PDGF␣ and PDGF␤, and the FGFs (69,
100, 303). In active and chronic active MS lesions,
astrocyte-derived neuregulin is dramatically reduced
(279). During the course of MS, there is evidence for
neuronal and axonal damage (23, 135, 177, 248), in
addition to white matter abnormalities, that can jeopardize the ability for neurons to maintain oligodendrocytes homeostasis; this phenomenon may contribute to
the absence of OPC full differentiation (40, 57, 135).
Recent work by Trapp and colleagues (49) suggest that
the lack of a physical substrate, a normal axon, is an
obstacle for terminal differentiation of PLP-positive
premyelinating oligodendrocytes. Thus some OPCs
may survive the initial nonpermissive milieu and
progress to more differentiated cells; however, the lack
of a complete normal axon could be a sufficient obstacle
for further differentiation.
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OPC via endogenous nitric oxide production (181), an
effect that can be also obtained by cocultures of OPCs
with activated microglial cells (207), probably through
Toll-like receptor-4 (TLR4) (140). In vivo microglial
activation is deleterious to oligodendrocyte progenitors
(307), and microgliosis was observed in association
with irradiation-induced neurogenesis dysfunction in
the hippocampus (183), pointing to the importance of
the environment for the fate of neural precursor cells.
Infiltrating immune cells are a source of glutamate
and can induce damage by excitotoxicity (209, 210).
Glutamate receptor AMPA-mediated excitotoxicity is
an independent and additional source of oligodendrocyte and axonal damage in EAE (212) and has been
shown to induce apoptosis of mature differentiating
oligodendrocytes (170, 212). Excitotoxicity may cause
damage to other progenitors and NSCs as well, since
both multipotent uncommitted and committed progenitors express functional AMPA receptors (81). Furthermore, glutamate agonists induce growth arrest and
inhibit oligodendrocyte progenitor differentiation (82).
Oligodendrocytes and adult OPCs of adult rats are
specifically susceptible to lytic effects of complement
(292). However, there are other potential damaging
mechanisms for NSC and progenitors during demyelinating injury, such as the expression of molecules that
may render these cells immunogenic to the attack of T
or B cells; IFN-␥ induces the expression of class I major
histocompatibility complex molecule (MHC-I) on neural progenitors, thus making these cells potential targets during an immune response (10, 171). Cytokinestimulated human immature neuroepithelial cell precursors express intercellular adhesion molecule 1
(ICAM-1) and interact with neutrophils by ICAM-1LFA ligation (20). We have demonstrated that murine
NSCs in vitro express MHC-I and functional CD80 and
CD86 costimulatory molecules, which are upregulated
after IFN-␥ stimulation and during stress-induced apoptosis (114). In summary, there is evidence to suggest
that OPCs and NSCs may be vulnerable to inflammation, since they express receptors for various mediators
of cell death. In vivo studies suggested that in some
cases these cells may disappear during acute attacks of
MS (50, 288). However, a systematic study of the dynamics of cell proliferation vs. cell death and its role in
progression of the disease is still lacking.
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Myelin itself can inhibit the maturation of OPCs in a
concentration-dependent manner, suggesting an effect
from membrane-associated proteins. Furthermore, axonal regeneration may be inhibited by molecules from
injured oligodendrocytes and myelin exerting negative
signals. Thus the potential neuronal self-repair and
axonal regenerative mechanisms maybe contravened
by negative signals released during myelin destruction. A molecule like NOGO-A with known inhibitory
effects on axonal regeneration is released after traumatic myelin and oligodendrocytes injury (51, 91, 110).
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However, it is not known whether these molecules are
released during MS flares nor whether these are responsible for the failure of remyelination in MS. It is
likely that several complementary mechanisms contribute to the lack of remyelination in MS (49).
Inhibitory Effects of Molecules Released by
Reactive Astrocytes
The lack of remyelination in MS may result in part
from the suppressive effects of gliotic astrocytes on
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Fig. 4. Effect of axon-myelin unit disturbance and astrogliosis on OPCs. A: scheme depicting a demyelinating
lesion. The plaque is composed for two concentric regions the core (blue oval) and the periphery (white oval) with
a gradient of pathological alterations; oligodendrocyte loss is represented as black cells with “membrane blebbing,”
myelin sheath with different degrees of injury represented by loss of the black color, axonal injury represented by
dashed lines, neuronal loss represented by cells with membrane blebbing, and astrocytosis and infiltrating immune
cells. This nonpermissive environment perturbs the differentiation of OPCs and blocks axonal regeneration. B:
astrogliosis during experimental autoimmune encephalomyelitis (EAE). Astrocytes exhibit thick processes and
increase were negative for glial fibrillary acidic protein (GFAP) immunoreactivity (green) compared with control
(C). Scale bar ⫽ 20 ␮m.
INVITED REVIEW
Evidence of Neuroprotective and Trophic Signals for
Neural Precursors
There is evidence that Th2 cytokines and neurotrophins, in contrast to Th1 cytokines, may be protective
Physiol Genomics • VOL
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in experimental models of MS and are able to induce
the differentiation of OPCs and NSCs in vitro. Certain
models of EAE mimic the relapsing-remitting form of
MS and are characterized by remission periods that
correlate with a shift toward Th2 cytokine production
in the CNS, such as TGF-␤ and IL-10 (118). Experimental treatments used in EAE may induce a change
toward Th2. For example, CD28-B7 costimulatory
blockade results in disease amelioration and inhibits
Th1 but spares Th2 cytokines in the CNS (129). In
addition to producing cytokines, T cells are able to
produce neurotrophins such as NT-3, nerve growth
factor (NGF), and BDNF (97, 180). In EAE, there is an
increase in NGF immunoreactivity in the SVZ (34).
NGF protects the common marmoset against EAE by
inducing a Th2 cytokine switch within the CNS by
IL-10 upregulation on astrocytes (281). More interestingly, neurotrophins such as NGF are mitogenic for
NSCs (47). NT-3 promotes survival, clonal expansion,
and proliferation of OPCs (13), and Th2 cytokines favor
oligodendroglial development from NSCs (172). The
cytokine GGF2 promotes the proliferation, survival,
and expansion of oligodendrocytes and enhances remyelination in animals with EAE (162); these animals
then evince reduced relapses and increased remyelination, IL-10 expression in the CNS, and upregulation of
exon-2 of MBP, indicative of remyelination (36). Furthermore, OPCs have been found to express receptors
for GGF2 (38). Additional evidence supporting the idea
that Th2 cytokines can interact beneficially with OPCs
includes the observation that IL-10 and IL-4 receptors
are expressed on OPCs and that these cytokines can
protect OPCs from oxidative stress and apoptosis (181).
These results suggest a protective role of Th2 and
neuropoietic cytokines in the survival and differentiation of OPCs in the CNS during demyelinating injury
such as in EAE and MS and suggest that the combination of neurotrophin and Th2 cytokine secretion may
improve disease not only by downregulation of autoreactive T cells, but also by improving NSC, OPC, and
oligodendroglial survival, leading to replenishment of
the oligodendrocyte population.
A Theoretical Model of the Role of Neural Precursor
Cells in Demyelinating Diseases
The heterogenous pathology of MS suggests diversity in the underlying mechanisms causing and/or promoting disease (157). The failure of oligodendrocytes to
repair demyelinated axons contributes to the cumulative neurological disability in MS (154). However, it is
clear from the experimental and clinical evidence that
in the diverse pathological types, OPCs and NSCs are
likely to be implicated. A model consistent with alterations in the endogenous potential and survival of
these cells is offered in Fig. 5.
In normal brain there is a paucity of new oligodendrocytes; OPCs divide infrequently and require signals
form neuron and axons for homeostasis (Fig. 5A). The
acute lesion of MS may be initiated by an attack from
autoreactive T cells, macrophages, and the production
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myelin formation. EAE and MS lesions are characterized by an increase in astrocyte reactivity demonstrated by hypertrophy and increase in the expression
of GFAP but not astrocyte proliferation, despite the
fact that MBP peptides are mitogenic in vitro for astrocytes (255). In vivo and in vitro experiments have
shown that an astrocytic environment is not permissive for migration of OPCs or for axonal regrowth (68).
Reactive astrocytes limit the remyelination capacity of
Schwann cells injected into the CNS (25, 241). Furthermore, in MS patients, Schwann cell remyelination is
seen in spinal cord lesions in areas that are devoid of
astroglial scar (119) (Fig. 4, B and C). In vitro data
support these in vivo observations: astrocyte explants
were shown to inhibit axonal myelination (117).
Interestingly, astrocytes can activate Notch1 receptor on oligodendrocyte precursors via the ligand
Jagged-1, which inhibits maturation of these cells.
This activation can be mediated by TGF-␤1, a cytokine
that is upregulated in MS. In vivo, Jagged-1 expression
was high in hypertrophic astrocytes, and Notch1 was
increased on immature oligodendrocytes, suggesting
that astrocytes release molecules may have a important regulatory activity on precursor differentiation
(123). Although astrocytes may induce a nonpermissive environment by diffusible factors, data from the
GFAP⫺/⫺ mice suggest that this intermediate filament
gene product (GFAP) expressed by astrocytes is required for long-term maintenance of CNS myelination.
When EAE is induced in GFAP⫺/⫺ mice, they exhibit a
worsened disease despite remyelination, indicating a
distinct functional role of GFAP in astrocytes in control
of the disease (148).
Astrocytes can modify the migratory properties of
OPCs. Fok-Seang et al. (71) studied the ability of cytokine-stimulated astrocytes on OPC migration and neurite outgrowth and found that IFN-␥ exerts an inhibitory effect on OPC migration, whereas IL-1␤ and bFGF
greatly increased axon outgrowth and that this effect
could be blocked by TGF-␤1 and IFN-␥. Interestingly,
others have found permissive signals from astrocytes
as well (72). Hippocampal astrocytes are uniquely
equipped to modulate neurogenesis of NSCs, by instructing the NSCs to adopt a neurogenic fate (253).
Taken together these data suggest that cytokine activation of astrocytes may influence both the degree of
axonal growth and OPC migration and differentiation; in
the case of immune-mediated demyelination, it is likely
that astrocyte-derived cytokine production results in a
blockade of axonal regeneration and arrest of OPCs differentiation. These cytokines together with other molecular mediators released during demyelinating injury
(e.g., tenascin, brevican, neurocan, N-cadherin) (68, 285)
may result in a nonpermissive environment for remyelination and axonal regeneration.
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of Th1 cytokines that induce demyelination. OPCs and
NSCs may undergo apoptosis through excitotoxicity,
oxidative stress, pro-apoptotic cytokines, and antibodymediated cytotoxicity. Some surviving OPCs may increase their numbers, accounting for the initial inPhysiol Genomics • VOL
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crease in NG2-positive cells (Fig. 5B). Inactive lesions
during the remission phase may show an increase in
OPCs with some remyelination (Fig. 5C). However, as
the disease progresses during the chronic phase, the
fate and the viability of endogenous progenitors may be
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Fig. 5. Stages of OPC behavior during demyelination. The inflammatory environment may influence the kinetics
of endogenous precursor cells during autoimmune-demyelination by altering the balance between apoptosis and
proliferation/differentiation of OPCs. A: in normal brain there is a paucity of new oligodendrocytes; OPCs divide
infrequently and require signals from neuron and axons for homeostasis. B: an acute multiple sclerosis (MS) lesion
may exhibit the same rate of both apoptotic cell death and cellular proliferation with preservation or minimal
deterioration of axonal-neuronal signals. C: inactive lesion during the remission phase or a change toward a Th2
environment by immunologic treatment (e.g., with glatiramer acetate) may help to increase proliferation and
differentiation of the endogenous pool, this would be protective for the axon as well. D: chronic active lesions and
relapses over time may induce four pathological and complementary effects: 1) a loss of the self-renewing capacity
of precursor cells as a result of age of the lesion, or the deleterious environment; 2) apoptosis as a direct result of
immune factors; 3) lack of trophic support or survival factors form axons and neurons that are failing; 4) direct
blockade of differentiation from molecules such as Notch ligands or because of the lack of axons (physical
substrate).
INVITED REVIEW
PROSPECTS FOR THERAPY
It remains unclear whether the best strategy for
repair will entail promoting remyelination by endogenous progenitors or transplanting in new exogenous
progenitors. Much depends on a better understanding
not only of the fundamental biological properties of
stem/progenitor cells but of the fundamental pathophysiological processes underlying demyelinating/dysmyelinating diseases. If the etiology for disease progression resides in the host genome (e.g., abnormal
lifespan, excessive vulnerability to stress, diminished
self-renewal capacity), then endogenous progenitors
will also be flawed and will not represent a good source
for repair (76, 84, 230, 286). If the process is not
cell-autonomous, then implanting exogenous cells may
be problematic unless they have been engineered to be
resistant to the environment that caused the injury. In
MS it is likely that both scenarios are implicated, and
a combined strategy may be needed. Either way, to
exploit the biological properties of precursors and to
promote their differentiation in desired directions (e.g.,
to remyelinating oligodendrocytes), we require a better
understanding of the molecular pathways governing
Physiol Genomics • VOL
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the NSC and OPC pools during development and disease.
Cellular therapies may need to be augmented or
optimized by adjunctive molecular therapies. For example, it has been demonstrated that the intraventricular injection of TGF-␣ in an animal model of Parkinson’s disease induces a massive proliferation of forebrain cells and their migration to the striatum; this
may be accompanied by clinical improvement (67).
Cannella et al. (36) showed that the neuregulin GGF2
induced clinical improvement and remyelination in
EAE. One of the potential mechanisms of recovery
could be mediated by the effects of GGF2 on OPC (36,
38), as OPCs survive and proliferate when exposed to
this neuregulin (39, 40, 69, 213). IGF-I is a mitogen for
OPCs, and several reports have suggested involvement
of IGF-I and PDGF␣ during remyelination in lysolecithin (103) and cuprizone-mediated demyelination models (169). IGF-I is also important for OPC proliferation,
and several reports have shown positive effects in
gliotoxic models of demyelination and EAE (298). In
EAE, clinical amelioration has been reported after
IGF-I treatment by some groups (152, 298); others
have reported less encouraging results (37). Others
investigators showed LIF to have a beneficial effect on
oligodendrocyte survival in EAE; whereas in CNTF⫺/⫺
mice EAE severity was increased and OPCs proliferation decreased by 60% and oligodendrocyte apoptosis
increased by 50% (150).
The continuous local infusion of exogenous cytokines
may have positive effects on recruiting endogenous
progenitors. In vivo infusion of EGF and FGF results in
proliferation and differentiation of progenitors cell
(167). In a model of hippocampal injury the infusion of
EGF restored the architecture and neurogenesis by
recruitment of endogenous progenitors (194). However,
it is not clear how long such manipulations are required in the clinical setting to induce an effect; on the
other hand a continuous infusion may induce SVZ
hyperplasia, raising questions about the tumorogenic
potential of such manipulations (136). It is important
to remember that trophic factors have pleiotropic effects on the brain: although some may be desirable,
others may be undesirable and may, in fact, work at
cross-purposes to the other. Indeed, administering the
trophic factors via cellular vehicles (such as via neural
stem/progenitor cells that have genetically engineered
ex vivo) may actually be an optimal delivery system
because the factors are provided in a site-specific and
in a regulated manner. In addition, because many
factors are intrinsically made by such neural-derived
cells, potential downregulation of a foreign transgene
may be compensated for.
Indeed, exogenous NSCs have been successfully isolated (109, 192), genetically manipulated, and transplanted to replace cells and introduce genes in models
of neurodegenerative disease in mice (70, 137, 231,
232, 250). Several authors have shown that NSCs
survive and differentiate in diverse disease models.
NSCs are able to differentiate into the three major cell
types in the mammalian CNS; thus they offer promiswww.physiolgenomics.org
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determined by the balance of neuroprotective vs. neurotoxic cytokines, the alteration of neuron-OPC signals, and the changes in self-renewing and differentiation capacity of progenitors. The initial increase in
OPC numbers may be lost during the chronic phase. A
relapse may induce neurotoxic cytokines in an already
altered milieu causing OPC differentiation arrest and
apoptosis. Moreover, the gradual alterations in axons
and neurons result in a lack of positive signals or the
induction of negative signals that arrest the differentiation of surviving OPCs; additionally, the lack of a
viable substrate (the axon itself) would be the last
event in an irreversible pathway. Repeated attacks
over prolonged periods of time may exhaust the pool of
cells that have repair ability resulting in complete
remyelination failure (Fig. 5D). Therefore, the fate of
stem and progenitor cells pools in MS and EAE may
depend on the delicate balance between apoptosis-inducing cytokines and proliferation and differentiation-inducing factors (e.g., T cell and neuropoietic
cytokines) that are dynamically regulated during inflammatory neurodegeneration or encouraged by immunologic treatments (15, 97, 118). It is likely that the
lack of remyelination is mediated by more than one
mechanism and that it is a dynamic process that cannot be fully understood with cross-sectional pathology
studies. It is possible that the known heterogeneity of
NSCs and progenitors extends to heterogeneity in their
susceptibility to the milieu; for example, it has been
shown that some acute MS lesions do not contain
OPCs, suggesting that susceptible cells die during the
initial attacks. However, the reappearance of OPCs in
the lesion suggests that a subpopulation of cells proliferates, migrates, and perhaps engages in remyelination.
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NSCs may be a better source of myelinating transplants than OPCs. (230) They seem to possess a greater
ability than the more differentiated OPCs for widespread migration toward sites of pathology (1, 297).
NSCs may also be easier to use because they can be
obtained in great numbers theoretically without the
need to predifferentiate them in vitro; allowing environmental cues present at the transplantation site to
drive their differentiation (252). Indeed, Yandava et al.
(297) found that an environment deficient in functioning oligodendrocytes forced multipotent NSCs to shift
their differentiation fate and yield an even greater
proportion of that cell type. Whether priming NSCs
toward an oligodendrocyte lineage ex vivo would optimize their efficacy remains an important area of investigation. Finally, NSCs may inherently, or after ex vivo
manipulation, provide additional neurotrophic factors
to repair axonal and neuronal abnormalities present in
MS and EAE (3).
SUMMARY
The goals for MS therapy are as follows: 1) the
induction and maintenance of immunologic tolerance
toward self-antigens, 2) the promotion of remyelination, 3) the promotion of axonal regeneration, as well
as 4) the prevention of further axonal degeneration and
neuronal dysfunction as soon as the diagnosis is made.
Current therapies deal substantially with the inflammatory and immunologic aspects. This strategy is critical to modulate the “nonpermissive environment” to
ensure success when contemplating repair mechanisms. There is a need, however, for a more comprehensive and interdisciplinary analysis of MS molecular
pathology. The complex dynamic between the cellular
mechanisms responsible for symptoms and for neurodegenerative damage pose important questions that
need to be addressed. Regardless of the initial mechanism, disability is cumulative. That is why considering
MS as a chronic inflammatory neurodegenerative disease is likely to reflect its true nature and should
prompt us to develop a more comprehensive therapy.
Although there are now therapies that can prevent
exacerbations, we still lack knowledge about how to
promote effective remyelination. Adult brain contains
adult NSCs and progenitors scattered throughout the
CNS in regional pools, and these cells may be able to
engage in some degree of endogenous repair. However,
the size of the lesion may overcome the capacity for
endogenous precursor cells to repair the damage (64,
76). On the other hand, precursor cells could be the
targets of the pathological process with adverse repercussions on the innate ability of the CNS to self-repair.
Thus any effort in this direction will have to be accompanied by strategies to improve precursors long-term
survival (288).
Boosting the endogenous pool may be achieved by
manipulation of specific molecular signals to induce a
preferential differentiation of endogenous NSCs and
their derived progenitors toward cells with remyelinating capability. On the other hand, these endogenous
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ing strategies for transplant as well as gene therapy
protocols (137). However, it remains to be determined
whether a particular CNS disease will benefit from
NSC transplantation (21). The chances for success
seem best in those diseases where clinical efficacy is
determined ostensibly by a single biological mechanism, e.g., a single gene defect in lysosomal storage
diseases. Parkinson’s and Huntington’s disease might
fit into that category, i.e., requiring the replacement of
a single neuronal cell type in a circumscribed region.
MS has always represented a major therapeutic challenge because its pathology is so widespread, affecting
multiple sites in the CNS, impairing neuronal as well
as glial function. Although targeting localized lesions
that cause great disability, such as in the spinal cord,
can be envisioned, addressing multiple lesions that
extend throughout the CNS remains a daunting prospect, even with extensively migratory stem cells. Careful strategic planning and extensive animal testing
will be required before clinical studies can be entertained.
Several practical aspects deserve consideration. For
instance, the development of methods for noninvasive
monitoring of neural stem transplant is required. Magnetic resonance imaging (MRI) tracking of neural progenitors has been developed using the transferrin receptor as an efficient intracellular delivery device for
magnetic nanoparticles. Transplanted tagged OPCs injected into the spinal cord of myelin-deficient rats
showed a close correlation between the areas of contrast enhancement and the achieved extent of myelination (29, 30). The survival of transplanted NSCs in a
potentially toxic environment remains another important consideration. There is some encouraging data on
migration and proliferation of transplanted OPCs (266)
and multipotent neural progenitors in the EAE model
(17). Recently, injection of adult neurospheres forming
cells (presumably neural stem/progenitors cells), either
intravenously or intracerebroventricularly, resulted in
significant numbers of donor cells entering into demyelinating areas of the CNS and differentiating into
mature brain cells. Within these areas, oligodendrocyte progenitors markedly increased, with many of
them being of donor origin and actively remyelinating
axons (213). Replication of these results and more
research in relevant models of immune demyelinating
disease are needed, especially to investigate the relationship of exogenous repair with the clinicopathological features of MS such as relapses and remissions,
axonal damage, sustained oxidative injury, and immune cell infiltrates. For instance, suppression of microglia activation was shown to be beneficial for the
survival of transplanted progenitors (307). Furthermore, the implantation procedure itself induces a local
injury and opening of the BBB for several weeks (116).
It is unknown whether the amount of injury inflicted
may trigger a worsening of the local inflammation in
an already diseased brain, which could lead to infiltration of immune cells in the region of injection and
decreased survival of exogenous progenitors cells (307).
INVITED REVIEW
We thank Drs. Byron Waksman and Khadir Radassi for critical
reading of the manuscript.
DISCLOSURES
This work has been funded by grants from the National Multiple
Sclerosis Society (to S. J. Khoury) and the National Institutes of
Health (to S. J. Khoury and E. Y. Snyder).
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NSCs may harbor genetic predisposition to malfunction or die or may be excessively vulnerable to the MS
milieu. Hence, transplanted exogenous NSCs from a
nondiseased source may be required. Such cells may be
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biology (including via transplantation) for MS requires
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