Stem_cell_therapies_for_perinatal_brain_injuries-libre

Stem cell therapies for perinatal brain injuries
Reaz Vawda a
, Jennifer Woodbury a
, Matthew Covey a
,
Steven W. Levison, Huseyin Mehmet*
RY80Y-215, Merck Research Laboratories, 126E Lincoln Avenue, Rahway, NJ 07065, USA
KEYWORDS
Children;
Head injury;
Hypoxia;
Ischaemia;
Regenerative medicine;
Stem cells
Summary This chapter reviews four groups of paediatric brain injury. The pathophysiology of
these injuries is discussed to establish which cells are damaged and therefore which cells rep-
resent targets for cell replacement. Next, we review potential sources of cellular replace-
ments, including embryonic stem cells, fetal and neonatal neural stem cells and a variety of
mesenchymal stem cells. The advantages and disadvantages of each source are discussed.
We review published studies to illustrate where stem cell therapies have been evaluated for
therapeutic gain and discuss the hurdles that will need to be overcome to achieve therapeutic
benefit. Overall, we conclude that children with paediatric brain injuries or inherited genetic
disorders that affect the brain are worthy candidates for stem cell therapeutics.
ª 2007 Published by Elsevier Ltd.
Clinical considerations
Perinatal hypoxic/ischaemic brain injuries
Hypoxiaeischaemia (H/I), which refers to both lack of
blood flow and low oxygen tension in the brain, is
associated with neurological deficits that range from severe
cerebral palsy to mild developmental disabilities.1
The
causes of H/I are complex and heterogeneous, including
stress during labour, cardiac insufficiency of the mother,
placental damage, prolapsed umbilical cord, uterine rup-
ture and acute neonatal or maternal haemorrhage. The
outcome from H/I is further influenced by a variety of fac-
tors that include the age of gestation, length of H/I, type of
insult and external factors. External factors include mater-
nal as well as fetal factors, such as cardiopulmonary insuf-
ficiency and immune status.
Term and preterm infants sustain different types of
injury. The type and severity of brain damage sustained by
the term infant is modulated by infection, extended labour
or repeated asphyxia after birth. Five general classes of
pathology are observed after H/I insults in the term infant:
selective neuronal necrosis, status marmoratus, parasagit-
tal cerebral injury and focal and multifocal ischaemic brain
necrosis.2
These injuries are caused by pathophysiological
events that are not fully understood. What is clear is that
transient energy failure sets off a chain of events leading
to cerebral cell death. With energy depletion, ionic homeo-
stasis fails, causing disturbances in Naþ
, Kþ
and ClÀ
.3,4
Neu-
rons depolarize, releasing excitatory amino acids (EAAs),
resulting in excitotoxicity.5
EAAs open neuronal N-methyl-
D-aspartate (NMDA) receptors, resulting in high levels of
free Ca2þ
as well as increases in water and other cations.6,7
Elevated intracellular calcium, in turn activates proteases,
* Corresponding author. Tel.: þ1 732 594 2511; fax: þ1 732 594
8255.
E-mail address: huseyin_mehmet@merck.com (H. Mehmet).
a
These authors contributed equally.
1744-165X/$ - see front matter ª 2007 Published by Elsevier Ltd.
doi:10.1016/j.siny.2007.02.003
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Seminars in Fetal & Neonatal Medicine (2007) 12, 259e272

endonucleases, phospholipases, caspases and calpains,
leading to cell death.8e15
EAAs also activate AMPA/kainate
receptor/channels, causing oligodendrocyte progenitor cell
death.16
Reperfusion after H/I also triggers the production
of oxygen free radicals.4,17
During an H/I insult, the natural
defences of the cells are overwhelmed, leaving them vul-
nerable to free-radical-mediated damage. Cell death also
induces an inflammatory response,18
which can e directly
or indirectly e lead to secondary cell death.19,20
The damage sustained by the preterm infant has been
classically referred to as periventricular leukomalacia
(PVL), which is defined as focal and diffuse damage to the
periventricular white matter. With advances in the clinical
management of low birth weight infants, focal lesions of
the white matter are less commonly seen, although
abnormalities in the subcortical white-matter damage
appear in 75% of preterm infants on magnetic resonance
imaging (MRI).21,22
More recently, it is beginning to be ap-
preciated that very low birth weight and low birth weight
infants have a reduced cortical grey matter volume at
term equivalent that is still present at 8 years of age.23e25
When these scans are correlated with neurodevelopmental
outcomes measured at 18e20 months corrected age they
are highly predictive of adverse outcome.26
Studies on ani-
mal models suggest that this reduced volume of cortical
grey matter is due to neuronal cell death, where subplate
neurons are especially vulnerable, thereby affecting the
formation of appropriate connections from subcortical re-
gions of the brain. Oligodendrocyte progenitors both in
grey and white matter are vulnerable and changes in synap-
togenesis have been documented.27e31
The pathophysiology observed in the preterm infant is
not identical to the term infant because of developmental
and maturation differences. The cerebrovascular system of
the premature infant is underdeveloped, resulting in both
incomplete local and global cerebral blood.32
In addition,
the immature vessels have poor cerebrovascular autoregu-
lation.33
The subcortical white matter of the premature in-
fant is especially poorly vascularized, which predisposes
this region to damage. In addition, oligodendrocyte progen-
itors are extremely vulnerable to damage during an H/I in-
sult.34
Specifically, oligodendrocyte progenitors at the O4þ
stage are highly sensitive to glutamate toxicity and lack the
ability to detoxify free radicals.35e37
(Fig. 1)
Paediatric traumatic brain injuries
Children who have sustained traumatic brain injuries
represent another group of patients who might benefit
from stem cell therapies. Traumatic brain injury (TBI) is
a major cause of death in the paediatric age group, and
approximately 475,000 children under the age of 14 sustain
a TBI yearly, and estimates are that 30,000e100,000
children aged <1 year sustain a TBI that requires admitting
them to an intensive care unit yearly.38
Although the most
common cause of injury is a motor vehicle accident, the
many other causes of paediatric brain injury include as-
sault, in the form of shaking as a form of punishment, which
is a major cause of TBI in infants.38
The extent of damage to
the perinatal brain depends on several factors, including
the size and object causing the injury, location of injury,
force of impact, and whether it is penetrating or blunt
and open or closed. It is important to recognize that exter-
nal signs might not indicate the severity of the injury.
Whereas skull fractures and lacerations might not damage
the brain parenchyma, a closed injury can cause quite se-
vere destruction.
Blunt head injury can cause: (1) focal haemorrhagic and
non-haemorrhagic lesions mainly involving grey matter; (2)
diffuse axonal injury (DAI); and (3) secondary injury caused
by oedema and space-occupying haemorrhages.39
Analogous
Figure 1 Severe hypoxic ischaemic encephalopathy. Severe hypoxiceischaemic encephalopathy in newborn infants leads to loss
of grey and white matter, with subsequent neurodisability. T1 transverse MR images of two infants with severe brain injury follow-
ing hypoxiceischaemic encephalopathy. (a) Transverse image acquired in an infant at 18 days of age demonstrating large areas of
low signal intensity in the white matter (arrows), which later atrophy. (b) An image at the level of the basal ganglia of an infant at
20 days of age showing loss of grey and white matter with cystic change in the basal ganglia (arrow).
260 R. Vawda et al.

to H/I injury, oxidative stress, excitotoxicity and mitochon-
drial dysfunction are major effectors of cell death, with
neuroinflammation, diffuse brain swelling and vascular al-
terations also contributors to the net outcome.40,41
Rodent models of TBI indicate that after lateral fluid
percussion brain injury, which models the type of injury
sustained as a result of head trauma during a motor vehicle
accident, there is both focal and diffuse brain injury.42
DAI
is often observed distal to the site of focal injury where the
damage is more cell-type specific and where neurons are
more selectively damaged than glial cells.43,44
Concussive
injuries to the head often involve shearing forces that cause
DAI in the subcortical white matter. Subsequent to the ini-
tial injury, there is often secondary or delayed injury (pro-
gressing from hours to months following injury and likely to
be partially reversible). The mechanisms of secondary in-
jury are complex and poorly understood, but include the
breakdown of the bloodebrain barrier (BBB), oedema,
vasospasm, ionic dysregulation, lipolysis, EAA toxicity,
free-radical generation, impairment and/or uncoupling of
energy metabolism, changes in intracranial pressure (ICP)
and or cerebral perfusion pressure (CPP), inflammation,
expression of both pathogenic and protective genes and
proteins and activation and/or release of autodestructive
factors. Whereas the initial insult typically causes necrotic
cell death, the cells that die during the second wave of in-
jury typically die of apoptotic cell death.45e47
As the brain
attempts to cope with the extensive tissue damage that has
occurred there is a strong astrogliotic response. This is ben-
eficial in that the bloodebrain barrier is restored and there
is some restoration of structural integrity; however, a glial
scar is typically formed and this inhibits regeneration.
Thus, in contemplating how to repair the TBI brain, one
must take into consideration the fact that multiple cell
types are damaged, and that the cells that survive might
not entirely resemble their premorbid state. Surviving neu-
rons might no longer be connected to their targets as a con-
sequence of diffuse axonal injury, there might be selective
elimination of specific neuronal cell types as a result of dif-
fuse damage, and the glial cells that once nourished their
neighbours might now be components of an anisomorphic
gliotic scar.
Like H/I, the severity of the TBI insult depends on many
different factors, including the age and state of the infant,
as well as the duration and type of injury. The injury can
manifest differently depending on the location of the
injury, and range from physical disabilities to memory
problems to social, emotional or behavioural difficulties.
The developing infant up to 4 years of age does respond dif-
ferently to TBI than an older child with a similar insult.48
Using MRI technology, Tasker has shown that there is
white-matter damage, especially in the hippocampus, in
adults who sustained TBI as a child, and thus it will be
safe to assume that these types of injuries will result in
long-term consequences.39
Metabolic diseases
A handful of metabolic diseases might benefit from stem cell
therapies in the perinatal brain. The scope of metabolic
syndromes extends from lysosomal, peroxisomal, mitochon-
drial and amino acid disorders to neurodegenerative
diseases and muscle diseases. The majority of such disor-
ders are seen in early childhood with progressive neurolog-
ical deterioration, while some manifest severely at birth.
Neuronal death results from the accumulation of substrates
in the cells due to a deficiency of an enzyme specific to the
catabolism of sphingolipids, mucopolysaccharides or muco-
lipids. Leukodystrophies include some lysosomal and perox-
isomal diseases that involve problems with the myelination.
Most metabolic syndromes are genetic in nature; autosomal
recessive inheritance is the most common but other forms
include autosomal dominant, mitochondrial and X-linked
disorders. Although it might not be necessary to determine
the genetic nature of the disease, the specific cellular
pathology is important to better understand which cell
population is most affected and what stem cell therapy
would be able to offer.
Peroxisomal disorders can be divided into two broad
categories depending on whether there is a problem with
peroxisome biogenesis or a single enzyme deficiency.
Zellweger’s syndrome is a severe form of a disorder caused
by a deficiency in peroxisomal biogenesis; adrenoleukodys-
trophy is a less severe form. Zellweger’s syndrome e also
known as cerebrohepatorenal syndrome e is a rare, auto-
somal recessive metabolic disease and is the most severe
phenotype of this group. It is characterized by severe
nervous system dysfunction, craniofacial abnormalities
and hepatic fibrosis. There is a build up of cerebral neutral
lipids and very long-chain fatty acids because peroxisomes
are unable to oxidize these and mitochondria are over-
whelmed. In the most severe cases, infants rarely live past
1 year. All Zellweger’s patients have defective peroxisome-
targeting sequences, PTS1 and PTS2 proteins, and 80% have
mutations in PEX1 and PEX6, which encode the ATPases re-
quired for peroxisome membrane biogenesis. Other muta-
tions have also been shown to decrease the number of
functional peroxisomes, such as PEX13. Interestingly, there
is a clear correlation between the number of peroxisomes
and the degree of severity of the disease. Pathological
studies have shown maldevelopment, especially in the
CNS, including neuronal migration abnormalities, cerebel-
lar atrophy and white-matter disease.49
Adrenoleukodystrophies are a less severe phenotype
than Zellweger’s syndrome but also include a defective
peroxisomal transporter. Although there is an X-linked form
of the disease, only the autosomal disorder with neonatal
onset will be discussed here. Affected children suffer from
hypotonia and seizures due to an inability to oxidize very
long-chain fatty acids, this inability results in lipid accu-
mulation. The disease is characterized by progressive de-
generation of the CNS white matter and adrenal gland.50
Additionally, the typical symmetrical, inflammatory, demy-
elinating lesions of this disease involve the cerebral and
cerebellar white matter, with both axonal loss and a de-
crease in oligodendrocytes.51
Lysosomal storage diseases are another potential stem-
cell therapy recipient. When grouped together, the in-
cidence rate is estimated 1 in 18,000 live births, and they
are considered a major cause of paediatric neurodegener-
ative disease.52,53
As in the peroxisomal disorders, we will
emphasize the neonatal forms, appreciating that these
disorders exist in juvenile and adult forms as well. As
expected, the infantile forms are most severe, usually
Stem cells for brain injuries 261

involving acute brain damage, and patients rarely live past
a few years of age. CNS symptoms, such as seizures, de-
mentia and brainstem dysfunction can complement periph-
eral symptoms, such as hepatosplenomegaly, heart and
kidney injury, muscle atrophy and abnormal bone forma-
tion, but they vary in the different phenotypic profiles of
individual diseases.52,53
Some diseases show more neurolog-
ical signs than peripheral symptoms in the neonatal form,
such as TayeSachs and type 2 Gaucher disease, which
show severe neurological impairment. TayeSachs disease
is a hereditary ganglioside storage disease due to a defi-
ciency in the hydrolytic enzyme, b-hexoaminidase; type 2
Gaucher disease is a glucocerebrosidase deficiency that re-
sults in a glucocerebroside storage disorder. The build-up of
these materials, whatever the substrate, is detrimental to
the neurons of the CNS.52,53
White-matter diseases
The common pathology of white-matter diseases is myelin
deficiency, either in the form of hypo- or dysmyelination
during development or demyelination in the postnatal
brain.54
The oligodendrocyte is clearly affected in these dis-
eases, however, it is becoming clear that their demise might
be secondary to dysfunction of white matter astrocytes.
Some of these leukodystrophies are caused by genetic muta-
tions in oligodendrocytes whereas others are a consequence
of astrocytic genetic mutations.54,55
Vanishing white-matter
(VWM) disease is a childhood disease that has an infantile
variant called Crees leucoencephalopathy. It is character-
ized as central demyelination, with progressive neurode-
generation, cerebellar ataxia, and sometimes seizures and
optic atrophy. It is caused by a mutation in any one of the
five subunits of eukaryotic translation initiation factor
eIF2B, which is important for protein synthesis. The severe
infantile variant affects infants between 3 and 9 months
with failure to thrive, irritability, feeding problems, limb hy-
potonia or hypertonia, seizures, coma and death by 2 years
of age. The prominent cell type affected in VWM disease is
the oligodendrocyte, showing an overall loss with an appar-
ently high number of mature oligodendrocytes, as well as
dysmorphic, astrocytes with blunt processes.56
Canavan disease is interesting because it is caused by
a genetic mutation in the aspartoacylase (ASPA) gene,
which is a metabolic enzyme restricted to the CNS and e
more specifically e to oligodendrocytes.57
As in VWM dis-
ease, the congenital and infantile types are the most severe
forms of the disease, exhibiting widespread vacuolization in
the lower cerebral layers and white matter, with a lack of
myelin.57
Canavan disease is estimated at 1 in 5000 live
births in the Ashkenazi Jewish population. Interestingly,
there is astrocytic involvement in this disease, with the hy-
pothesis that vacuoles are generated from ruptured astro-
cytes that split the myelin lamellae, which then disperse
and widen to form extracellular sponginess.
Alexander disease is an autosomal dominant disorder
caused by a dominant gain-of-function mutation in the
GFAP gene, causing toxicity in a still unknown manner. In-
termediate filament inclusions, known as Rosenthal fibres,
accumulate within astrocytes, whereas oligodendrocytes
appear histologically normal. Symptoms of the infantile
form of include progressive psychomotor retardation, loss
of developmental milestones, megalencephaly, seizures,
ataxia, hyperreflexia, and pyramidal signs, with death usu-
ally ensuing by 2 years of age.58
(Fig. 2)
Sources of stem cells
From the outset it must be emphasized that there are many
different types of stem cell, which have a greater or lesser
utility for repairing the damaged brain. As a consequence
of this variety there can be no single definition for a stem
cell, although the following characteristics are shared by
most cells classified as stem cells. Stem cells are karyo-
typically normal, undifferentiated, possess extensive pro-
liferative capacity, are capable of long-term self-renewal
Figure 2 White-matter abnormality in extremely preterm infants. T2-weighted transverse MR images. (a) Image of a preterm
infant at term-corrected age demonstrating patchy high signal intensity in the white matter (arrows). Overt white-matter cystic
change (periventricular leukomalacia) is now very rare but more subtle white-matter signal change on MR imaging occurs in the
majority of infants at 28 weeks. This pattern represents abnormality59
and is not present in normal term-born infants. (b) This
MR feature probably represents loss or maldevelopment of oligodendrocytes and their precursors.
262 R. Vawda et al.

and are multipotent. Stem cells that are being considered
and evaluated for neural cell replacement include embry-
onic stem cells, embryonic germ cells, embryonic carinoma
cells, fetal and postnatal neural stem cells, bone marrow
stromal cells, placental stem cells and umbilical cord stem
cells (Fig. 3). For many cell replacement strategies, ex-vivo
expansion and specification will be required before
transplantation.
Embryonic stem cells
Embryonic stem (ES) cells are totipotent (i.e. they give rise
to all tissues in the body, including those of the nervous
system).60
As such, they are a promising starting material
for therapeutic applications. Undifferentiated ES cells ex-
press genes such as Oct-4, SSEA-1, SSEA-3, SSEA-4, TRA
1e60, TRA 1e81 and nanog.61
They can be propagated in vi-
tro and can be engineered to express therapeutic genes.
The first demonstration that mouse ES cells can be
differentiated into multiple neural phenotypes in culture
was reported by Bain and colleagues62
using retinoic acid.
The newly formed neurons not only expressed lineage-spe-
cific markers but were also capable of generating action po-
tentials. Several groups have now enriched neural
progenitors from murine and human ES cells.63,64
The latter
can incorporate into brain tissue and differentiate in vivo.65
ES cells provide the most promising source of cells for
therapeutic transfer into neural tissue. They are multi-
potent, can be propagated in vitro and can be engineered to
express therapeutic genes. They migrate and differentiate
into regionally appropriate cell types and do not appear to
interfere with normal brain development.66
ES cells can also
be differentiated in vitro into oligodendrocyte precursors
that effectively myelinate host axons in animal models of
human demyelinating disease.67,68
Early successes in neural differentiation of ES cell grafts
in vivo has led to further work in injury models to
demonstrate that transplanted ES cells can integrate and
functionally improve outcome following CNS injury.69,70
However, it is clear that there is still a significant gap in
our knowledge of how to direct the appropriate differenti-
ation of ES cells into specific lineages in vivo.
Ignoring the restrictions placed on using ES cells, the
capacity of ES cells for unlimited growth in culture reflects
their tendency to form teratomas after implantation. Until
reliable means of completely eliminating undifferentiated
ES cells from populations intended for implantation are
developed and tested, ES cells remain an experimental tool
with which to explore proof-of-principle therapies for
neurodegenerative conditions.
Neural stem cells: fetal and postnatal
Traditionally, the precursors of the CNS are classified as
either primary or secondary neuroepithelial cells. Primary
neuroepithelial cells are direct descendants of the neural
plate and reside in the walls of the ventricles as so-called
ventricular zone (VZ) cells. Like the cells of the primitive
neuroepithelium, the cells of the VZ extend processes that
span the width of the developing CNS. These cells form
a pseudostratified epithelium. As development proceeds,
progeny of the VZ become postimitotic neuroblasts. They
leave the VZ to migrate apically towards the pial surface
using radial glia as their guide.71,72
The progeny of the VZ
colonize specific cortical laminae as dictated by their birth
date, with earlier-born neurons generally settling into the
Figure 3 Sources and strategies using stem cells for neural cell replacement.

deeper laminae and later-born neurons migrating past them
to colonize more superficial layers.73
In this manner, the
layered cortices of the brain are formed in an inside-out
pattern. Beginning with the report by Gray and Sanes,74
it
has become clear that radial glia divide in a self-renewing
manner and are capable of producing both neurons and as-
trocytes; hence, they can no longer be regarded simply as
guides for emigrating neuroblasts but also as bipotential
neural stem cells (NSC).75e78
Another important realization
is that the radial glia of the VZ predominantly generate the
large projection or pyramidal neurons.
The emergence of the first neurons coincides with the
appearance of another proliferative population subjacent
to the VZ. These secondary neuroepithelial cells reside the
subventricular zones (SVZ). As the VZ decreases in promi-
nence the SVZs expand. They peak in humans in the
35th week of gestation,79
whereas in the rodent they
peak in number during the first postnatal week.80
The
SVZs are densely populated and SVZ cells can be identified
as far caudally as the third and fourth ventricles. At the
light microscopic level, SVZ cells are small, compact cells
that are usually round or oval and have little cytoplasm
and few organelles. SVZ cells often possess a single thin
process, and this process is not necessarily oriented per-
pendicular to the pial surface as are those of VZ and radial
glia cell processes.
The fetal brain contains large expansions in the ventral
forebrain. These expansions e termed the ganglionic
eminences e are an important source of the interneurons
of multiple subcortical nuclei, including the basal ganglia,
hippocampus and thalamus, they are also an important
source of the interneurons of the neocortex. As fetal
development proceeds the ganglionic eminences recede,
but a prominent SVZ persists at the dorsolateral angles of
the lateral ventricles. Studies on rodents have shown
that this region is a prominent source of GABAergic in-
terneurons that populate the olfactory bulb,81,82
as well as
a major source of macroglia, especially the myelinating
oligodendrocytes.83,84
The brain also contains another mitotically active area
that participates in development and is retained through-
out life, the subgranular zone (SGZ) of the hippocampus.
The SGZ is formed from a specialized pool of cells in the SVZ
at approximately the same period.85
As the number of pre-
cursors expands, these granular cells migrate radially to the
area where the primordial granular layer is formed. Once in
place, the cells proliferate locally and, by approximately
postnatal day (P) 10 in the rodent, an identifiable layer of
precursor cells is visible at the border between the granular
layer and the hilus of the hippocampus. From this region,
granule cells, which populate the hippocampus, are born
throughout life.
In-vivo and in-vitro studies have provided evidence of
cells distributed throughout the brain that continue to
divide throughout the life span. These cells are clearly
a source of additional glial cells and in-vitro studies have
shown that they can also behave as stem cells.86e88
How-
ever, whether these cells actually participate in generating
new neurons in vivo remains quite controversial.89,90
Although the bulk of experimental data has been obtained
using rodent NSCs, similar multipotent cells have been
identified in the human.91,92
When considering NSCs for replacement therapies, it is
important to recognize that cells from different gestational
ages and anatomical sites are not identical, displaying
different growth characteristics, trophic factor require-
ments and specific patterns of differentiation.93e97
Fetal NSCs can be propagated rapidly in vitro with little
or no apparent change in their plasticity. In one study,
human neural progenitors isolated from embryonic fore-
brain were expanded for up to a year in culture using
Epidermal Growth Factor (EGF) Fibroblast Growth Factor
(FGF) and leukaemia inhibitory factor (LIF). Subsequent
injection of these cell lines into the developing rat brain
showed extensive migration and integration.98,99
Clinical use of fetal tissue for stem-cell transplantation
is made difficult by ethical constraints. Confronted with the
spectre of couples conceiving for the sole purpose of
obtaining aborted brain tissue for the treatment either of
a parent or of an afflicted sibling, scientists have turned to
less conventional sources for NSCs. Indeed, investigators
have claimed to isolate functional NSCs from adult post-
mortem brain tissue as late as 5 days after death.100
Al-
though it is suspected that adult NSCs have a more limited
ability than fetal NSCs to form all the neural subtypes, they
might have a broader potential than first thought.
Stem cells from non-neural tissues
Recent studies have suggested that mesenchymal stem cells
(MSCs) from certain adult and fetal tissues have the potential
to exhibit phenotypic characteristics of cells not expected
within the tissue of origin,101,102
including neural pheno-
types. These tissues include bone marrow,103
peripheral
blood,104e106
umbilical cord blood107e109
and umbilical cord
matrix (Wharton’s jelly) cells.110,111
As well as representing
a plentiful, ethically acceptable and easily accessible source
of neural tissue for CNS repair, these cells could potentially
be used autologously, thereby reducing the risk of tissue re-
jection. To date, however, little is known about the sour-
ce(s), frequency and characteristics of cells with the
potential to adopt neural lineages. Although there is cur-
rently no specific antigenic marker for these cells, they are
known to express CD105, CD73, STRO-1 and proly-4-hydroxy-
lase. They do not express markers of the haematopoietic lin-
eage, such as CD34 and CD45.61
They also have osteogenic,
adipogenic and chondrogenic differentiation potential.
Wharton’s jelly (WJ) is the gelatinous connective
tissue that constitutes the umbilical cord. It is composed
of myofibroblast-like stromal (Wharton’s jelly) cells,
collagen fibres and proteoglycans.112
WJ cells express
several stem-cell markers, including c-kit and Oct-4, as
well as telomerase, an enzyme that inhibits cell senes-
cence by maintaining telomere length. They also seem
to have neurogenic potential.110
WJ cells have been
shown to survive for at least 6 weeks following intracere-
bral transplantation or systemic infusion without the need
for immunosuppression of the host rat. Cells labelled with
enhanced green fluorescent protein (eGFP) migrated ex-
tensively after implantation and co-expressed neuronal
filament 70 (NF70).111
To date, no electrophysiological
confirmation of neuronal differentiation has been re-
ported for WJ cells and, similarly, no behavioural assess-
ment of animals transplanted with WJ cells has yet been
264 R. Vawda et al.

published, because they have not yet been used in any
disease model.
The generation of neural cells from bone marrow could
be due either to the presence of a minute subpopulation of
highly pluripotent cells in the marrow or to the reprogram-
ming (trans- or de-differentiation) of an already committed
blood progenitor. Indeed, Verfaillie’s group has described
the ‘multipotent adult progenitor cell’ (MAPC) as a bone-
marrow-derived cell with multitissue potential,113
including
neural lineages. When transplanted, these cells have been
shown to ameliorate neurological deficits in a rat model
of cerebral ischaemia.114
There are several reports of non-neural stem cells
undergoing transdifferentiation to a pro-neural form. Al-
though controversial, much of the transdifferentiation data
are tantalizing and are not easily explained by the fusion of
stem cells with more differentiated ones. However, no
study has yet isolated, purified or expanded neural-like
cells from bone marrow or Wharton’s jelly, and many have
used non-physiological (toxic and carcinogenic) stimuli to
induce or promote the emergence of neural-like cells,
which would limit their clinical application. The use of
substances toxic to cells can cause them to react non-
specifically with a range of antigenic neural markers.115
An-
other problem with the majority of transdifferentiation
studies is that the starting population of cells is heteroge-
neous and there remains the possibility that small numbers
of contaminating neural cells, or more multipotent cells,
account for the result.
MSCs offer a number of advantages over NSCs and ES
cells for clinical implantation:
They are more easily and ethically isolated than NSCs.
They have a greater ability to home in on the brain than
NSCs after intravenous infusion, although no systematic
comparison has yet been carried out.116e119
They negate the need for immunosuppression in the case
of autologous transplants and possibly even in the case of
heterologous transplants.111,120,121
The same might not
be true of NSCs,122,123
MSCs have already been used in
several clinical trials of autologous transplantation for
a wide range of conditions and were found to be well tol-
erated with minimal side-effects.124
They present fewer ethical constraints than NSCs iso-
lated from human fetal CNS tissue and human ES cells.
They are likely to be confronted with fewer regulatory ob-
stacles.Autologous transplantations ofbonemarrowstem
cells (BMSCs) are already possible and such cells from
postnataltissueopenupthepossibilityofusingautologous
transplants to treat neurodegenerative conditions.103
They have a greater differentiation potential than
NSCs, which might be restricted to neural fates.125e130
There are a number of possible drawbacks to using non-
neural sources of neural-like cells for intracerebral implan-
tation. Tumour formation after BM cell intracerebral
implantation in rats has been reported (D. Bonnet, personal
communication, November 2003). So far, there has been
only one report of tumour formation following NSC implan-
tation.131
Furthermore, neural-like cells derived from non-
neural tissue might not be able to respond appropriately to
positional signals within the recipient brain, as indicated by
their presence in inappropriate areas [H. Mehmet, personal
communication, November 2003]. This latter observation
contrasts with published observations of the fate of do-
nor-derived BM cells in the human CNS,132
and of BM-de-
rived MAPCs implanted into blastocyst-stage mouse
embryos,133
which have indicated that they might respond
to local positional and migrational signals within the recip-
ient brain. These discrepancies highlight the need for cau-
tion during the design of transplantation studies and the
subsequent interpretation of results.
Immortalized cell lines
As an alternative to fetal tissue, immortalized cell lines
have been used in animal models of brain injury. Neurons
grafted from a human teratocarcinoma cell line into rats
with focal ischaemia resulted in histological integration and
functional improvement,134
as did grafting a hippocampal
neuroepithelial cell line into damaged hippocampus in the
mouse.135
A number of studies have also demonstrated
the successful transplantation of oligodendrocyte progeni-
tor cell lines for demyelinating diseases, including experi-
mental autoimmune encephalomyelitis136
and ethidium
bromide-induced demyelinating lesions in the spinal
cord.137
There are, however, considerable fears that im-
mortalized cell lines are prone to tumourogenesis and
that they are unable to reconstitute the wide variety of
cell types lost in cerebral injury. This makes them of only
limited use in clinical applications.
Perinatal clinical applications for stem
cell therapy
Perinatal H/I and TBI
Theaim ofanytherapy after a perinatal braininjury,whether
it be H/I or TBI, is functional repair. For this to occur it is
necessary for new projection neurons to be generated in
addition to new interneurons and glial subtypes.
There is increasing evidence to support the existence of
endogenous compensatory mechanisms, which are acti-
vated in response to injury and disease.138e140
For example,
a low level of ongoing neurogenesis has recently been shown
to occur in the adult mammalian striatum.88
Similarly, tar-
geted apoptotic degeneration of murine cortical neurons
has been shown to trigger the formation of new neocortical
projection neurons, whose axons extend into the thala-
mus,141
and a similar process has been observed following is-
chaemia, which promotes neurogenesis in the rat SVZ, with
newly generated neurons migrating into the striatum where
they mature into spinal striatal neurons.142,143
In other studies, neurogenesis has been demonstrated in
models of newborn hypoxic ischaemic brain injury,144
and
similarly active neurogenesis has been demonstrated in
aged and young rats following stroke.145
SVZ cell prolifera-
tion is enhanced further in rats housed in an enriched envi-
ronment following stroke.146
Similar observations have been made in demyelinating
diseases, such as multiple sclerosis (MS), which might have

implications for ischaemic white-matter injury in the
neonate. In chronic MS lesions, the presence of NG2þ
premyelinating oligodendrocytic progenitors has been re-
ported,147,148
although the relationship between endoge-
nous gliogenesis and remission is still unclear.
Studies using BrdU labelling of proliferating cells, whose
migration was confirmed by retroviral tracing, have dem-
onstrated the expansion and subsequent differentiation of
endogenous neural precursors following experimental
stroke.149
Similarly, NSC proliferation has been found to in-
crease ten-fold in the subgranular zone of the dentate gy-
rus after global ischaemia in the gerbil.150
Endogenous
repair in response to stroke can also involve the prolifera-
tion of neural progenitor cells in the SVZ. Following middle
cerebral artery occlusion, injection of BrdU specifically la-
belled astrocytes in the ependymal and subependymal
layers that later acquired the characteristic antigenic
markers of neurons after injury.151
In a separate model em-
ploying chemically induced seizures in the rodent, a pro-
nounced increase in the generation of new neuronal
precursors in the subventricular zone (SVZ) and their subse-
quent migration and integration towards the olfactory bulb
was reported.152,153
While it has been proposed that ischae-
mia-induced neurogenesis might contribute to the specific
recovery of memory function lost following injury, a high
proportion of the dividing cells are lost over the weeks after
injury. Current evidence suggests that SVZ-derived cells
that migrate in response to injury either form interneu-
rons154
or do not survive long term.144,155
The failure of the SVZ to repopulate the brain might
reflect the maturational state of the perinatal brain. As
reviewed earlier, the projection neurons of the brain are
descended from radial cells, which are also the essential
physical scaffold neurons require to migrate from their
periventricular origin into the neocortex. In late develop-
ment, the radial glial scaffold collapses as most of these
radial glial cells differentiate into astrocytes,156
potentially
blocking migration of any newly generated pyramidal neu-
rons. A recent study by Plane et al.155
showed Dcxþ cells
adjacent to GFAP-positive astrocytes and suggested that
they were using these glial cells to support their migration.
Also, Fagel et al.157
reported a similar phenomenon where
the migrating cells were closely associated with GFAP-pos-
itive cells. Ganat et al.158
had shown earlier that there was
an increase in cells expressing markers associated with ra-
dial glia after chronic hypoxia and, given the role of the ra-
dial cells in both neurogenesis and migration, suggested
that these cells were participating in the regeneration of
neurons lost during the insult. However, they also failed
to find any of their newly generated neurons expressing
projection neuron markers. To date, the only experimental
paradigm where new projection neurons are generated af-
ter cerebral injury is in the targeted cell ablation model
pioneered by Dr Jeffrey Macklis and colleagues. Their stud-
ies have demonstrated that the mature brain retains the
capacity to generate new projection neurons, but that their
production occurs only under highly controlled conditions in
which neuroinflammation is curtailed.141
Given the limited replacement of brain cells that occurs
naturally, it is likely that the numbers of endogenous pre-
cursors available are insufficient to fully repopulate the
brain. Moreover, given that pyramidal cells are not replaced
after ischaemic insults, strategies must be formulated to
expand the regenerative potential of the somatic NSCs, and/
or exogenous stem-cell transplantation might be necessary.
Issues related to where these exogenous cells are obtained,
how and where they will be transplanted, and whether they
will be retained in vivo need to be considered. Given their
ability to migrate extensively and integrate after trans-
plantation into the brain,98,99,159
it might be possible to use
neural stem progenitors (NSPs) derived from fetal sources,
but these cells are in very limited supply. Accordingly, ES-
cell-derived neural precursors represent the most feasible
source of cells for transplantation, because they also effec-
tively migrate and differentiate into mature cell types after
implantation.160
Ironically, obtaining neural precursors for
transplantation might be the least difficult hurdle towards
implementing brain cell replacement. Transplanting new
stem cells into the brain will not guarantee successful repair.
The success of any attempted repair will depend on the se-
verity of the insult, the status of growth and survival factors,
and the ability of the transplanted cells to migrate, differen-
tiate and survive.
Another issue to be address is the massive cell death
after injury. Anti-apoptotic agents cannot address the
necrotic cell death that occurs immediately after an
ischaemic event, although they can decrease the amount
of delayed cell death in the subsequent hours, days and
weeks. In severe cases, however, the amount of damage
caused by the ischaemic event can be so extensive that
a lasting motor or cognitive deficit is sustained. Despite the
established knowledge that widespread cell death follows
such cerebrovascular incidents, pharmacological interven-
tions to minimize this (using anti-apoptotic agents) are not
common practice. In such cases, cell replacement would be
an ideal way to restore lost cells and function.
If stem cell therapy is to be implemented to repair the
infant brain after perinatal brain injury, it is likely that
certain groups of infants will benefit more than others.
Infants who are younger and have survived a less severe
insult might be better candidates for treatment than older
infants who have sustained a more serious insult. After an H/I
insult, for example, there is limited damage to neurons in the
brain of a premature infant, and one only needs to contem-
plate strategies to replace the deleted oligodendrocytes.
The somatic neural stem cells of the SVZ are fully competent
to generate oligodendrocytes, but they might require some
specification cues to perform appropriately. The provision of
specification cues for individual cell types would be a simpler
task than for multiple cells types, making the successful
treatment of a preterm infant via expansion and specifica-
tion of the endogenous stem cells a worthy goal.
By contrast, repairing the term infant brain that has
sustained neocortical damage, such as TBI or more severe
cases of H/I, will require a multilayered strategy. A strategy
similar to the following might be required for successful
treatment: the first step could be to suppress the pro-
duction of proinflammatory cytokines, which might inhibit
repair by stem cells and progenitors. Once that is achieved,
matched embryonic stem cells could be specified into radial
cells. Radial cells are a logical choice for transplantation
because they can function as both mediators for migration
and as bipotential precursors that are capable of generating
new projection neurons. Obviously, transplantation would
266 R. Vawda et al.

occur in conjunction with trophic factor supplementation.
The addition of growth factors such as FGF, EGF, LIF or
neuregulin161e163
would help to maintain the transplanted
radial cells as precursors and would alter the environment
in the brain to one that supports proliferation and differen-
tiation of progenitors. Once these precursors are trans-
planted, a period of time would need to pass to allow the
new cells to migrate, differentiate and form new connec-
tions. During and after this period, it would be necessary
to continue the supply of trophic factors and cytokines to
promote the proliferation of endogenous stem cells as
well as the transplanted ones. This supplementation would
also include factors to suppress astrogliogenesis to ensure
that cells are differentiating into necessary cells types
(i.e. neurons and oligodendrocytes). This supplementation
would probably need to be continued long term, with inten-
sive physical therapy to stimulate and maintain newly
formed cells and their connections. Indeed, even with ad-
vanced imaging methods, it remains a challenge to give
an early estimate of long-term prognosis in moderately af-
fected infants, and thus difficult to define a population for
study so as to be confident of outcome differences. The na-
ture of the term brain and the complexity of this treatment
makes the goal of repairing the term infant brain a more
difficult prospect than regenerating the preterm infant
brain, however advances in the understanding of stem
cell biology might make it achievable.
Metabolic brain diseases
One of the major advantages of considering perinatal cell
therapy for inborn errors of metabolism is that, if the
diagnosis is known, treatment could be commenced early to
prevent or minimize ongoing brain damage or deteriora-
tion. It is important to recognize, however, that the
majority of infants with metabolic diseases (frequently
autosomal recessive) do not have affected parents and so
treatment before the onset of symptoms or manifestations,
especially in utero, would not generally be possible. There
are other important issues to take into account. First, it
could be argued that metabolic diseases are multiorgan
diseases and should therefore be treated with global cell
therapy, such as bone marrow transplantation (BMT),
although this approach might have little impact on neuro-
logical deterioration. One example of this is the treatment
of metachromatic leukodystrophy (arylsulfatase deficiency)
with BMT, where it was found that lipid storage was
improved only in the kidney and liver of transplanted
animals, and that neuronal damage in the brain was as
severe as in the untreated animals.164
Second, in a given metabolic disorder where the major-
ity of cells are likely to be affected, it would be unlikely
that a cell replacement strategy would be curative. Cell
replacement therapy might attenuate the clinical course of
the disease and this has been demonstrated with oligoden-
drocyte progenitor cell therapy in metachromatic leuko-
dystrophy.165
However, stem cells could be used as vehicles
to deliver a missing or aberrant gene or protein, or simply
to generate trophic support for endogenous cells to slow
their degeneration.
Also, cell therapy would have to be designed in such a way
that grafted cells would escape the pathological processes
affecting host cells. Already, several researchers have
examined NSC therapy in models with inborn errors of
metabolism with mixed results. Meng et al. investigated
the possibility of using NSC in the treatment of metabolic
brain disease in a murine model of mucopolysaccharidosis
type VII.166
This condition arises from a defect in the alpha-
glucuronidase gene and results in lysosomal accumulation of
glycosaminoglycans in the brain, with subsequent neurode-
generation. In this study, NSCs were modified to overexpress
the missing enzyme (alpha-glucuronidase) and transplanted
into the cerebral ventricles of newborn affected mice.
These NSCs migrated widely and produced large quantities
of alpha-glucuronidase, resulting in a dramatic clearance
of the lysosomal accumulation in host cells to near normal
levels. Such experiments prove e in principle e that NSCs
can be used for gene delivery in genetic deficiency disorders.
One downside in this experiment was that graft survival was
limited by apoptotic cell death of the grafted cells, limiting
the duration of the benefit achieved.
Newborn white-matter disease
Although in the majority of CNS diseases a number of
different cell types are affected, cell replacement therapy
has been most successfully used in models where damage to
a single cell type is predominant. One example of this is
white-matter disease and, indeed, there are already
several rodent models with specific abnormalities in oligo-
dendrocytes e the myelin-forming cells of the CNS. As well
as demonstrating proof of principle, these models will
provide useful prototypes for perinatal therapy. There is
accumulating evidence that, although periventricular leu-
komalacia is becoming rare, brain injury or abnormalities
found in the majority of survivors of extremely preterm
birth remain predominantly in white matter and involve
oligodendrocyte precursor loss.
Magnetic resonance imaging studies have confirmed
involvement of the white matter21,22
and in vitro data
also suggest that oligodendrocyte precursors, abundant in
the preterm brain, are very much more vulnerable to a vari-
ety of stressors compared to mature oligodendrocytes.35
Oligodendrocyte death or maldevelopment may be a pri-
mary event in preterm brain injury. Despite the distance
between the theory and clinical practice of NSC trans-
plants, studies examining oligodendrocyte replacement in
demyelinating models of multiple sclerosis have provided
some encouraging results; however, no work is currently
underway in preterm brain injury.
If cell-based therapy is to be considered for these infants,
better tools will be needed to estimate long-term neuro-
developmental outcome in the perinatal period, so as to
optimize patient selection, and a better understandingof the
pathogenesis of the condition is necessary. At present,
neither of these obstacles is close to being overcome.
Future perspectives
Many issues remain to be clarified about stem-cell trans-
plantation into injured or diseased brains, including the
fundamental one as to which cell sources are best suited for
therapy.167
The pathogenesis of many CNS disorders is not

fully understood and this precludes the directed use of
stem cells for restorative therapy in many cases. In an ideal
world, one would be able to stimulate the proliferation and
appropriate differentiation of endogenous stem cells. In-
deed, a number of gene-delivery-based therapies might
work, at least in part, through this approach. Early experi-
ments in stem-cell transplantation suggested that embry-
onic cells are significantly more plastic than adult ones.
Any research that relies on fetal tissues (especially when
derived by therapeutic cloning) will be ethically controver-
sial. Consequently, efforts should also focus on adult sour-
ces of stem cells for neural cell replacement. Although
research has indicated that adult NSCs possess a broader
developmental potential than was first thought, they do
have a more limited lifespan than ES or fetal-derived cells.
Whether the starting material is embryonic, fetal or adult-
derived, cell replacement strategies must also contend
with the influence of environmental signals. In several
models of adult brain repair, transplants are prone to apo-
ptosis for prolonged periods after transfer and so clinical
improvement might only be temporary.69
Considerable
work is therefore needed to identify the triggers for specific
neural cell survival and integration, and to further deter-
mine how the environment of the injured brain may be ma-
nipulated to become more permissive for effective repair.
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