[Frontiers in Bioscience S4, 121-132, January 1, 2012]
Neural crest stem cells and their potential application in a therapy for deafness
Margriet A. Huisman1, Marcelo N. Rivolta2
1
Department of Otorhinolaryngology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands,
Centre for Stem Cell Biology and Department of Biomedical Sciences, Western Bank, University of Sheffield, S10 2TN, United
Kingdom
2
TABLE OF CONTENTS
1. Abstract
2. Deafness: its social impact and the lack of a curative treatment
3. The neural crest and the otic placode: different structures but similar progeny
3.1. The neural crest
3.2. The otic placode
4. Molecular comparison between neurogenesis in the neural crest and otic placode
4.1. Neural induction from the neural crest
4.2. Sensory neurons from the otic placode
5. Potential sources for Neural Crest Stem Cell isolation
6. Conclusions
7. Acknowledgements
8. References
1. ABSTRACT
2. DEAFNESS: ITS SOCIAL IMPACT AND THE
LACK OF A CURATIVE TREATMENT
Neurosensory hearing loss is a common condition
that has major social and economic implications. Recent
advances in stem cell research and in cochlear implantation
are offering renewed hopes to people suffering from
damage to the auditory hair cells and their associated
neurons. Several putative donor cell types are currently
being explored, including embryonic stem cells, different
types of adult stem cell and the recently described inducedpluripotent stem cells. In this review, we draw attention to
the potential application of neural crest stem cells for the
treatment of deafness. This population shares a similar
developmental origin with the cells of the otic placode, the
molecular machinery controlling their maturation and
differentiation is comparable and they can produce related
sensory neurons. More importantly, pockets of neural crest
stem cells remain in the adult body in regions of relatively
easy access, facilitating their use for autologous
transplantation and therefore avoiding the need for
immunosuppression and the problems of tissue rejection.
Their exploration and application to hearing conditions
could facilitate the development of a clinically-viable, cellbased therapy for deafness.
Hearing is a sense of paramount importance for
verbal communication, pleasure and awareness. The impact
of a hearing deficit, especially during childhood, is huge. It
can lead to problems with the development of speech and
language which has implications for social integration, and
affects quality of life as a whole. According to 2005
estimates by the World Health Organization (WHO), 278
million people worldwide have moderate to profound
hearing
loss
in
both
ears
(www.who.int/mediacentre/factsheets/fs300/en/index.html)(
1).
Many individuals, each with their variable
genetic background, are predisposed to hearing loss
through environmental factors, such as noise or ototoxic
drugs. This leads to age-related hearing loss affecting over
50% of the population by the age of 65.
The most common reason why people become
deaf is because the sensory hair cells in the auditory organs
-the cochlea- become damaged and die. Since the
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Neural crest stem cells and deafness
mammalian inner ear lacks the capacity to regenerate
cochlear hair cells, the loss of hearing is permanent. Injury
to the hair cells leads to the degeneration of their
unstimulated nerve fibres and subsequently, to the death of
the second-level cells in the sensory pathway, the auditory
neurons (2). This neural degeneration process is
irreversible, although the application of neurotrophic
growth factors or electrical stimulation may have some
protective effects (3). Today, the only therapy for hearingimpaired people is the use of prosthetics, such as hearing
aids, bone-anchored hearing devices and the cochlear
implant (CI). These devices help many hearing-impaired
people although, in spite of the many benefits of a CI for
the profoundly deaf, its performance in some patients can
be suboptimal. These limitations are partly due to the
number of available channels, and partly due to the low
resolution of the CI. Improvement of the resolution with
better signal processing or more electrodes is hardly
possible due to the relatively large physical distance
between the CI electrodes and the degenerated auditory
nerve (4). Since the CI functionally replaces the hair cells,
it is also crucial that a critical number of healthy auditory
neurons remain present for its adequate performance (4, 5).
stem cells can apparently surpass the transitional zone
between the central and the peripheral nervous part of the
auditory nerve; embryonic stem cells grafted on the
transected auditory nerve at the base of the cochlea
migrated not only peripherally to the nerve fibres in the
cochlea but also in the opposite direction, centrally, close to
the cochlear nucleus in the brain stem (11).
However, the promising results obtained in early
transplantation experiments could be compromised in
prolonged follow up studies, when long term cell survival
may well become a relevant issue. The causes for limited
cell survival are complex and most probably a combination
of different factors: it may not be due solely to the
traumatic effects of the transplantation procedure but the
microenvironment within the cochlea may also be hostile to
stem cells. The fluid-filled scalae might not facilitate
adequate attachment and survival of the transplanted cells.
The loss of hair cells and their trophic influence on the
sensory neurons may also limit the survival of exogenous
neurons. Cell transplantation could benefit from the
combined application with growth factors, which when
applied in the scala tympani of deaf animals either via a
mini osmotic pump, by a sponge positioned at the entrance
of the cochlea or by using nanoparticles (12, 13) (14) led to
an increased survival of sensory neurons. Unfortunately,
the beneficial effect of growth factors was not permanent
since after the cessation of the therapy, survival decreased.
The auditory sensory neurons, also known as
spiral ganglion neurons (SGNs), are located in the conicalshaped, spongy bone of the central axis of the cochlea, the
modiolus. The main population (90-95%) of the SGNs are
bipolar and myelinated and are commonly named type 1
SGN. These neurons participate in the afferent innervation
of the inner hair cells (IHC), thus directing most of the
afferent input to the brainstem. The thick, myelinated axons
of these SGNs bundle with the vestibulocochlear nerve
which synapses, in the brainstem, on the cochlear nucleus
complex, constituting a link to the auditory cortex. A small
part of the SGN population (~10%) are the type 2 cells.
These are bipolar or pseudo-unipolar and their central and
peripheral processes are mostly thin and unmyelinated.
Type 2 SGNs innervate the OHCs and their central
projections reach the cochlear nucleus area. The
arrangement of the type 2 fibres within the cochlea,
vestibulocochlear nerve and cochlear nucleus is in general
similar to that of type 1 fibres.
Another important survival-limiting factor might
also be that the donor cells are xeno- or allogenic. As a
result, the transplanted cells will be subjected to a graftversus-host response in the recipient animal. Embryonic or
fetal neural progenitor/stem cells should trigger a minimal
immune response in the inner ear because of their immature
antigenic profile and thus are favorable candidates for a
cell-based therapy.
Many reports have demonstrated that ESCs are a
good choice in animal models. Still, in a clinical setting,
these cells would be subjected to allogenic transplantations
which would influence their survival. The question then
arises whether ESCs are really immuno-privileged, as it has
been shown, for instance, that human ESCs induced a
similar immune response as human fibroblast cells on naïve
and immunized T-cells, and did not inhibit immune
responses during direct or indirect antigen presentation
(15). Recently, auditory stem cells were harvested from the
human fetal cochlea (hFASCs) (16). These stem cells could
be expanded in vitro and differentiated into functional
auditory neurons and hair cell-like cells, bringing the
advances made in animal models closer to a clinical
application. However, the use of human embryonic and
fetal stem cells is subject to ethical restrictions and moral
objections from some groups, making the search for a less
controversial source of human cells highly relevant.
Cell-replacement therapy could provide benefits
in conjunction with a CI (6). Neural progenitor/stem cells
are promising candidates for this type of therapy as they
have the potential to provide large numbers of replacement
neurons to the degenerating auditory nerve (7). Moreover,
it has been shown that neural cells are reactive to chronic
electrical stimulation, which may be supportive to the
regeneration process (8). Encouraging demonstrations of
stem cells as a valid therapeutic option come from in vivo
experiments whereas transplanted ESC-derived neural
progenitors were able to differentiate into neurons with
extensions arborizing into the organ of Corti (9) (10). It has
also been established that stem cells implanted in the
cochlea are able to reach functionally relevant regions
beyond the actual transplantation site. This migratory
behavior is of importance because it is extremely
complicated to operate the tiny inner ear, and some of its
regions are almost inaccessible surgically. The migration of
Autologous stem cell transplants might lead to
increased survival of the cells, but neural progenitor/stem
cells from autologous sources are often very difficult to
harvest. In this context, an attractive and theoretically
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Neural crest stem cells and deafness
which increase the probability of oncogenesis. In addition,
the in vivo safety of iPSCs established by different means
has not been analyzed thoroughly (26). Clinical
applications of iPSCs can only be considered if the cells
generated have been validated extensively, and other safety
issues with respect to the transplantation of pluripotent
stem cell derivatives have been solved (32). One important
aspect besides the safety is the efficient generation of the
desired cell type from induced pluripotent stem cells, but
the improvement of their number and purity remains a great
challenge. At the moment, iPSCs are solely a research tool
holding promise as a therapeutic agent.
The pre-requisite of a genuine, continuous and
sufficient population of well characterized adult human
neural precursor cells with the ability to differentiate into
glial cells and neurons also holds true for stem cells derived
from adult tissues. Several investigators have claimed
success in isolating a purified population of neural
precursors from different tissues, but the procedures often
require selective, extensive in vitro cell expansion. This
has been shown for neural progenitors isolated from several
sources, such as blood, bone marrow, neuroblasts from the
olfactory bulb and fat tissue (33-36). Multiple passages, in
order to enhance the number of a certain type of stem cell
from a heterogeneous cell population, carry the risk of
genetic alterations and stem cell senescence/exhaustion
(37). However, the prerequisite of a genuine, continuous
and sufficient population could be better met for some
types of adult neural progenitor stem cells that can be
isolated from adult tissues such as teeth, palatum or hair
follicles (38-41). These stem cells are part of a rich source
of a multipotent stem cell population: the neural crest (NC),
which has been found in various, easily accessible locations
in the body. The differentiation of NC from adult tissue,
under neurogenic conditions, results in the production of
many cells that fulfill most criteria for neuronal
differentiation (42). The NC has also been reported to be
able to differentiate into non-neural lineages, thus showing
pluripotency. For use in inner ear therapy, neural crest stem
cells (NCSCs) could have some advantages when
compared to neural progenitors from other origins, because
during embryogenesis, development of the neural crest is
closely related to the generation of the otic placode.
Figure 1. Schematic representation of the migratory
behaviour of the neural crest. Waves of neural crest cells
wild populate different regions of the body, primary in the
upper trunk and face. In color are the location of the paired,
sensory placodes (orange, otic; purple, optic and green,
olfactory).
useful source would be the induced-pluripotent stem cells
(iPSCs).
The use of iPSCs circumvents all ethical
discussions about the use of human embryonic material and
shows great potential. Since the first reports on iPSCs
generated from mouse fibroblasts, many laboratories have
reprogrammed human and mouse somatic cells into a
pluripotent stem cell-like state by the forced expression of
different sets of transcription factors (Klf4, Oct4, Sox2, and
c-Myc or Oct4, Sox2, Nanog, and Lin28) (17) (18). A
plethora of somatic cells such as murine hepatocytes,
gastric cells, keratinocytes, hematopoietic cells and murine
neural stem cells can be turned into iPSCs (19-22). With
respect to inner ear regeneration, mouse iPSCs appear to be
able to generate auditory lineages (23, 24). However,
reprogramming by defined transcription factors is
inefficient (from 0.0005 % to 0.1 %) and requires
expression of the transcripts for approximately 14 days (25,
26). This is achieved by gene delivery through lentiviral or
retroviral vectors, consecutive transient transfections,
adenoviral vectors, episomally replicating DNA, or
membrane penetrating fusion proteins (19, 27, 28) (29-31).
The most efficient reprogramming method seems to be
retroviral transduction (19). As a result the generated iPSCs
harbor numerous viral integration sites in their genomes,
3. THE NEURAL CREST AND THE OTIC
PLACODE: DIFFERENT STRUCTURES BUT
SIMILAR PROGENY
3.1. The Neural Crest
The neural crest is a multipotent population of
cells, unique to vertebrates, born at the interface of the
neural tube and the dorsal ectoderm (Figure 1). Neural crest
cells undergo epithelial-to-mesenchymal transition and
delaminate from the developing neural tube and overlying
ectoderm early in development. They then migrate through
spatially and temporally coordinated changes in cellsubstratum adhesiveness to different destinations, where
the cells differentiate into a wide variety of derivatives.
There used to be a fundamental question in
developmental biology about whether the neural crest was a
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Neural crest stem cells and deafness
Neural crest cells are also involved in the
integration of placodal neuroblasts with the hindbrain.
Peripheral neurons involved in cephalic sensory systems
are born at a distance from the neural tube. These
neuroblasts migrate internally, coalesce to form ganglia and
extend axons to the central nervous system. The
coordination of this migration and the integration on these
cells with the hindbrain occurs through interaction with
neural crest cells, where the migrating placodal neuroblasts
would follow the pathway of the neuroglial crest cells (53).
Hence the neural crest plays a key role in neuroblast
migration, axon guidance and the subsequent neuronal
ensheathing process and is therefore of great importance in
generating a functional sensory circuit.
homogenous population of multipotent stem cells whose
fates are determined post-migration by localized
environmental cues, or whether it was composed of a
heterogeneous mixture of precursor cells whose individual
fates are specified by intrinsic mechanisms prior to their
migration from the neural tube. Although considerable
transplantation evidence supported the first theory, lineagetracing studies provided evidence for the presence of both
restricted subpopulations of precursor cells and multipotent
stem cells whose fates could be altered by local
environmental cues (43-47). Back-transplantation studies
were consistent with the latter idea, such that although
phenotypically distinct precursor cells may be prespecified, many of them are not committed and their fate
and/or those of their progeny can be determined by cues in
their local environment.
3.2. The otic placode
The inner ear in the vertebrate arises from a
simple ectodermal thickening in the head region called the
otic placode. Placodes are discrete areas of columnar
epithelium derived from non-neural ectoderm. They give
rise not only to the paired sensory organs (olfactory, lens,
auditory-vestibular) and, in aquatic vertebrates to the lateral
line system, but they also make vital contributions to the
peripheral sensory nervous system. Some placodes
invaginate and form a pit (olfactory), or a vesicle (lens,
otic), or placodal cells can delaminate and migrate to a
secondary position (cranial ganglia, lateral line). Depending
upon their placode of origin, the cells are capable of
adopting a variety of fates including glia, sensory receptor
cells, neurons and supporting/structural cells. Placodes can,
to a point, be compared to the neural crest because both
arise from the neural plate border, and both contribute to
the peripheral nervous system (54). It has often been
suggested that both are derived from a common neural
plate border region, being the interface between future
neural and non-neural ectoderm. In this neural plate border
model, additional signals subsequently induce dedicated
neural crest and pre-placodal ectoderm (55, 56). Recently,
an alternative model was proposed, which questions this
common origin and hypothesizes that the competence to
form neural crest and pre-placodal ectoderm is restricted to
neural and non-neural ectoderm respectively, and inductive
signals acting on this border induce neural crest and preplacodal ectoderm at opposite sides of the border (57).
There are ‘for’ and ‘against’ arguments for the complex
succession of events involved in both models and they are
currently under intensive investigation.
In the last five to ten years it was recognized that
the developmental program that regulates neural crest cell
fate is both plastic and fixed. Specifically, as a cohort of
interacting cells, neural crest cells carry information that
directs the axial patterning and species-specific
morphology of the head and face. As individual cells,
neural crest cells are responsive to signals from each other
as well as from non-neural crest tissues in the environment.
Depending on which tissues they contact during their
migration and which signals are received when they reach
their final resting place, these highly migratory cells form
diverse derivatives including sensory and autonomic
neurons for the peripheral nervous system, glia as well as
bones, cartilage, and connective tissues of the face.
Because this review is focussed on one particular neural
crest derivative, the sensory neurons, we refer the reader to
the reviews of Kelusa et al. (48) and Davies (49), for
insight into the contribution of the neural crest to the
autonomic nervous system.
A complex gene regulatory network mediates the
various processes of delamination from the neural tube,
emigration of the neural crest progenitors along distinct
pathways, overt differentiation into diverse cell types and
maintenance of the neural crest pool (50). Timing plays a
key role in determining the types of progeny that are
generated (43). This is illustrated by the three successive
waves of NC migration, leading to differential sensory
neurogenesis (51). The large proprioceptive neurons are
born first, followed then by small neurons. The third wave
generates mainly small neurons that consist largely of
nociceptors, contributing ~5% of adult mouse DRG
neurons (51).
Transcriptional networks, influenced by extrinsic
signals, drive the simple spheroid otocyst into a complex
construction in which neural and non-neural portions are
regionally patterned. The mechanosensory and neuronal
lineages of the inner ear appear to be generated in different
regions of the inner ear placode, with only a small region of
overlap in areas giving rise to the utricular and saccular
sensory organs (58). The otic placode gives rise to both the
auditory and vestibular parts of the entire inner ear,
including the mechanosensory hair cells, all supporting
cells, the biomineralized otoliths and the neurons that will
form the auditory/vestibular ganglia and the VIIth cranial
nerve (54, 59). The neural crest stem cells, however, will
The derivatives of the neural crest population in
the hindbrain region can be broadly divided into two subpopulations: ectomesenchymal and neuroglial. The ectomesenchymal population fills the branchial arches to
produce the head cartilage and bone, while the neuroglial
population remains above the branchial arches to produce
the neurons of the proximal sensory ganglia and the
Schwann cells that ensheath the nerves (52). The two
populations can be distinguished by gene expression, for
example using Sox10 to label neuro-glial cells and Dlx2 to
label ectomesenchymal cells.
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Neural crest stem cells and deafness
produce the Schwann cells to myelinate the neuronal
processes in the cochlea (60).
sequential waves and leading to the appearance of specific
sensory subtypes in the dorsal root ganglia (DRG). The
basic helix-loop-helix transcription factors Neurog1 and
Neurog2 are required for neurogenesis and the specification
of peripheral sensory neurons (51, 81-85). In the first wave,
SOX10+ cells migrate and express Neurog2, which biases
them towards a sensory fate (51). Cells with high levels of
Neurog2 subsequently commit to a sensory neuronal fate as
defined by the expression of the forkhead transcription
factor Foxs1 during migration (46). The newly created,
postmigratory, neurons of the first wave express Brn3a and
form large proprioceptive and mechanoreceptive neurons
that will also express the runt-related transcription factor 3
(Runx3) and the neurotrophic tyrosine receptor kinase C
(TrkC) at early developmental stages (46, 51, 81, 86-88). In
conclusion, the first Neurog2-mediated wave of
neurogenesis
produces
mainly
TrkB/TrkC
mechanoreceptive and proprioceptive neuronal subtypes,
arising from an initial TrkC+ pool(51). In the second wave
of neurogenesis, a subset of NC cells, characterized by the
continuous expression of Sox10 throughout migration,
starts to express Foxs1, Brn3a and Neurog1 in the DRG,
before it expresses RUNX factors (89). This wave probably
produces both the small TrkA+ and TrkC+ populations of
neurons by expressing Runx1 or Runx3, respectively (9092). The third wave of neurogenesis arises from boundary
cap cells expressing Sox10 and Krox20; they contribute
mainly to the RUNX1/TrkA population of neurons and to
glia (93).
4.
MOLECULAR
COMPARISON
BETWEEN
NEUROGENESIS IN THE NC AND OTIC PLACODE.
4.1. Neural induction from the neural crest
Although there may be species-specific
differences, it is generally thought that neural induction is
driven within the ectoderm by mutually antagonistic
signalling molecules that promote an epidermal fate (54,
61). Several BMP-antagonists are secreted from the
underlying mesoderm to promote neural plate formation.
Noggin and Chordin each bind directly to BMPs as well as
wingless (WNT), Nodal ligands and fibroblast growth
factor (FGF) (62-69). Several studies indicate that at
intermediate concentrations of BMP antagonists, neural crest
formation is induced (70-72). Since these factors presumably
diffuse locally from the different dorsal midline tissues, it has
been proposed that a concentration gradient of neural inducers
patterns the embryonic ectoderm into several subdomains:
neural plate at the highest concentration of BMP (low
antagonist), epidermis at the lowest BMP concentration (high
antagonist) and neural crest in between (54, 62). Dependent on
the BMP gradient, FGFs and Wnt produced in the dorsal
neural tube induce the expression of Pax3 and Zic1, which in
turn upregulate neural crest critical genes such as Snail1, Slug
and FoxD3 (61). Further definition of neural crest identity is
conferred by a set of transcription factors, termed NCspecifiers, such as Twist, c-Myc, id-family members, AP-2 and
the SoxE transcription factors: sox-8,-9 and-10 (73). These
transcription factors guide a complex series of events to
specify the NC cells to their fates. These events lead to an
epithelial- mesenchymal transition, which allows the neural
crest to segregate and delaminate from the neuroepithelium
and migrate away from the neural tube (74). During this
migration, NC cells travel along precise paths determined
by cell adhesion molecules that integrate internal and
environmental guidance signals (75, 76). In vivo gain-offunction studies indicate that WNT and β-catenin direct the
specification of early neural crest towards the sensory
lineage (77). Data on WNT signalling in clonal neural crest
cultures corroborate this conclusion. Interestingly, exposure
to BMP2 induces an autonomic fate (78). The exposure to
WNT in the presence of BMP2, however, maintains the
pluripotency of the neural crest cells preventing the
formation of sensory neurons. In any case, early migratory
NCSCs are multipotent and able to generate both sensory
and autonomic lineages.
4.2. Sensory neurons from the otic placode
Although the auditory sensory neurons are
derived from the otic placode and not from the neural crest
like the sensory neurons described above, they share
similar molecular events during their specification and
differentiation.
The ear develops from the otic placode and
undergoes morphogenesis to form the otocyst through the
interaction of several diffusible factors from the
surrounding ectoderm and the underlying mesoderm and
endoderm, such as FGFs, sonic hedgehog, WNTs and BMP
(94-98).
The process of neural crest differentiation
involves a small cohort of genes in which NC specifiers,
such as SoxE transcription factors, often regulate effector
genes that give derivative cells their terminally
differentiated characteristics. During sensory neuron fate
specification, Sox10 is involved in the upregulation of
neurogenin1 (Neurog1) and neurogenin2 (Neurog2)
expression, while it also directly regulates gliogenesis via
Schwann cell-specific genes such as protein zero (79, 80).
The HMG-domain-containing transcription factor
Sox9, a member of the SoxE subfamily of Sox genes, is
expressed early in the otic placode in several species and
studies in Zebrafish and Xenopus have provided evidence
that Sox9 is essential for otic formation and specification
(99). In addition to Sox9, Sox8 and Sox10, the two other
members of the SoxE subfamily, are also expressed during
ear development but expression of both starts later than that
of Sox9, and Sox8 is expressed at much lower levels.
Interestingly, it has been reported that the expression of
Sox10 in the otic vesicle is similar to that in the NC, being
affected when FGF or Wnt8 activity is perturbed,
suggesting that the same molecular mechanisms that induce
neural crest could be important in specifying the placode
regions (100).
Neural crest neurogenesis and specification to the
sensory lineage are linked, driving neurogenesis in
Neurons and hair cells arise from adjacent and
partially overlapping areas and may in certain cases share a
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Neural crest stem cells and deafness
clonal relationship. Neuronal and hair cell differentiation is
driven by the upregulation of specific bHLH genes,
Neurog1 for neurons and Atoh1 for hair cells (101, 102).
This process is enhanced through the interaction with other
factors such as FOXG and RUNX (94, 101). Neurog1 is the
bHLH gene which is found to be upregulated first in the
mammalian inner ear and it activates the downstream genes
Neurod1, Nhlh1 and Nhlh2, which govern further neuronal
development (101-105). Neurod1 primarily functions in
regulating neuronal differentiation and survival (104, 106).
It has been reported that Nhlh2 cooperates with Neurod1 in
neuronal differentiation, while the function of Nhlh1 in
neuronal differentiation has not yet been fully explored
(105). In this time window of otic development, Brn3a has
been shown to be expressed in the facial-stato-acoustic
ganglion prior to sensory neuron differentiation and
innervation of the otocyst (107). Loss of Brn3a leads to
downregulation of TrkC, Brn3b and Parvalbumin in the
spiral ganglion, suggesting that these are downstream
targets of Brn3a. Brn3a is required for the proper growth
and migration of inner ear neuroblasts and is critically
involved in target innervation and axon guidance by
spiral and vestibular ganglion neurons by regulating
different downstream genes. This parallels NC
neurogenesis, in which RUNX and FOXG are also
involved, although it is not yet clear, whether this is
before or after Brn3a expression (51, 90).The onset of
neurogenesis and the genes and morphogens involved in
NC and otic vesicle are very similar, from the early
beginning (WNT, BMP, FGF), through different time
intervals (SOXE subfamily) to later in neuronal
development (Neurog1, Brn3a). This would suggest that
NCSCs and their early neuroblastic lineages as identified
by the expression of Snail, Slug and SOX10, could be
plausible candidates for SGN regeneration.
been taken out of the centre of the tooth while entire hair
follicles can be cultured with subsequent outgrowth of
NCSCs (113, 114). However, the harvest of dental pulp is
invasive because it requires the extraction of a tooth; we
therefore believe that the hair follicle would be the most
useful source of NCSCs.
It has been shown that hair follicle NCSCs are
slightly more restricted in their fates than the “true”
pluripotent NCSCs, although there is a considerable degree
of heterogeneity (115). Depending on the species, the
isolation procedure and the culture methods, stem cells
with different molecular characteristics have been
generated. This heterogeneity is also reflected also in the
nomenclature for hair follicle stem cells. They are known
variously as skin derived precursor cells, epidermal neural
crest stem cells, follicular stem cells and hair follicle neural
crest stem cells (40, 41, 116, 117).
The diversity in the hair follicle NCSC
population is also confounded by the lack of a universal,
useful marker. In the mouse, CD34 has been recognized as
a reliable marker for hair follicle NCSCs, but its expression
is controversial in humans (40, 118). Conversely, these
differences underline the exceptionally diverse and
dynamic stem cell population located in distinct regions of
the hair follicle (119).
Hair follicle stem cells can generate all
ectodermal derivatives, including neurons, nerve
supporting cells, smooth muscle cells, bone/cartilage cells
and melanocytes (118, 120). However, a potential caveat of
their use for the generation of sensory neurons lies in the
fact that early exposure of migrating NCSCs to BMP2
appears to suppress sensory neurogenesis (78). In
agreement with this observation, adult skin-derived
precursors appear to differentiate primarily into autonomic
neurons (41, 42). It is possible then that the competence of
adult skin neural crest cells to produce sensory neurons has
been lost during development, although this is not entirely
clear for, on the other hand, epidermal neural crest stem
cells can differentiate into Brn3a-expressing cells (121) and
can elicit recovery of sensory function when transplanted
into a model of spinal cord injury (122). Moreover, an
independent group has obtained functional neurons
displaying some features of sensory cells, like sodium
channels. (123). As mentioned above, a more precise
definition of the population under exploration using surface
markers and the exploration of purpose-defined, specific
culture conditions could help to establish if sensory
lineages can indeed be obtained from adult skin neural crest
derivatives.
5. POTENTIAL SOURCES FOR NCSC ISOLATION
Neural crest stem cells persist into adulthood in
the tissues that were originally derived from it. This allows
their potential isolation from various sources such as the
gut, dorsal root ganglion, heart, hair follicles, olfactory
sheath and craniofacial tissue (35, 38-40, 108-112). For
stem cell-based therapy it is obviously of importance to
harvest these NCSC from a minimally invasive, easily
accessible source. When the possibility of autologous
transplantation is added to these criteria, olfactory sheath,
palatum, dental pulp or the hair follicle are considered the
most advantageous sources (35, 38-40, 111, 112). Taking
into consideration that extensive expansion of cell numbers
requiring multiple passages could scale up the potential
costs of the procedures and also increase the chances of
introducing unwanted chromosomal anomalies, the sources
are further narrowed down to the craniofacial tissue and the
hair follicle. The isolation of stem cells from the palatum
requires several steps which might affect the quality of
cells, such as mechanical chipping and the use of a high
concentration of proteolytic enzymes (39). On the other
hand, isolation of stem cells from the dental pulp and hair
follicles do not need a pre-treatment, since they can be
cultured directly by allowing them to migrate out of their
natural niches. The soft tissue of the dental pulp can easily
Despite their ectodermal origin but in agreement
with their neural crest nature, hair follicle stem cells can
also generate cell types that are typically derived from the
mesoderm, such as endothelial and hematopoietic cells
(124, 125). Besides the contribution of Hu et al. (122),
further application of hair follicle stem cells for neural
repair has been demonstrated by Amoh et al. in an
exceptional experiment where newly generated Schwann
cells supported the recovery of injured peripheral nerve
fibres (117).
126
Neural crest stem cells and deafness
8. A. N. Ide, A. Andruska, M. Boehler, B. C. Wheeler and
G. J. Brewer: Chronic network stimulation enhances
evoked action potentials. J Neural Eng, 7(1), 16008 (2010)
6. CONCLUSIONS
A regenerative treatment for the inner ear is
needed to restore the damaged population of sensory cells.
Since the currently available cochlear implant can
substitute, albeit partially, for the role of the hair cells, a
promising strategy could concentrate on replacing the lost
auditory neurons with stem cells. This aim will probably be
facilitated by the use of autologous cells, which should
improve the survival of the grafted cells by removing the
problem of immunogenic rejection. Adult neural crest stem
cells, available from several easily accessible sources, have
so far not been applied to the inner ear regenerative field.
They are, in our opinion, worthy of exploration. Hair
follicle stem cells are NCSC descendants, likely to retain
the potential to differentiate towards functional sensory
neurons. We postulate that hair follicle stem cells are
highly suitable as a donor cell type and could be of great
use in the development of a cell-based therapy to treat
deafness. Ongoing experiments in our laboratories are
aiming to test their potential.
9. C. E. Corrales, L. Pan, H. Li, M. C. Liberman, S. Heller
and A. S. Edge: Engraftment and differentiation of
embryonic stem cell-derived neural progenitor cells in the
cochlear nerve trunk: growth of processes into the organ of
Corti. J Neurobiol, 66(13), 1489-500 (2006)
10. N. Jongkamonwiwat, W. Chen and M. N. Rivolta:
Functional Recovery Obtained by Human ESCs-Derived
Otic NeuroProgenitor Cells (ONPs) Transplanted Into the
Deafened Gerbil Cochlea. In: Assoc. Res. Otolaryngol.,
(2010)
11. M. Ulfendahl, Z. Hu, P. Olivius, M. Duan and D. Wei:
A cell therapy approach to substitute neural elements in the
inner ear. Physiol Behav, 92(1-2), 75-9 (2007)
12. M. J. Agterberg, H. Versnel, L. M. van Dijk, J. C. de
Groot and S. F. Klis: Enhanced survival of spiral ganglion
cells after cessation of treatment with brain-derived
neurotrophic factor in deafened guinea pigs. J Assoc Res
Otolaryngol, 10(3), 355-67 (2009)
7. ACKNOWLEDGEMENTS
MAH and MNR were supported by a grant from
the British Council Partnership Programme in Science.
MNR is supported by the MRC, the RNID and a DRUK
Centre of Excellence Award. We are indebted to Leila
Abbas for critically reading the manuscript.
13. S. Takemoto, N. Morimoto, Y. Kimura, T. Taira, T.
Kitagawa, K. Tomihata, Y. Tabata and S. Suzuki:
Preparation of collagen/gelatin sponge scaffold for
sustained release of bFGF. Tissue Eng Part A, 14(10),
1629-38 (2008)
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Key Words: Deafness, Spiral Ganglion Neurons, Neural
Crest Stem Cells, Hair Follicle, Stem Cell Therapy, Review
Send correspondence to: Marcelo N. Rivolta, Centre for
Stem Cell Biology and Department of Biomedical
Sciences, Western Bank, University of Sheffield, S10 2TN,
UK, Tel: 44-0-114 222 2385, Fax: 44-0-114 222 2787, Email: m.n.rivolta@sheffield.ac.uk
http://www.bioscience.org/current/vol4S.htm
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