Keywords
hearing loss - stem cells - organoids - otic sensory cells
Hearing loss is one of the most common neurosensory deficits among children and adults
worldwide.[1] Sensorineural hearing loss (SNHL) affects approximately 25 to 48 million Americans
with approximately 1 in 1,000 children having profound to severe SNHL.[2] SNHL is caused by damage to the auditory hair cells that line the sensory compartment
of the cochlea. Hair cells are sensory cells that are responsible for transducing
mechanical stimuli, such as sound and movement, into an electrical stimulus, which
then travels to the auditory cortex of the brain via spiral ganglion neurons (SGNs).[3] Both hair cells and SGNs are unable to regenerate or self-repair, therefore, damage
to these sensory structures leads to irreversible hearing loss. There are many different
etiologies responsible for the permanent damage to otic sensory cells including congenital
defects, ototoxic medications, and exposure to loud noise.[4]
Stem cell therapy is an exciting and promising approach to restore sensory cells that
are damaged in SNHL. Research has suggested the possibility of restoring sensory cells
for hearing and balance with the use of in vitro differentiation of stem cells into
hair cells or auditory neurons. The utility of stem cell-based therapy for SNHL is
dependent on the ability of transplanted cells to not only survive and migrate to
the appropriate damaged areas of the cochlea, but also successfully transduce sound
to the brain. Many studies describe the differentiation of stem cells into inner ear
progenitor and sensory cells using various types of stems cells, mammalian models,
and methods of differentiation.[4] Despite these advancements, many limitations prevent these techniques from being
used in the clinical setting.
Another promising area of interest in SNHL treatment is the development of organoids.
Organoids are three-dimensional (3D) stem cell cultures that can function as an external
cellular environment and serve as a powerful tool to study the pathways involved in
both SNHL and generation of otic sensory cells.[5] Though organoids are a relatively new technology with their own limitations, they
address some of the pitfalls that hinder traditional methods of stem cell culturing.
In this review, we will discuss the utilization, success, challenges, and possible
future directions of both stem cell therapy as well as organoids for the treatment
of SNHL.
Principles of Inner Ear Stem Cell Therapy
Principles of Inner Ear Stem Cell Therapy
Stem Cell Types and Delivery
Stem cells are characterized by their ability to differentiate into various cell types
and are classified by the lineages they descend from[6] ([Fig. 1]).[7] The stem cells used in studies involved with SNHL include embryonic stem cells (ESCs),
induced pluripotent stem cells (iPSCs) ([Fig. 3]), and mesenchymal stem cells (MSCs). ESCs are derived from an embryo during the
blastocyst stage and can differentiate into both hematopoietic and mesenchymal cell
lineages. All tissues can descend from these two cell lines that gives ESC their pluripotent
potential. iPSCs have the same capacity to differentiate into any tissue but are derived
from somatic cells. These somatic cells, such as fibroblasts, usually come from adult
tissue and are induced to dedifferentiate back into pluripotent cells. While ESCs
and iPSCs are both pluripotent, MSCs, which are multipotent cells, are only capable
of differentiate into certain types of tissue. Though easily isolated, MSCs are limited
by a lack of proven efficacy in differentiating and functioning as specialized cells
[6] Each type of stem cell mentioned above has been studied to evaluate their efficacy
in becoming functional otic sensory cells that can replace the damaged tissue responsible
for SNHL.
Fig. 1
Stem cell lineage. Stem cells have the ability to differentiate into specific cell types. There are
three major classes of stem cells: totipotent cells that can give rise to any cell
type or form an embryo, pluripotent cells that can become any cell in the adult body,
and multipotent cells that are restricted to becoming a more limited population of
cells. Adapted from Zhang et al 2009.[7]
The Delivery of Stem Cells into the Cochlea
A major hurdle to overcome in the use of stem cell therapy for hearing loss is successfully
delivering in vitro generated cells into the cochlea ([Fig. 2]).[8] Three main techniques have been investigated for stem cell delivery to the inner
ear; systemic administration, trans-tympanic administration, and intracochlear administration
([Table 1]). The tightly regulated blood–labyrinth barrier (BLB) separates the inner ear from
systemic blood circulation, seemingly separating the two structures from cellular
migration. However, MSCs have demonstrated the ability to migrate to SGNs and hair
cells within the cochlea when they are injected into the brachial vein of guinea pigs.[9] These findings suggest MSCs are able to penetrate highly regulated barriers, such
as BLBs, and potentially the round window membrane (RWM), to reach the cochlea and
migrate to the area of neuronal damage.
Table 1
A summary of various stem cell delivery techniques
|
Mode of delivery
|
Advantages
|
Disadvantages
|
|
Intratympanic
|
• Anti-inflammatory paracrine signaling without direct engraftment.
• Rapid and proximal delivery
|
• Difficulty reaching target locations due to limitations of the round window membrane
permeability.
|
|
Intracochlear
|
• Most direct route of administration.
• Can bypass protective barriers.
|
• Invasive
Only performed in conjunction with surgery (i.e., cochleostomy or round window incision
and insertion of catheter)
High risk for damaging adjacent structures.
|
|
Vascular/Systemic
|
• Therapeutics can be developed to cross the blood–labyrinth barrier.
Drug delivery vehicles may reduce the chance of off target delivery.
|
Off-target delivery to locations with similar cell surface markers leading to adverse
reactions.
Lack of full understanding of the cochlear microcirculation.
|
Fig. 2
Stem cell delivery to the inner ear: The inner ear is located behind the tympanic membrane and can be approached with
an incision in the tympanic membrane. Although the inner ear is surrounded by bone,
this area is filled with endolymph and perilymph fluids. Mechanical and hydraulic
damages to the inner ear as a result of injection of stem cells directly into the
cochlea may lead to further hearing loss. Conversely, systemic administration of stem
cells through vasculature may have other type of side effects (stem cells must traverse
the blood–labyrinth barrier or may reach other unwanted organs). Adapted from Nyberg
et al 2019.[8]
Fig. 3: Use of inner ear stem cells: Human and rodent embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)
can be induced to form otic epithelial progenitors (OEPs) that develop into hair cells,
otic neural progenitor (ONP) cells that develop into sensory neuron-like neurons,
and 3D inner ear organoids which can be used to model and experiment with healthy
and diseased inner ear structures. Adapted from Tang et al 2020.[4]
Trans-tympanic administration of stem cells has also shown promising results. Injection
of stem cells through the tympanic membrane and into the middle ear allows for the
stem cells to be in close proximity to the cochlea. Stem cells are traditionally thought
to drive much of their regenerative potential from direct replacement and repair of
injured tissues. However, there is an increasing body of evidence that shows the paracrine
signaling between grafted stem cells and host tissue can be otoprotective.[10] In this way, stem cells can be injected in close proximity to the inner ear and
still have an effect without being directly injected into the inner ear. In fact,
many studies have observed the beneficial therapeutic effects of stem cell administration
despite the failure of cells to engraft within the target tissues.[11] Additionally, studies have demonstrated that stem cells secrete many biologically
active molecules without engraftment: insulin-like growth factor-1 (IGF-1), vascular
endothelial growth factor-D (VEGF-D), and interleukin-10 (IL-10).[12] In one study looking at hypertrophic scar formation and wound healing, the paracrine
signaling of various factors from transplanted MSCs showed anti-inflammatory, antiapoptotic,
pro-mitotic, and angiogenic properties.[13] This combination of signaling may garner an otoprotective effect that potentially
helps hair cells and SGNs to regenerate.
Intracochlear administration of stem cells is by far the most direct route of stem
cell administration to the inner ear. Intracochlear injection is beneficial due to
the precise delivery of stem cells into the cochlear space. This allows cells to bypass
many of the barriers protecting the inner ear. Unfortunately, the use of these injections
is currently limited in vivo due to the risk of damaging sensitive local structures
during injection.[14] This limitation relegates intracochlear injections to potentially only cases of
profound hearing loss. However, one promising development has been the creation of
biohybrid cochlear implants. Biohybrid implants coat the electrode array with stem
cells prior to insertion in the hopes of preserving residual hearing post implantation
because the stem cells release cytokines, chemokines, and growth factors that exert
anti-inflammatory and neuroprotective effects.[15] These effects in turn reduce fibrosis and cochlear ossification thereby potentially
increasing the residual SGN counts.[15]
Stem Cell Therapy in the Inner Ear
Stem cell therapy can be divided into three categories based on cell type: ESCs, adult-derived
stem cells (ASCs), and induced pluripotent stem cells (iPSCs). Each of the different
cell types within this framework provides distinct advantages and disadvantages.
Embryonic Stem Cells
As previously mentioned, ESCs display unlimited capacity to proliferate and can differentiate
into any tissue type. This aspect makes them attractive for cellular therapy but highly
controversial since they need to be isolated from embryos. Many studies have observed
exciting results using animal ESCs to derive otic sensory cells ([Fig. 3]). A study developed a protocol to guide differentiation of mouse ESCs to otic sensory
neurons (OSNs) using bone morphogenetic protein (BMP) signaling and transforming growth
factor-β (TGF-β) signaling inhibition. The study successfully derived a population
of neurons that expressed neuronal morphology and functional properties of OSNs.[16] Another study also developed a protocol to generate otic sensory cells by treating
human ESCs with various proteins such as human bone morphogenic protein-4 (BMP4),
wingless-related integration site 3a (Wnt3a), fibroblast growth factor-2 (FGF-2),
epidermal growth factor (EGF), and mitogenic factors. The induced cell population
was functionally and phenotypically similar to spiral ganglion cells.[17]
A study generated early primitive ectoderm-like (EPL) cells by culturing mouse ESCs
in a conditioned medium. Subsequently, the ESC-derived EPL cells were induced with
a combination of FGF3, FGF10, EGF, and IGF-I to generate otic progenitor cells. The
induced cells developed stereociliary hair bundle-like structures and contained functional
mechanotransduction channels.[18] Functional recovery of auditory neurons in vivo has only been demonstrated in one
study with ESCs. The successful restoration of inner ear function was observed following
transplantation of human embryonic-derived otic progenitor cells into mice with deafness
induced by Ouabain treatment. In this study, there was a detectable improvement in
the auditory brainstem response (ABR) thresholds of transplanted animals starting
at 4 weeks post transplantation, with the mean auditory threshold improving to 50.46 dB
by 10 weeks post-transplantation. The transplanted mice were observed to have an overall
functional improvement of 46% with some of the animals experiencing near total restoration
of hearing.[19]
Adult-Derived Stem Cells
Adult stem cells do not pose the same ethical issues as seen with ESCs; however, they
lack the same degree of pluripotency because they are more differentiated into a particular
tissue type. MSCs have been used in experiments looking at SNHL due to their low side
effect profile and relatively straightforward mode of isolation. A phase 1 clinical
trial was conducted to evaluate the intravenous administration of human umbilical
cord blood (hUCB) in children with SNHL. The primary objective of the study was to
evaluate the safety and feasibility of cord blood autologous transplants as well as
to determine functional and structural improvements in hearing. Results showed five
of eight subjects experienced a reduction in ABR thresholds after transfusion. The
reduction in ABR threshold was evident throughout a follow-up period of 12 months.
Additionally, fractional anisotropy (FA), a proxy for myelination, and white matter
quality usually decreased in individuals with SNHL, was measured. Out of the five
patients who had improved thresholds, three presented with improvement in FA, suggesting
possible improvement in nervous system structures associated with the auditory pathway.[20] A case study reported a patient with SNHL who underwent an autologous bone marrow-derived
MSC transplant for hearing loss regeneration. The cells were transfused through a
subclavian line and then homed to the cochlea by applying electrical stimulation to
the promontory. Electrical stimulation has previously been established as a helpful
tool for cardiac human stem cell differentiation and brain stimulation.[21] The researchers hypothesized that this technique would aid in localizing the stem
cells to the damaged cochlea. Although the patient did not experience any complications
or side effects, the authors were unable to observe any change in ABR thresholds up
to 1 year.[22]
Besides MSCs, there has been increased interest in dental pulp-derived stem cells
for developing therapeutic modalities for hearing loss. A study aimed to use stem
cells derived from dental pulp and deciduous teeth and differentiate them into SGNs
using neurotrophins.[23] Dental pulp cells are close in origin to ESCs but lack the ethical issues with isolation.
Using basic fibroblast growth factor and EGF, the study induced the stem cells into
neuronal differentiation. The cells demonstrated long neuronal processes with spherical
bodies and expressed SGN-specific markers.[23]
Induced Pluripotent Stem Cells
iPSCs can be derived from an autologous source similar to adult stem cells, however,
when these cells are induced, they have pluripotent potential. A study transplanted
mouse-derived iPSCs into mice cochleae. After 4 weeks, the injected stem cells were
observed to differentiate into hair cell-like cells and SGN-like cells. Although there
was a significant difference in ABR thresholds between the treated mice and controls,
the mice still exhibited severe hearing loss following transplantation.[24] Another study isolated urinary cells from a healthy human donor and dedifferentiated
them into iPSCs.[25] The iPSCs were then induced to become otic progenitor cells, which were observed
to further differentiate into hair cell-like cells. These cells were analyzed for
their potential to synapse with SGNs in vitro and transplanted into mice cochleae
in vivo for assessment of engraftment. The results of this study showed afferent synaptogenesis
between hair cell-like cells and SGNs and successful migration of cells into the scala
media and scala tympani. Furthermore, some of the stem cells migrated to the site
of resident hair cells and demonstrated differentiation into hair cell-like cells.[25]
Inner Ear Organoids
Organoids were developed initially as mimics for gut and brain tissue, organoids are
3D cell cultures derived from stem cells that are representative of a larger organ
in regards to cell types and function.[26] By containing multiple cell types and proper spatial arrangement, 3D organoids are
able to better represent their target organ compared with two-dimensional culture
methods.[27] Organoids provide an unprecedented opportunity to expand existing knowledge of the
inner ear and improve current treatment modalities. Many of the problems encountered
in inner ear research and stem cell therapy are hoped to be addressed with organoids.
Organoids can model the human inner ear better than traditional animal models that
use zebrafish and rodent species. While these models have been invaluable in developing
our current understanding about the inner ear, there are several anatomical and molecular
differences between animal models and the human inner ear. For example, murine cochlear
explants, a commonly used inner ear model, are not mature at birth, while human cochleae
are fully mature by the 20th week of embryogenesis.[28] Additionally, murine cochleae must be dissected before post-natal day seven and
can only be kept ex vivo for approximately 2 weeks.[4]
[29]
[30] Other animal models such as zebrafish have more hair cells and a higher capacity
for spontaneous hair cell regeneration.[31]
[32] Despite these advantages, zebrafish do not accurately represent the human inner
ear; access to the inner ear in humans is highly restricted by the surrounding bone,
and attempted access can cause damage to the fragile structures within the inner ear,
significantly limiting in vivo sampling. Additionally, noninvasive imaging techniques
do not provide the level of detail needed to study inner ear pathology.[4]
[33] Organoids overcome these issues, as they are more easily accessible, sustainable,
and modifiable, all while more closely recapitulating the human cochlear function.
Additionally, unlike other animals, the mature human cochlea cannot spontaneously
regenerate both sensory and neural cells after damage. This lack of innate reparative
ability makes the concept of assembling complex cellular structures in 3D particularly
appealing. A study induced the differentiation of human-induced pluripotent stem cells
(hiPSCs) into otic progenitors to form SGNs and hair cells using organoid techniques.
The generated cells were then injected through the RWM and after 4 weeks, were observed
to migrate past the membrane that contained perilymph and endolymph. Some of the transplanted
cells migrated into the scala media, however once there, they failed to transform
into hair cells. Furthermore, only a few cells were identified to have integrated
to the site where hair cells were originally lost.[25] The findings from this study were consistent with the previous study that transplanted
hiPSCs through the round window niche. Results from this study showed that 4 weeks
after transplant, the cells expressed auditory hair cell markers and SGN markers.[34] A study performed in vivo transplantation of inner ear organoids in an adult mammal.
The high potassium level in the endolymphatic compartments can easily damage or kill
transplanted stem cells thus the researchers injected the cells into the scala tympani
at the basal turn by cochleostomy, which maintained an intact bony rim between the
injection point and the round window. Cyclosporine was used as a pretreatment to induce
immunosuppression and it was observed that the grafted cells localized preferentially
within damaged regions of the cochlea. It was also demonstrated that hair cell progenitor
cells engrafted into the cochlea and were able to survive as cochlear sensory epithelium.[1]
Use of PSC built organoids to replace and repair damaged sensory epithelium and neurons
could potentially be curative for these conditions. Indeed, thus far, experiments
have shown that transplantation of early PSC-derived otic progenitors has been successful,
although the long-term viability and function of these transplants remain unclear.[4] Currently only a few early-adopting laboratories are investigating the potential
of organoids. More widespread investigation and use of these novel experimental modalities
are needed to increase our understanding about human inner ear pathophysiology and
potentially develop treatment modalities for inner ear disorders. To this end, we
will discuss the current state of organoid research.
Organoid Creation
Organoids are human pluripotent stem cells (hPSCs) which are cultured in a way to
replicate in vivo embryological development ([Fig. 4]).[35] To begin, hPSCs are aggregated in low-binding plates treated with extracellular
matrix proteins (Matrigel) to promote epithelialization of the surface. Next, a series
of key growth factors that control molecular signaling pathways are introduced in
a stepwise fashion, such as TGF, FGF, Wnt, and BMP ([Fig. 5]).[36] This series of signaling molecules induce the formation of non-neural ectoderm (NNE),
otic-epibranchial progenitor (OEP) domain, and otic placodes in sequential order.
The otic placodes then self-differentiate into otic vesicles that evolve to form sensory
epithelia consisting of hair cells, support cells, and neuronal cells needed for innervation.[28]
[37]
[38] This process is similar to those used to make cerebral and retinal organoids with
the crucial branch points being the TGFβ, BMP signaling-induced NNE formation, and
BMP and FGF signaling-induced otic placode formation.[39] Additionally, the physical cues provided by the extracellular matrix are vital to
the efficacy of differentiation and assembly into the hair cell lines vesicles.[37]
[40]
[41]
Fig. 4
Inner ear organoids: both guided differentiation and spontaneous self-organization in three-dimensional
cultures have allowed for the successful generation of otic vesicle-like structures
containing functionally mature sensory hair cells from mESCs. The use of extracellular
matrix proteins and epithelial support cells allows for an extracellular matrix and
supportive cellular environment in which signaling molecules can function to control
stem cell proliferation and differentiation. Adapted from Munnamalai and Fekete 2017.[35]
Fig. 5
Steps to generation of sensory epithelium: Key signaling mechanisms guide the process from embryonic stem cell to definitive
ectoderm and eventually to sensory epithelia. A TGF-β inhibitor blocks formation of
mesoderm/endoderm and promotes induction of definitive ectoderm while BMP signaling
is used to induce non-neural ectoderm. BMP inhibition and FGF activation are necessary
for the development of pre-placodal ectoderm which with subsequent FGF signaling and
endogenous Wnt become an otic placode. Adapted from Longworth-Mills et al 2016.[36] BMP, bone morphogenetic protein; FGF, fibroblast growth factor; TGF-β, transforming
growth factor-β.
The most groundbreaking step in the creation of inner ear organoids was pairing both
the mechanosensory cell lines and neuronal cell lines within the same model system
to replicate the mechanism of sound transduction in vitro. These two systems are intimately
related in transducing sound yet were previously generated separately in model systems.[4] Indeed, these models have already been used to investigate inner ear physiology
and disease.[42]
[43] However, despite these advances, further characterization of these systems is still
needed.
Additionally, this process is not without limitations. Researchers report that the
efficiency of organoid culture can be affected by stem cell passage number, variability
in the number of reagents, seasonal variations, as well as variations in dose and
timing within the protocol.[39] For example, the extracellular matrix, Matrigel, as a biological product, has a
high degree of variability and unpredictability between lot numbers; however, there
is currently no effective alternative to mitigate these challenges.[44]
Experimental and Therapeutic Use of Organoids
As mentioned previously, organoids present an entirely new experimental paradigm with
which researchers can investigate cochlear function and disease, as well as a large
step forward in using stem cells as treatment modalities in the inner ear. The use
of inner ear organoids to investigate these avenues is particularly attractive given
the potential ease and scalability of the experimental design.
Drug Identification and Screening
Cochlear organoids have a promising role in drug development and discovery. Current
testing pipelines for otologic drugs have challenges since they rely heavily on animal
models to test the safety and efficacy of drugs. The organ of Corti explants used
in current regenerative studies are from generally P7 post-natal animals which mean
they still have immature cochlea. In addition, these explants may have a significantly
different capacity for cellular regeneration and toxicity compared with adult rodents
as well as to their human counterparts.[28]
[45] If the experiment is performed in vivo, it is then highly limited in throughput
due to feasibility issues as it is difficult to handle large number of animals at
the same time. Even high throughput in vivo models such as zebrafish are limited by
their physiological differences compared with mammalian hearing.[27] Given these limitations, the use of human-derived cochlear organoids is particularly
appealing and can serve as a powerful tool for developing regenerative therapies for
hearing loss.
Inner Ear Regenerating and Repair
Finally, human-derived organoids are being studied in the context of direct stem cell
therapy. Current research into inner ear stem cell therapies face several problems,
especially regarding adequate engraftment into target tissues and adequate function
once administered.[28]
[46] The ability to manipulate cells post transplantation into damaged cochleae is a
significantly challenging area for sensory regeneration. Barboza et al harvested inner
ear progenitor cells from mice and transplanted them into guinea pigs with neomycin-induced
SNHL. Following transplantation, the cells were found in all scala of basal turns.
Of the transplanted stem cells in the scala media, 42.6 ± 5.7% were positive for the
essential hair cell marker MYO7A.[47] It is theorized that the level of differentiation of donor cells may affect the
subsequent rate of engraftment of cells into target organs. For example, research
has revealed that stem cells grafted at lower levels of differentiation are more at
risk for tumorigenesis, while cells grafted at moderate levels of differentiation
have a lower survival rate.[48]
[49]
Despite advances in delivery technique and technology, very few stem cells migrate
appropriately, and even fewer of those survive after intracochlear injection.[50]
[51] These issues in cell survival and differentiation partially derive from the inaccessibility
of the inner ear structures to stem cell placement. Cell survival is also affected
by the toxic environment created by the endolymph.[4] Moreover, these transplanted cells frequently struggle to differentiate into hair
cells and neurons, rendering them functionally useless.[52] Organoids will help to solve this problem by delivering more differentiated otic
neural progenitors (ONPs) and OEPs into the target tissue. In experiments injecting
human-derived OEPs into gerbil cochlea, cells demonstrated migration, engraftment,
and differentiation. Furthermore, they were able to form synapses with sensory neurons.
In this study, auditory functioning post-transplant was not assessed.[53] While this is a very promising finding, much more research is needed to investigate
the functionality of organoids and to increase the number of synaptic connections
within the SGN.
Challenges with Regenerative Stem Cell Therapy
Challenges with Regenerative Stem Cell Therapy
Stem cell-derived therapy is associated with limitations that pose a significant barrier
in its potential translation from bench to bedside. Once cells are successfully transplanted
into the cochlea, besides from functioning properly, they must exhibit biocompatibility.
In a study, guinea pigs were transplanted with mouse stem cells. Although an immunological
rejection would seem likely due to the differing species, the researchers did not
see any evidence of infiltration by inflammatory cells or other signs of rejection.[47] Other studies have observed similar findings with xenologous transplantations, which
may indicate that the cochlea is an immune-privileged organ similar to the eye.[48]
[54] On par with these findings, we also observed that MSCs are biocompatible with the
cochlea in a rat model. There was no evidence of an immune reaction or inflammation
throughout the adjacent structures, cochlea, or middle ear on histological examination
following transtympanic administration of bone marrow-derived MSCs to rats without
immunosuppressive therapy. The results of our study suggest the possible efficacy
of MSCs as a modality of treating SNHL without immunological complications.[55]
Previous studies have also reported the potential association between transplantation
of stem cells and higher risk of tumor formation particularly after the administration
of undifferentiated stem cells.[56] In the study previously mentioned by Chen et al, no tumor formation was detected
in the mouse cochlea 4 weeks following transplant.[34] However, another study also evaluated the tumorigenesis risk of iPSCs and found
that after transplanting the iPSCs derived from different somatic cells into mice,
the iPSCs derived from adult mouse tail-tip fibroblasts had a higher risk of tumorigenesis
than iPSCs cells from mouse embryonic fibroblasts.[57]
Despite advances in delivery technique and technology, very few stem cells migrate
appropriately, and even fewer of those survive after intracochlear injection.[50]
[51] These issues in cell survival and differentiation partially derive from the inaccessibility
of the inner ear structures to stem cell placement. Cell survival is also affected
by the toxic potassium-rich environment of the endolymph.[4] Moreover, these transplanted cells frequently struggle to differentiate into hair
cells and neurons, rendering them functionally useless.[52] Organoids will help to solve this problem by delivering more differentiated ONP
and OEP into the target tissue. In experiments injecting human-derived OEPs into gerbil
cochlea, cells demonstrated migration, engraftment, and differentiation. Furthermore,
they were able to form synapses with sensory neurons. However, in this study, auditory
functioning post-transplant was not assessed.[53] While this is a very promising finding, further studies are warranted to explore
the regenerative potential of organoids, to increase the number of synaptic connections
within the SGN, and to evaluate the potential of providing functional benefits.
Conclusion and Future Directions
Conclusion and Future Directions
SNHL is a prevalent condition that causes significant morbidity for millions of individuals
around the world. There is currently no curative treatment for SNHL and the therapeutic
interventions available, including hearing amplification devices, cochlear implants,
and other implantable devices, are often expensive and inaccessible to a large proportion
of the population. For these reasons, the scientific community has been pushed to
explore stem cell therapy for the restoration of inner ear function. Many studies
and preclinical models have demonstrated the potential for stem cell therapy to address
the permanent hearing loss associated with SNHL, while simultaneously revealing the
large leaps the research community still needs to make. One area that must continue
to develop is the route and mode of delivery of stem cells to the inner ear. Studies
have revealed the difficulty of administering stem cells into the organ of Corti and
ensuring localization of the cells to damaged areas for engraftment.
The various types of stem cells also pose clinical challenges. ESCs have pluripotent
potential and demonstrate an ability to differentiate into otic sensory cells and
improve hearing function. Despite the success observed in preliminary studies that
utilized this cell type, stem cells derived from embryos pose technical and ethical
difficulties. Adult-derived stem cells are an attractive choice due to their relative
ease of collection and ability to be used by patients themselves for autologous transplant.
This advantage makes them more accessible, but due to their later state of differentiation,
they lack the same pluripotent potential as ESCs. IPSCs address the issue of potency
since adult stem cells can now be dedifferentiated into pluripotent cells and then
redifferentiated into specific otic sensory cells.
Despite these advancements, further research is necessary to characterize the differentiation
pathways involved in restoring inner ear hair cell function with stem cells. Wnt,
β-catenin, and Notch are established important signaling pathways in the generation
of hair cells, but the numerous cross-interactions and molecular interplay that are
also necessary have yet to be fully elucidated.[58] The development of organoids is an exciting opportunity to address many of the challenges
faced with traditional stem cell techniques. Organoid models closely recapitulate
the inner ear organization and cellular composition and therefore well suited for
the study of genetic defects associated with SNHL. Furthermore, organoids provide
a reliable model to test toxicity of drugs on otic sensory cells. Importantly, though
studies have shown minimal complications and side effects, stem cell therapy has the
potential to cause inflammatory reactions, including transplant rejection and tumorigenesis.
It is imperative that the safety of stem cell therapy is fully explored before clinical
use. Rapid technological advancements in the research hearing community make stem
cell technology and organoid cultures a promising future treatment modality for SNHL.
