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Genetics, Auditory and Vestibular Disorders
Korean Journal of Audiology 2010;14(3):163-172.
The Past, Present and Future of Cochlear Stem Cell Research: We Have No Conclusion But Now We Have Hope
Dong-Hee Lee
Department of Otolaryngology-Head Neck Surgery, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbu, Korea
The Past, Present and Future of Cochlear Stem Cell Research: We Have No Conclusion But Now We Have Hope
Dong-Hee Lee
Department of Otolaryngology-Head Neck Surgery, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbu, Korea
Abstract

Millions of patients sufferfrom hearing loss worldwide, caused by damage of sensory hair cells and consequent degeneration of the auditory nerve in the cochlea. The underlying reasons for hair cell loss are highly diverse, ranging from genetic disposition, drug side effects, noise exposure, and inflammation to the aging process. Nowadays, hearing aids, as well as cochlear implants, can help resolve hearing loss. Hearing aids amplify sound and require intact inner hair cells. Cochlear implants directly stimulate the auditory nerve fibers and can be helpful for patients with damaged outer and inner hair cells. Despite their successes, hearing aids and cochlear implants are not perfect. Recent scientific achievements in cochlear regenerative medicine promise more complete solutions to patients with hearing loss and their families. Until recently, it has been assumed that mammalian cochlear hair cells can never be replaced or regenerated, such that cumulative damage to the cochlea causes progressive and permanent deafness. However, non-mammalian vertebrates are capable of replacing lost hair cells, which has recently led to efforts to understand the molecular and cellular basis of regenerative responses in different vertebrate species with the eventual goal of human cochlear regeneration. In this review, I survey progress in understanding the limits to mammalian cochlear hair cell regeneration and recent efforts in cochlear regenerative medicine.

Keywords: Stem cell;Otic progenitor cell;Hair cell;Supporting cell;Cochlea;Regenerative medicine;Hearing loss.

Address for correspondence : Dong-Hee Lee, MD, PhD, Department of Otolaryngology-Head and Neck Surgery, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, 65-1 Geumo-dong, Uijeongbu 480-717, Korea
Tel : +82-31-820-3564, Fax : +82-31-847-0038, E-mail : leedh0814@catholic.ac.kr

Introduction


Verbal communication is one of the attributes that makes us uniquely human. So hearing impairment makes us to be isolated socially in a human world. Hearing impairment is one of the most common disabilities in the world. A large population of human race with hearing impairment lives largely untreated, with as few as 20% of people who might benefit from hearing aids actually wearing one.1) Hearing aids are just a tool for rehabilitation, not for treatment of hearing loss and people with profound hearing loss cannot get any benefit from it. Although cochlear and auditory brainstem implants can provide immense benefit to the profoundly deaf, they needs much cost and are not indicated currently for the people with mild to moderate hearing impairment. That is why we need another treatment strategy option.
Sensorineural hearing loss-which includes the loss of sensory hair cells in the organ of Corti-accounts for a significant proportion of all hearing impairment and it is incurable until now. Of all the cochlear structures and cell types, the sensory hair cells, fewer than 15,000 at birth, are the Achilles' heel of the auditory system. Generally, outer hair cells are more sensitive than inner hair cells to the insults that damage hearing and to the aging effect. After hair cell loss, the organ of Corti undergoes gradual cytomorphological dedifferentiation of supporting cells.2,3,4)
Regeneration of cochlear hair cells is considered the ultimate remedy for sensorineural hearing loss. However, just regeneration of cochlear hair cells is not the end of our journey to the cochlear stem cell therapy because a simple replacement of a single cell type is a remarkably complex endeavor and that is not all in the cochlea. We should consider the very different functions of inner and outer hair cells, as well as their precise integration together with several supporting cells into complex structures. Consequently, the cochlear stem cell therapy cannot be viewed as simply seeding new hair cells, replacing or regenerating some hair cells and getting them connected to the afferent auditory nerve.
I divide this literature review into four parts: in the first part, I summarize the cell fate in the mammalian cochlea. In the second part, I introduce the discovery of cochear stem cell or otic progenitor cell in avian and mammalian cochleae. In the third part, I discuss current basic research in cochlear stem cell and inner ear cell regeneration. In the last part, I focus on therapeutic approaches and roadblocks, including delivery of stem cells, genes and small compounds.

Summary of cell fate in the mammalian cochlea

Specification of prosensory cells (Fig. 1)
Otocyst-derived cells develop into three major lineages, prosensory (cells that will develop as either hair cells or associated supporting cells), proneural (cells that will develop as auditory or vestibular neurons) and nonsensory (all other otocyst derived cells) with cells within each lineage developing in topologically and temporally defined domains of the otocyst. Jagged1, Lfng and Bmp4 are expressed in prosensory patches and Jagged1-dependent Notch activation has a role to the specification of prosensory identity and subsequent formation of sensory patches. Sox2, Eya and Hedgehog have been implicated as another regulator of prosensory fate.5,6,7)

Specification of hair and supporting cells (Fig. 2)
Once formed, prosensory cells develop as either hair cells or supporting cells as a result of cross-regulation between factors that either promote hair cell fate, in particular Atoh1, and factors that act to prevent hair cell formation through antagonism of Atoh1, such as Sox2 and Prox1.5,6,7)
Atoh1 expression is dependent on the presence of a prosensory cell population. Sox2 antagonizes directly the ability of Atoh1 to induce a hair cell fate and conversely, Atoh1 downregulates sufficiently Sox2. Overexpression of Prox1, the Sox2 target gene, also inhibits Atoh1 activity. Although expression of Sox2 is initially required for the establishment of prosensory identity, continued expression of Sox2 essentially acts to inhibit hair cell formation, suggesting that subsequent downregulation of Sox2 is required for normal sensory development. In addition, fibroblast growth factor (Fgf) signaling pathway has been shown to be important for inner ear development in most vertebrates. In addition to essential roles in early otic induction and morphogenesis, Fgf receptor1 (Fgfr1) is required for the formation of both hair cells and supporting cells within the cochlea.5,6,7)
While considerable progress has been made in the identification of factors that specify a hair cell fate, the specification of supporting cells is poorly understood. Although a focus on hair cells as the chief element of organ of Corti has contributed to the limited work on supporting cells, a greater impediment has been the lack of definitive markers for specific supporting cell types. Hair cells are known to induce supporting cells, but in general, the specific mediators of this process have not been identified. One exception is the specification of pillar cells, which is the unique cell type that only present in mammalian cochlear sensory epithelia and of which development is regulated through fibroblast growth factor receptor 3 (Fgfr3) and hairy/enhancer-of-split related with YRPW motif 2 (Hey2). Beginning at approximately E16.5, Fgfr3 is up-regulated in a population of progenitor cells that develop as pillar cells, outer hair cells, and Deiters cells.5,6,7)

Discovery of cochear stem cell or progenitor cell in avian and mammalian cochleae

Discovery of regeneration from damaged cochlea; lessons from birds, frogs and fish
Although cells in some organs are constantly replenished throughout lifetime and cell in other organs are capable of regeneration following injury, the inner ear is stubbornly refractory to damage, with no hair cell replacement or proliferation occurring in the cochlea,8,9,10) although only a very modest amount of proliferation and very little hair cell replacement are seen in the vestibular system.9,11,12) 
Starting in the early 1980s, it became clear that the cochlea of non-mammalian vertebrates have the capacity to generate new hair cells after the birth and to replace dead hair cells after damage to sensory epithelium. Both fish and amphibians were discovered to add new hair cells to their lateral line organs or vestibular organs as part of their ongoing growth.13,14,15) Ongoing replacement of vestibular hair cells was also observed in birds,16,17) that also have the ability to regenerate both auditory and vestibular hair cells after damage,18,19,20,21) leading to significant functional recovery.22) Corwin and Cotanche, independently, reported that regenerated hair cells originate from mitotic divisions of supporting cells or some unidentified latent stem cells.20,23) Ryals and Rubel reported that the regenerative potential is retained in adult animals, suggesting that a dormant stem cell population is retained but inactive state throughout life.19)
The mechanisms of avian hair cell regeneration have recently been reviewed by Stone and Cotanche in detail (Fig. 3).24) Initially, supporting cells appear to transdifferentiate directly into hair cells in the absence of any cell division (direct transdifferentiation). After 3-4 days, some supporting cells begin to re-enter the cell cycle and give rise to both hair cells and supporting cells after division (asymmetric division). It is not clear whether all avian supporting cells or a smaller subpopulation with stem cell-like characteristics has the capacity to divide and differentiate into hair cells. Unlike hair cells, whose cell bodies are confined to the luminal region of the sensory epithelium, most supporting cells have elongated cell bodies that appear to contact both the lumenal and basal surfaces of the epithelium. When quiescent, the nuclei of supporting cells are typically located basal to those of hair cells. After the damage of hair cells, some supporting cells display behaviors characteristic of stem/progenitor cells through asymmetric division, while others resemble precursor cells, forming new hair cells through direct transdifferentiation. Quantitative analyses after ototoxic damage of hair cells demonstrate that approximately 1/4 of supporting cells divide, 1/4 of supporting cells transdifferentiate and 1/2 of supporting cells exhibit neither response.25) 
Still we do not know how individual supporting cells are instructed to select each response. It is possible that only a portion of supporting cells may be restricted to behave only as stem/progenitor cells poised for transdifferentiation. Or it is also possible that all supporting cells may have equivalent potential to be stem/progenitor cells, but subpopulations respond in a given manner due to locally regulated signals.

Discovery of regeneration from damaged cochlea in mammals
Why is the capacity for hair cell regeneration absent in mammals but present in other non-mammalian vertebrates? During a long, long time of the evolution in mammal species, specialization of the organ of Corti for high-frequency hearing led to a reduction in hair cell numbers, an elaboration of cochlear supporting cells into morphologically distinct subtypes and an increase in the mechanical sensitivity of the basilar membrane.26) It is likely that these evolutionary changes lead to the stereotyped arrangement of inner and outer hair cells and to the specialization of supporting cells. However, these evolutionary changes restricted the ability of supporting cells to divide and transdifferentiate after hair cell loss. Ancestors in the mammal species exchanged the ability to repair the damaged cochlea with the highly-efficient specialization for high-freq hearing.
Anyway, non-mammalian vertebrate hair cell regeneration reveals the existence of inner ear stem cells and shows the possibility of mammalian cochlear stem cell. In 1993, it was reported that hair cell regeneration in response to aminoglycoside ototoxicity occurs in the vestibular sensory epithelia of adult mammals.27,28) In mammalian vestibule, hair cell regeneration seems to originate from supporting cells that reenter the cell cycle when neighboring hair cells are dying and mitotic supporting cells seems to divide asymmetrically, generating new hair cells and supporting cells. In some instances, a phenotypic conversion also described as transdifferentiation into hair cells has also been observed. Actually, it was not surprising that the mammalian vestibular system has cells with stem cell features, because vestibular sensory epithelia have regenerative capacity.29,30)
Recent experiments finally revealed that neonatal cochlear supporting cells feature proliferative potential and the ability to generate cells expressing hair cell markers in vitro. Stem/progenitor cells for hair cells are present in the mature mammalian cochlea, but their recruitment for transdifferentiation into hair cells does not occur spontaneously after hair cell loss in vivo. Newly formed hair cells can potentially arise from stem/progenitor cells in the greater epithelial ridge (GER) and/or the lesser epithelial ridge (LER) of mouse organ of Corti.10) Two studies found that this proliferative potential is lost between the second and third week after birth in mice.10,31) Cells can be mechanically dissociated from the organ of Corti of newborn rats and cultured in suspension in the presence of epidermal growth factor (EGF) and/or fibroblast growth factor 2 (FGF2). Under these conditions, some of them proliferate and form floating colonies. Some of the dividing cells among them retain the ability to differentiate into supporting cells or hair cells. The most recent study made by Oshima and Stefan presented a stepwise guidance protocol starting with mouse embryonic stem (ESCs) and induced pluripotent stem cells (iPSCs) and producing the hair cell-like cells with mechanosensitive stereociliary bundles (Table 1).32)
Although it is has been reported that mammalian cochlea has cells with the stem cell capacity even in adult, we still do not know that the identity of the specific type (s) of supporting cell that have sphere-forming capacity. 

Current basic research in cochlear stem cell and inner ear cell regeneration

Control of the cell cycle in the cochlea; p27 in supporting cell and p19, p21, Rb in hair cell
A variety of mechanisms prevent mature cochlear cells from entrance into cell cycle and maintain the postmitotic state of the organ of Corti in the adult animal.33,34,35) The embryonic precursor of the organ of Corti exits from cell cycle between E12 and E13 in mice.17,36) At this time, cells in the mid-basal region of the cochlea begin to express the first markers of differentiating hair cells, such as the transcription factor Atoh1.37,38,39,40) The wave of prosensorycell cycle exit coincides with the expression of the cyclin-dependent kinase inhibitor p27Kip1.17,36,41)
In p27-knockout mice, apical-basal wave of cell cycle exit fails to occur and otic progenitors of organ of Corti continue to proliferate for longer than normal until they are driven out of the cell cycle by the basal-apical wave of differentiation. This leads to supernumerary numbers of hair cells and supporting cells, most prominently in the apical region of the cochlea. The p27 expresses strongly in supporting cells as it differentiates, but appears to be down-regulated in differentiating hair cells.17) Recent study showed that culture of dissociated purified neonatal mouse cochlear supporting cells is associated with a rapid down-regulation of p27 protein and mRNA and cell cycle re-entry. Some of these supporting cells are also able to transdifferentiate into hair cells either after division or by direct transdifferentiation. However, mouse supporting cells can no longer down-regulate p27 or divide by the time mice are able to hear at two weeks after birth.10)
Unlike supporting cells, hair cells express a different cyclin-dependent kinase inhibitor, p19Ink4d, as they differentiate. The organ of Corti of p19 mutant mice develops normally, but shows hair cell loss beginning 17 days after birth. The p19 seems to make hair cells re-enter into the cell cycle and then them die by programmed cell death.42)
Another class of cell cycle regulators is p21Cip1 and Rb (retinoblastoma) genes. The mutation of p21 together with p19 causes significant hair cell death and aberrant cell cycle re-entry.43) Deletion of the Rb gene in mice causes a significant loss of the postmitotic hair cells and aberrant proliferation.44,45,46,47) Both p19 and Rb are expressed in hair cells but not in supporting cells in the organ of Corti.

Control of hair cell differentiation in the inner ear; Atoh1 and Notch (Fig. 4)
The first sign of hair cell differentiation in the cochlea is the expression of the basic helix-loop-helix transcription factor Atoh1 (also known as Math1) in the prosensory precursor to the organ of Corti, starting at embryonic day 14 in mice.37,38,39,40) Atoh1 is expressed in the prosensory patches that give rise to the auditory and vestibular sensory epithelia. Atoh1 is down-regulated in hair cells as they mature, indicating it is primarily a regulator of hair cell differentiation.37) It has been suggested that Atoh1 could be employed in the regeneration of hair cells after damage by helping to recapitulate the early events of hair cell development and several studies have presented some evidences. Atoh1 knockout mice completely lack hair cells in both the auditory and vestibular parts of the ear.37,38) Ectopic expression of Atoh1 in non-sensory regions of the cochlea such as the future inner sulcus either in organ culture or in the intact animal leads to the formation of ectopic hair cells that are capable of attracting spiral ganglion innervation.11,48,49) More recently, in utero electroporation of Atoh1 into the embryonic day 11 mouse ear primordium was shown to generate large numbers of ectopic hair cells in the cochlea, that have somewhat electrophysiological features of normal hair cells.50) Another study used adenoviruses to express Atoh1 in the organ of Corti of mature guinea-pigs that had been deafened by administration of ototoxic drugs. Some animals in this study showed significant recovery of hair cells and somewhat normal hair cell patterning, together with some improvement in auditory brainstem responses after 8-10 weeks.11) 
Adenoviral-mediated expression of Atoh1 can promote formation of new hair cells in drug-damaged vestibular organ cultures and in experimentally damaged animals.51,52)
Atoh1 probably generates hair cells by the transdifferentiation of supporting cells. It seems that many of the cells infected with Atoh1 adenovirus were supporting cells but the source of new hair cells generated by Atoh1 treatment was not identified because of the lack of good markers to distinguish supporting cells from otic progenitors.
The second signal to suppress hair cell fate in the supporting cell neighbors is Notch signaling pathway.33,34) During development, Notch receptor activation suppresses hair cell differentiation by means of upregulating Hes and Hey genes, which are potent inhibitors of Atoh1. Lewis proposed that cells that produces more Notch ligands directs its neighboring cells to produce less Notch ligands (lateral inhibition), and that this enables the signaling cell to increase its ligand production even further. This lateral inhibition feedback loop tends to drive neighboring cells into different developmental pathways and is frequently used to generate fine-grained, salt-and-pepper arrangements of cells such as the stereotyped mosaic of hair cells and supporting cells. He also proposed that Notch-mediated lateral inhibition might suppress hair cell fate in differentiating supporting cells.53,54) Further experiments have supported this proposal as follows. First, embryonic supporting cells express Notch1 and Notch3 receptors, while differentiating hair cells express two Notch ligands, Delta1 and Jagged2.15,55,56,57,58) Second, supporting cells express Hes and Hey downstream Notch effectors.59,60,61,62,63) Third, Hes and Hey downstream Notch effectors have been shown to repress transcription of Atoh1 in embryonic cochlear tissue and can prevent the hair cell-promoting effect of Atoh1 when co-expressed in inner sulcus tissue.59,62) Fourth, supernumerary hair cells are produced after genetic inactivation of Notch signaling in mice by deletion of Notch ligands such as Delta1 and Jagged2.55,64,65) Fifth, pharmacological inactivation of Notch signaling can also up-regulate Atoh1 and produce supernumerary hair cells at the expense of supporting cells.13,14,59,60) Finally, Notch ligands such as Delta1 are up-regulated during the early steps of hair cell regeneration in birds.66)
Although the role of Notch signaling in hair cell and supporting cell fate during cochlear embryonic development, it is not clear whether the Notch signaling pathway is still active in the mature organ of Corti.

Therapeutic approaches including delivery of stem cells, genes and small compounds

Stem cells therapy for hearing loss
Several laboratories have begun to explore the techniques and approach for the implantation of stem cell-derived progenitor cells into the damaged cochlea. Now we can harvest stem cell and make stem cell-derived progenitor cells.32) To find out how to delivery these cells into the cochlea is one of the important steps in the field of stem cell therapy. 
However, several technical and conceptual issues are addressed in this point.67) First, it is unclear how transplanted cells would be able to reach the whole length of the cochlear duct. Second, the scala media, one of the potential target compartments, is filled with an extracellular solution rich in K+, providing a challenging environment for transplanted cells. It may be toxic or harmful for transplanted cells. Third, integration of cells into the damaged organ of Corti requires breaking the tight junctions of reticular lamina at the apical side of organ of Corti. Fourth, the transplanted cells must be able to efficiently home in within the organ of Corti. Fifth, after successful transplantation of progenitor cells, the signaling pathways to direct differentiation into the correct hair cell types with correct hair bundle orientation would have to be active in the damaged adult organ of Corti. Finally, even replacement of the damaged organ of Corti might not be sufficient because of the potential lack of support structures such as the tunnel of Corti or matching with the tectorial membrane. This is exemplified by the significantly reduced hearing seen in p27 mutant mice, where supernumerary, misaligned hair cells and supporting cells likely change the extreme mechanical and morphological specialization of the cochlea.17,41,68)

Delivery of cells, genes and modulators of gene expression into the cochlea; pharmacotherapeutics (Table 2, 3, 4)
Stem or otic progenitor cells, genes and modulators of gene expression can be used for the therapeutic tools for a hearing loss in the future. The manipulation of these therapeutic agents and task of defining its atraumatic delivery are ones of the effective therapies to the inner ear disease including a hearing loss.
Because the cochlea should maintain constant ionic conditions of endo- and perilymph that is essential for mechanoelectrical transduction, physical entry into the membranous labyrinth to deliver the therapeutic agents to the organ of Corti must not permanently compromise this delicate ionic homeostasis. General safety considerations, such as prevention of tumor formation and graft-versus-host disease should be considered. 
In addition, viral vectors used for gene delivery are highly variable according to the cell types that they infect, the size of promoter and coding region that they can accommodate, and their potential to trigger an undesirable immune response. At present, there is no ideal vector system and delivery method for therapeutic, exogenous gene transfer to the inner ear.

Conclusion

Much progress has been made in recent years to accumulate tools that potentially can be used, alone or in combination, to develop the strategies for hair cell regeneration. Many researchers have studied transplantation of stem/progenitor cells, viral gene delivery, and administration of cell cycle inhibitors (p27Kip1, retinoblastoma, or other cyclin-dependent kinase inhibitors), Atoh1-activating compounds and Notch inactivator (γ-secretase inhibitor). At the same time, the ongoing accumulation of the knowledge about the organ of Corti will present new vision for cochlear hair cell regeneration.
The publicity of stem cells and gene therapy and recent scientific achievements in cochlear regenerative medicine have generated an emerging spirit of optimism among patients. We should be encouraged to put us in the position of a hearing impaired patients or their family. We can list the main directions of current stem cell research aimed to cure a hearing loss but we should understand the limitations of current stem cell research and regenerative medicine. It is important for patients as well as clinicians to discriminate between advancing science and publicly announcing potential ''breakthroughs'' for treatment method. As a result, mass media can make patients utterly confused and they are often unable to discriminate between valid and absurd treatment options.
We should review these roadblocks systematically before it will be judged whether mammalian cochlear hair cell regeneration will become a practical treatment option. As scientists, clinicians or otologic surgeons, we should develop appropriate devices and methods that will allow progenitor cells, gene therapy vectors and drug candidates to deliver to the appropriate locations inside the cochlea.
I hope that this review can be helpful for the understanding of recent advances in the field of cochlear stem cell therapy.


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