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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Neurosci. Author manuscript; available in PMC 2013 April 10.
Published in final edited form as:
PMCID: PMC3525344

Regenerative Medicine for the Special Senses: Restoring the Inputs

Our senses connect our brains to the world: communicating with others depends on our auditory system, and navigating through space relies heavily on our visual system. And what would life be like without our sense of smell that mediates much of our ability to appreciate flavors of food and alert us to dangers in our environment? It is therefore not surprising that degenerative diseases of the special sense organs can have a devastating impact on the quality of life. Many of the conditions that lead to sensory impairment are age related and are therefore on the rise as the population ages. However, early-onset forms of sensory impairment can be even more devastating, since loss of sensory inputs during critical periods of development can lead to permanent disruptions in brain maturation. With the exception of the olfactory epithelium, the sensory cells of the special sensory organs are like most of the neurons in the brain: they are not replaced after they are lost to disease. Therefore, the loss of these cells leads to permanent sensory impairment. However, in recent years, many laboratories have focused the tools of regenerative medicine and gene therapy on diseases of sensory systems. In many ways, the special sensory organs provide highly amenable targets for regenerative approaches in the nervous system, due in part to their accessibility and the rigorous methods for characterization of functional restoration. The work in this field is already providing a “proving ground” for gene therapy and stem cell therapy with some of the first successful clinical trials. In this review, some of the key approaches will be discussed, and the successes high-lighted. In addition, we will review some of the critical challenges that lie ahead in the application of gene therapy and stem cell approaches to sensory organ disorders, with the hope of further stimulating research in this area. This article is not meant to be a comprehensive review of this area, but rather to highlight a Symposium at the Society for Neuroscience Annual Meeting (for a recent more thorough review, readers are referred to Bermingham-McDonogh and Reh, 2011).

Successful regeneration in the olfactory epithelium: implications for other sensory systems

The mammalian olfactory system is particularly susceptible to environmental insults, pathogenic exposure, and traumatic injury. In this sensory tissue, unlike hearing and vision, the primary sensory cells that transduce external stimuli, the olfactory sensory neurons (OSNs) directly contact the outside world and project axons directly into the CNS. Two important consequences of this organization have been recognized. First, OSNs, as well as other cells within the epithelial layer, have a remarkable ability to regenerate and establish new functional connectivity with the brain after extensive damage. Second, this inherent regenerative capacity appears tightly controlled, such that, under some modes of damage, proliferation is rapidly reinitiated to re-establish a normal epithelium. In contrast, lesions induced by other kinds of damage to the tissue result in prolonged proliferative suppression followed by subsequent regeneration. Recent studies have revealed new details of the molecular, genetic, and cellular basis for the initial establishment of the olfactory sensory epithelium and its robust regeneration upon damage.

The pseudostratified olfactory epithelium (OE) consists of four major cell types. The OSNs, residing in the middle layer of the OE, extend a short dendrite to the luminal surface terminating in the specialized cilia containing the odor transduction components and project a single unmyelinated axon through the cribriform bone and into the olfactory bulb at the front of the brain. Sustentacular cells reside in the most apical epithelial layer and provide barrier and support functions for the epithelium. The ability of the OE to undergo regeneration resides within a population of transit-amplifying and multipotent stem cells comprised of globose basal cells (GBCs) and horizontal basal cells (HBCs) that lie near the basal lamina.

Experimental lesioning paradigms have revealed two distinct mechanisms for neuronal replacement. Axotomy or removal of the olfactory bulb leads to rapid and selective loss of the OSNs, a proliferative burst of mash1+ GBCs, and the subsequent repopulation of the neuronal layer within 14 −30 d. In contrast, exposure of the OE to methyl bromide gas produces free radical damage from the apical surface and loss of sustentacular, neuronal, and globose cells. Cell fate mapping studies in adults suggest that the origin of the regenerated cells lies within the mash1+ population (or their immediate GBC precursors) in the first paradigm, and within the normally quiescent HBC population in the latter scenario (Leung et al., 2007). The HBCs pass through a brief proliferation phase that generates new GBCs and then become quiescent (Fletcher et al., 2011). Together, these observations suggest two distinct reservoirs of stem cells that differentially contribute to robust regeneration in the olfactory system.

Disease-induced inflammation from pathogens and other agents represents an additional insult that produces olfactory tissue damage and neuronal loss (Lane et al., 2010). In contrast to the situation in acute traumatic lesions when the progenitor proliferation occurs simultaneous with neuronal loss, persistent inflammation results in a depleted neuroepithelium as well as suppressed proliferation of progenitors. When the inflammation resolves, progenitors rapidly re-establish the epithelium. The molecular mechanisms controlling the cellular loss, maintenance of the depleted state, and subsequent neuronal repopulation are not known. It is interesting to speculate that the olfactory system has developed processes that promote rapid re-establishment of OSNs and their connections to the brain when the damage is traumatic, and transient other processes that suppress these connections when injury arises from pathogenic organisms that might use these pathways in gaining direct access from the outside world to the brain.

In summary, the regeneration of olfactory sensory neurons occurs continually throughout adult life, primarily from a pool of committed progenitors that also serve as the reservoir for replenishment after acute neuronal injury. Upon more significant damage, HBCs provide a quiescent stem cell population that re-establishes the progenitor pool and gives rise to both neuronal and non-neuronal populations. The origin of HBCs and GBCs during embryonic development is poorly understood but recent cell fate mapping studies in the embryo and analysis of genetic knock-out mice suggest that a common GBC-like cell may directly generate HBCs during embryonic development (Packard et al. 2011) and subsequently form the GBC population. The simplicity of the olfactory system has made it particularly amenable to modeling the dynamics and homeostasis of cell types in this tissue and to manipulating these pathways in the embryo (Gokoffski et al., 2011) and the adult (Beites et al., 2005). The identification and characterization of the molecules and cells that create and regulate the robust regenerative capacity of this tissue should provide insights that may unlock regenerative processes in the other sensory organs.

Inner ear cells from scratch: implications for regenerative medicine

The ~15,000 sensory hair cells of the human cochlea provide sound sensitivity that underlies our speech communication, and hair cells in five vestibular epithelia sense linear and angular accelerations triggering reflexes that are critical to gaze stability and balance. Unfortunately, loud sounds, infections, and certain antibiotics and chemotherapeutics can kill hair cells, causing sensory deficits that are widespread and permanent. The human ear does not produce hair cells after birth, but the situation is quite different in nonmammals. Fish, amphibians, and birds produce hair cells throughout life and recover sensory functions within weeks of experiencing the same forms of hair cell damage that cause permanent deficits in humans. Recovery in these species depends on glia-like epithelial supporting cells that produce replacement hair cells, which become innervated and restore sensory function. In birds, for example, the supporting cells of the cochlear sensory epithelia respond to hair cell loss with two types of regenerative processes: cell division and direct transdifferentiation (Cafaro et al., 2007). Asymmetric divisions are the signature mechanism of somatic stem cell activity, and they result in new hair cells with preservation of the supporting/stem cell pool. The process of transdifferentiation is the direct conversion of supporting cells into hair cells. Mammalian supporting cells, on the other hand, lose the ability to regenerate lost hair cells. Nevertheless, recent findings suggest that the mammalian inner ear bears rudimentary regenerative capacity. Some vestibular supporting cells of rodents proliferate in vitro, and in neonates the progeny of such cells are able to give rise to new hair cells (Li et al., 2003; Burns et al., 2012). Even cochlear supporting cells display regenerative capacity in vivo, but only during the first neonatal weeks (White et al., 2006; Oshima et al., 2007; Sinkkonen et al., 2011).

So what accounts for the failure of regeneration in mammals? Greater cellular differentiation may be the answer. At least five highly differentiated and specialized types of supporting cells are present in the precisely ordered architecture of the organ of Corti auditory epithelium. This organization is only found in the mammalian cochlea, making it a much more complex sensory epithelium that harbors more specialized cell types with unique cytomorphologies when compared with nonmammalian cochlea or vestibular organs. The degree of differentiation of the supporting cells and the important functional consequences of individual cell positions in the organ of Corti may present substantial challenges for efforts to stimulate the functional regeneration. For this reason, the mammalian balance epithelia may hold greater potential for regeneration research. While the vestibular organs of very young mice can regenerate new hair cells, the tissue rapidly loses this ability as it matures (Burns et al., 2012). The loss of hair cell regeneration in mice occurs contemporaneously with unique thickening of F-actin belts that bracket intercellular junctions in all epithelia, but which become so thick that they fill 89% of the average adult vestibular supporting cell at the level of its intercellular junction in mice (and apparently in humans as well; Burns et al., 2008). In contrast with this, the F-actin belts in the supporting cells of chickens, sharks, zebrafish, and bullfrogs remain thin even in adulthood, and all those species readily regenerate hair cells throughout life. The 13-fold thickening of F-actin belts as mice mature from E18 to adulthood is closely paralleled by declines in supporting cell spreading (r = −0.99) and cell proliferation near sites of wounding (r = −0.98). In contrast, the F-actin belts in the supporting cells of chickens, sharks, zebrafish, and bullfrogs remain thin even in adulthood, and all these species readily regenerate hair cells throughout life. Cadherin proteins that adhere supporting cells to their neighbors, also differ between intercellular junctions in the ears of humans and mice and those of sharks, bony fish, amphibians, and birds (Hackett et al., 2002; Warchol, 2007; Collado et al., 2011). These and other findings appear consistent with the notion that specialized characteristics of the mature mammalian inner ear may limit effective regeneration rather than the absence of essential molecular circuitry found in nonmammalian ears; however, alternative hypotheses deserve consideration since a definitive test for causation remains to be conducted. Also, there is a continuing need for greater understanding of how specific subcellular mechanisms may restrict regenerative responses in mammalian ears (Chen and Segil, 1999; Lin et al., 2011; Loponen et al., 2011).

Strategies to entice adult supporting cells to show regenerative capacity include the forced expression of developmentally important transcription factors such as Atoh1 (Shou et al., 2003), deactivation of cell cycle inhibitors (Chen and Segil, 1999; Löwenheim et al., 1999; Sage et al., 2005), or cellular reprogramming toward a phenotype equivalent to progenitor (prosensory) cells that transiently exist during development. Forced expression of Atoh1, for example, is sufficient to entice some inner ear cells, such as young supporting cells to transdifferentiate into hair cells, whereas many other cell types are not responsive to Atoh1 expression. This observation suggests that Atoh1-induced transdifferentiation requires a form of cellular competence. In addition, Atoh1 expression in competent cells such as adult supporting cells does not lead to cell division (Shou et al., 2003), although recent findings suggest that some neonatal supporting cells might respond to forced Atoh1 expression with S-phase re-entry (Kelly et al., 2012). This still poses a problem with respect to using this transcription factor for regenerative therapy in the adult because turning the limited number of remaining cells in the hair cell-depleted organ of Corti solely into hair cells will deplete supporting cells, which are essential for inner ear function. As an alternative to the introduction of a single transcription factor, cellular reprogramming has been put forward as a potential strategy to convert adult organ of Corti nonsensory cells into prosensory cells. Prosensory cells remain committed to the otic lineage, and the prevailing hypothesis is that they will differentiate into hair cells and supporting cells. Researchers are actively investigating the molecular pathways required for reactivation of regenerative programs in the damaged mammalian cochlea.

Finally, promising experiments with embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have used knowledge of the cellular signaling steps that are active when the inner ear forms during embryonic development (Oshima et al., 2010). For example, inhibition of endoderm and mesoderm formation during the process of ESC and iPSC differentiation results in an enrichment of ectodermal cells, which are competent to respond to otic inducers such as FGF2. The resulting early otic cells, generated from either murine or human sources, can be further differentiated into inner ear cell types. Cytohistological, cytomorphological, and functional analyses revealed that in vitro-generated epithelial patches of inner ear cells display characteristics of nascent inner ear hair cells as well as surrounding supporting cells. The ability to generate sensory hair cells in culture combined with iPSC technology provides an unprecedented opportunity to study the cellular phenotypes caused by inner ear disorders directly. For cases of hereditary human hearing loss, this might be done without generating animal models. Stem cell guidance technology can also be used to study inner ear developmental processes, which might lead to identification of signaling pathway combinations that could be used to stimulate regenerative processes in mammalian cochlear supporting cells. Since, cell-based assays can be scaled up for high-content screening approaches, it is also conceivable that stem cell-generated inner ear cell types can be used for drug discovery. Future screening technology could specifically be used to gain novel insights into ototoxicity, otoprotection, as well as regeneration of sensory hair cells and potential novel treatments.

Gene therapy for blindness: moving into the clinic

Stem cells and regenerative medicine are also beginning to show promise in the repair of the retina. Over the past 10 years, several groups have developed protocols for directing embryonic stem cells to form retinal cells in vitro (Lamba et al., 2006, 2009; Meyer et al., 2009), and in some cases these cells can even form organized retinal structures (Eiraku et al., 2011; Phillips et al., 2012). The ability to generate human retinal cells in large quantities has led to attempts to transplant these into animal models of retinal degenerations, and human ESC-derived photoreceptor cells have even been shown to restore light responses to congenitally blind mice. To date, the most success has been obtained with a non-neural cell in the retina, the pigmented epithelial cell. These cells form a layer adjacent to the rods and cones of the neural retina, and are important for the phagocytosis of the outer segment disc material from the photoreceptors. In age-related macular degeneration (AMD), a common cause of visual impairment in individuals over the age of 60 years, the pigmented epithelial cells become atrophic, particularly those underlying the fovea. One of the first clinical trials using human embryonic stem cell derivatives was initiated last year by advanced cell technology, in which pigmented epithelial cells derived from human ESCs were transplanted into the subretinal space to replace the atrophic pigmented epithelial cells in patients with AMD (Schwartz et al., 2012). An early report on this Phase I trial suggests that the cells have not caused any immediate problems, e.g., teratomas, but careful follow-up will be needed to determine whether the cells will survive and benefit the patient.

Investigations of stem cell repair of the retina are still in their infancy, but gene therapy for retinal disease has already produced breakthroughs. Most impressive have been the results in patients with Leber congenital amaurosis type 2 (LCA2). LCA2 causes childhood blindness due to a visual cycle defect in the Rpe65 gene responsible for isomerizing the bleached visual pigment all-trans-retinal back to its active 11-cis-form. LCA2 had been considered incurable. Preclinical efficacy and safety basis for LCA2 was established and an adeno-associated virus (AAV) vector clinical trial for LCA2 initiated ~4 years ago (Hauswirth et al. 2008). Each of the first three LCA2 patients received 150 μl (5.9 × 1010 vector genomes) of GMP grade AAV2-CBA-hRPE65 vector sub-retinally at a single site, and their visual function was followed periodically (Hauswirth et al., 2008; Cideciyan et al., 2009a). No adverse events were noted for any patient and all patients tolerated the procedure without incident. All three patients also exhibited substantial and significant improvement in light sensitivity, but only in the area of retina that received the vector, as documented by high-density threshold perimetry. After correcting for the fraction of photoreceptors lost in each patient before treatment, two of the three patients experienced full recovery of retinal function within the vector-treated area.

At 1 year post-treatment, but not before, one patient reported new visual perceptions that mapped to the treatment area (Cideciyan et al., 2009b). When asked to detect a very bright target that she could see before treatment, she continued to use her fovea, her only area of useable, although poor, vision. If, however, she was asked to detect a dimmer target that she could not detect at pretreatment baseline, she could not see it at any time up to 9 months post-treatment. However, at 12 months the patient reported seeing the dim object for the first time. When detecting this target, the patient now shifted her locus of visual perception away from her central fovea to the treated retinal area. In effect, the patient had developed a second fovea or “pseudo-fovea” that was used only when the target was too dim to be perceived by her anatomical fovea. Subsequently, five other treated patients have developed a pseudo-fovea after a significant delay. This slow emergence of a pseudo-fovea suggests that cortical “learning” is possible but slow in children or young adults.

A longer-term study (Jacobson et al., 2012) of all 15 patients currently treated (3 months to 3 years of follow-up) showed the following: (1) all patients gained in full-field light sensitivity from 10-fold to 10,000-fold; (2) all patients gained in local light sensitivity in the retinal region treated from 200-fold to 60,000-fold; (3) 13 of 15 patients gained in pupillary light reflex; (4) 5 of 6 patients gained in maze mobility performance; (5) 12 of 15 patients gained in visual acuity, with 4 of those patients gaining more than three lines; and (6) 6 of 15 patients have presently developed a pseudo-fovea at their retinal treatment locus.

What has not worked? Subfoveal vector delivery, which necessarily detaches the fovea from the underlying retinal pigment epithelium cell layer, seems to cause more damage than benefit for vision. Five of the 15 LCA2 patients received subfoveal vector, and 3 of those experienced loss of foveal cones. Of those 3 patients with foveal thinning, none experienced improvement in visual acuity, the only patients of the 15 whose visual acuity did not benefit.

We conclude that AAV-mediated gene therapy for LCA2 is safe, effective at restoring useful vision, and stable for at least 3.5 years. All patients gained significant vision benefit except those experiencing a foveal detachment during vector delivery. Moreover, vitreal injection of novel mutant AAV vectors that can nontraumatically deliver DNA to foveal cones is showing promise.


The degeneration of the special sensory systems is a growing societal problem, and there is an urgent need for advances in the treatment of these disorders. While there are ongoing efforts to intervene early in the course of sensory cell degeneration, millions of individuals continue to suffer sensory impairment; frequently, patients only seek treatment once a significant number of sensory cells are already lost. The developing fields of gene therapy and regenerative medicine are beginning to provide some hope for both slowing the sensory cell loss and potentially even for restoring the input function. Moreover, success in these approaches in the sensory receptor organs, where the effects of treatment can be more rigorously monitored, will likely aid other clinical neuroscientists in the design of similar studies in other less tractable regions of the nervous system. Neuronal degenerations are complex disorders, but perhaps the relative simplicity of the sensory receptor organs will make them more amenable to these promising new therapies.


This work was supported by NIH Grants R01DC005953, R01DC009991, and R21DC010862 to O.B.-M.; by NIH GrantsRO1DC004553andRO1DC008295toR.R.;byNIDCDGrantRO1-DC000200toJ.T.C.;byNIDCDGrantsDC006167 and DC012250 to S.H.; by NIH Grants 1R01EY021482 and RO1EY021374, and support by the Macula Vision Research Foundation (MVRF) and the Foundation Fighting Blindness (FFB) to T.A.R.; and by NIH Grant P30EY021721, and support by the MVRF, FFB, Elden Family Foundation, Vision for Children, and Research to Prevent Blindness to W.W.H.


W.W.H. and the University of Florida have a financial interest in the use of AAV therapies and own equity in a company (AGTC Inc.) that might, in the future, commercialize some aspects of this work.


  • Beites CL, Kawauchi S, Crocker CE, Calof AL. Identification and molecular regulation of neural stem cells in the olfactory epithelium. Exp Cell Res. 2005;306:309–316. CrossRef Medline. [PubMed]
  • Bermingham-McDonogh O, Reh TA. Regulated reprogramming in the regeneration of sensory receptor cells. Neuron. 2011;71:389–405. CrossRef Medline. [PubMed]
  • Burns JC, Cox BC, Thiede BR, Zuo J, Corwin JT. In vivo proliferative regeneration of balance hair cells in newborn mice. J Neurosci. 2012;32:6570–6577. [PMC free article] [PubMed]
  • Burns JC, Christophel JJ, Collado MS, Magnus C, Carfrae M, Corwin JT. Reinforcement of cell junctions correlates with the absence of hair cell regeneration in mammals and its occurrence in birds. J Comp Neurol. 2008;511:396–414. CrossRef Medline. [PMC free article] [PubMed]
  • Cafaro J, Lee GS, Stone JS. Atoh1 expression defines activated progenitors and differentiating hair cells during avian hair cell regeneration. Dev Dyn. 2007;236:156–170. CrossRef Medline. [PubMed]
  • Chen P, Segil N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development. 1999;126:1581–1590. Medline. [PubMed]
  • Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EA, Conlon TJ, Sumaroka A, Pang JJ, Roman AJ, Byrne BJ, Jacobson SG. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at one year. Hum Gene Ther. 2009a;20:999–1004. CrossRef Medline. [PMC free article] [PubMed]
  • Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EAM, Conlon TJ, Sumaroka A, Roman AJ, Byrne BJ, Jacobson SJ. Vision one year after gene therapy for Leber congenital amaurosis. N Engl J Med. 2009b;361:725–727. CrossRef Medline. [PMC free article] [PubMed]
  • Collado MS, Thiede BR, Baker W, Askew C, Igbani LM, Corwin JT. The postnatal accumulation of junctional E-cadherin is inversely correlated with the capacity for supporting cells to convert directly into sensory hair cells in mammalian balance organs. J Neurosci. 2011;31:11855–11866. CrossRef Medline. [PMC free article] [PubMed]
  • Eiraku M, Sasai Y. Mouse embryonic stem cell culture for generation of three-dimensional retinal and cortical tissues. Nat Protoc. 2011;7:69–79. CrossRef Medline. [PubMed]
  • Fletcher RB, Prasol MS, Estrada J, Baudhuin A, Vranizan K, Choi YG, Ngai J. p63 regulates olfactory stem cell self-renewal and differentiation. Neuron. 2011;72:748–759. CrossRef Medline. [PMC free article] [PubMed]
  • Gokoffski KK, Wu HH, Beites CL, Kim J, Kim EJ, Matzuk MM, Johnson JE, Lander AD, Calof AL. Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate. Development. 2011;138:4131–4142. CrossRef Medline. [PubMed]
  • Hackett L, Davies D, Helyer R, Kennedy H, Kros C, Lawlor P, Rivolta MN, Holley M. E-cadherin and the differentiation of mammalian vestibular hair cells. Exp Cell Res. 2002;278:19–30. CrossRef Medline. [PubMed]
  • Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19:979–990. CrossRef Medline. [PMC free article] [PubMed]
  • Jacobson SG, Cideciyan AV, Ratnakaram R, Heon E, Schwartz SB, Roman AJ, Peden MC, Aleman TS, Boye SL, Sumaroka A, Conlon TJ, Calcedo R, Pang JJ, Erger KE, Olivares MB, Mullins CL, Swider M, Kaushal S, Feuer WJ, Iannaccone A, et al. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in fifteen children and adults followed up to three years. Arch Ophthalmol. 2012;130:9–24. CrossRef Medline. [PMC free article] [PubMed]
  • Kelly MC, Chang Q, Pan A, Lin X, Chen P. Atoh1 directs the formation of sensory mosaics and induces cell proliferation in the postnatal mammalian cochlea in vivo. J Neurosci. 2012;32:6699–6710. CrossRef Medline. [PMC free article] [PubMed]
  • Lamba DA, Karl MO, Ware CB, Reh TA. Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A. 2006;103:12769–12774. CrossRef Medline. [PubMed]
  • Lamba DA, Gust J, Reh TA. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crxdeficient mice. Cell Stem Cell. 2009;4:73–79. CrossRef Medline. [PMC free article] [PubMed]
  • Lane AP, Turner J, May L, Reed R. A genetic model of chronic rhinosinusitis-associated olfactory inflammation reveals reversible functional impairment and dramatic neuroepithelial reorganization. J Neurosci. 2010;30:2324–2329. CrossRef Medline. [PMC free article] [PubMed]
  • Leung CT, Coulombe PA, Reed RR. Contribution of olfactory neural stem cells to tissue maintenance and regeneration. Nat Neurosci. 2007;10:720–726. CrossRef Medline. [PubMed]
  • Li H, Liu H, Heller S. Pluripotent stem cells from the adult mouse inner ear. Nat Med. 2003;9:1293–1299. CrossRef Medline. [PubMed]
  • Lin V, Golub JS, Nguyen TB, Hume CR, Oesterle EC, Stone JS. Inhibition of notch activity promotes nonmitotic regeneration of hair cells in the adult mouse utricles. J Neurosci. 2011;31:15329–15339. CrossRef Medline. [PMC free article] [PubMed]
  • Loponen H, Ylikoski J, Albrecht JH, Pirvola U. Restrictions in cell cycle progression of adult vestibular supporting cells in response to ectopic cyclin d1 expression. PloS One. 2011;6:e27360. CrossRef Medline. [PMC free article] [PubMed]
  • Löwenheim H, Furness DN, Kil J, Zinn C, Gültig K, Fero ML, Frost D, Gummer AW, Roberts JM, Rubel EW, Hackney CM, Zenner HP. Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of Corti. Proc Natl Acad Sci U S A. 1999;96:4084–4088. CrossRef Medline. [PubMed]
  • Meyer JS, Shearer RL, Capowski EE, Wright LS, Wallace KA, McMillan EL, Zhang SC, Gamm DM. Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2009;106:16698–16703. CrossRef Medline. [PubMed]
  • Oshima K, Grimm CM, Corrales CE, Senn P, Martinez Monedero R, Géléoc GS, Edge A, Holt JR, Heller S. Differential distribution of stem cells in the auditory and vestibular organs of the inner ear. J Assoc Res Otolaryngol. 2007;8:18–31. CrossRef Medline. [PMC free article] [PubMed]
  • Oshima K, Shin K, Diensthuber M, Peng AW, Ricci AJ, Heller S. Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell. 2010;141:704–716. CrossRef Medline. [PMC free article] [PubMed]
  • Packard A, Schnittke N, Romano RA, Sinha S, Schwob JE. ΔNp63 regulates stem cell dynamics in the mammalian olfactory epithelium. J Neurosci. 2011;31:8748–8759. CrossRef Medline. [PMC free article] [PubMed]
  • Phillips MJ, Wallace KA, Dickerson SJ, Miller MJ, Verhoeven AD, Martin JM, Wright LS, Shen W, Capowski EE, Percin EF, Perez ET, Zhong X, Canto-Soler MV, Gamm DM. Blood-derived human iPS cells generate optic vesicle-like structures with the capacity to form retinal laminae and develop synapses. Invest Ophthalmol Vis Sci. 2012;53:2007–2019. CrossRef Medline. [PMC free article] [PubMed]
  • Sage C, Huang M, Karimi K, Gutierrez G, Vollrath MA, Zhang DS, García-Añoveros J, Hinds PW, Corwin JT, Corey DP, Chen ZY. Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein. Science. 2005;307:1114–1118. CrossRef Medline. [PubMed]
  • Schwartz SD, Hubschman JP, Heilwell G, Franco-Cardenas V, Pan CK, Ostrick RM, Mickunas E, Gay R, Klimanskaya I, Lanza R. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379:713–720. CrossRef Medline. [PubMed]
  • Shou J, Zheng JL, Gao WQ. Robust generation of new hair cells in the mature mammalian inner ear by adenoviral expression of Hath1. Mol Cell Neurosci. 2003;23:169–179. CrossRef Medline. [PubMed]
  • Sinkkonen ST, Chai R, Jan TA, Hartman BH, Laske RD, Gahlen F, Sinkkonen W, Cheng AG, Oshima K, Heller S. Intrinsic regenerative potential of murine cochlear supporting cells. Sci Rep. 2011;1:26. CrossRef Medline. [PMC free article] [PubMed]
  • Warchol ME. Characterization of supporting cell phenotype in the avian inner ear: implications for sensory regeneration. Hear Res. 2007;227:11–18. CrossRef Medline. [PubMed]
  • White PM, Doetzlhofer A, Lee YS, Groves AK, Segil N. Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature. 2006;441:984–987. CrossRef Medline. [PubMed]