Regulated Reprogramming in the Regeneration
of Sensory Receptor Cells
Olivia Bermingham-McDonogh1,* and Thomas A. Reh1,*
1Department of Biological Structure, Institute for Stem Cells and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA
*Correspondence: email@example.com (O.B.-M.), firstname.lastname@example.org (T.A.R.)
Vision, olfaction, hearing, and balance are mediated by receptors that reside in specialized sensory epithelial
organs. Age-related degeneration of the photoreceptors in the retina and the hair cells in the cochlea, caused
many nonmammalian vertebrates, these sensory epithelia show remarkable regenerative potential. We
summarize the current state of knowledge of regeneration in the specialized sense organs in both nonmam-
malian vertebrates and mammals and discuss possible areas where new advances in regenerative medicine
might provide approaches to successfully stimulate sensory receptor cell regeneration. The field of regener-
ative medicine isstill inits infancy, butnew approaches usingstem cells and reprogrammingsuggest ways in
which the potential for regeneration may be restored in individuals suffering from sensory loss.
Our special senses, vision, olfaction, taste, hearing, and balance
are mediated by receptors that reside in specialized epithelial
organs. To best capture the physical stimuli required for their
function these receptors are ‘‘exposed’’ to the environment
and subject to excesses in the very stimuli they are optimized
to detect. Olfactory receptor cells have an average lifetime of
a few months. Excessive noise leads to the degeneration of
auditory hair cells; constant high levels of illumination can cause
retinal photoreceptor loss. In addition, sensory receptor cells
have many specialized proteins that are not present in other
tissues; mutations in the genes coding for these proteins are
often not lethal due to their very specific expression but can
cause sensory receptor degeneration, leading to devastating
syndromes in humans. Individuals with Usher’s syndrome, for
example, in which both the photoreceptors in the retina and
the hair cells in the cochlea degenerate, ultimately become
both blind and deaf. While thankfully these disorders are rare,
more common degenerative disorders of the retina and cochlea,
such as macular degeneration and most acquired sensorineural
viduals as the aged human population increases. It is estimated
that over 50% of the individuals over 60 have significant hearing
and at least some part of this decline may be related to a re-
duction in receptor neurons; estimates of olfactory impairment
range from 50% to 75% of people over the age of 65 (Doty
et al., 1984). Although there are focused efforts in medical and
gene therapy to treat these conditions and slow the degenera-
tion of sensory receptor cells, there are many millions of individ-
uals with varying degrees of impairment already. Moreover,
of the sensory receptors have already degenerated. For these
patients, prosthetic devices or regenerative medical approaches
may be the only options.
What hope have we for stimulating the functional regeneration
of sensory epithelial receptor cells in the human retina and inner
ear? The field of regenerative medicine is still in its infancy, but it
is rapidly developing. New approaches using stem cells and
reprogramming have provided insights into the plasticity of cell
identity, suggesting new ways in which the potential for regener-
ation may be restored. Moreover, although sensory receptor
cells in the mammalian retina and inner ear show only limited
or no regeneration, in many nonmammalian vertebrates, these
sensory epithelia show remarkable regenerative potential. In
newts, for example, most parts of the eye regenerate. In birds,
the sensory receptors in the auditory and vestibular (balance)
organs regenerate almost completely after various types of
injury. In this review, we will summarize the current state of
knowledge for regeneration in the specialized sense organs in
both nonmammalian vertebrates and mammals and discuss
possible areas where new advances in regenerative medicine
might provide approaches to successfully stimulate sensory
receptor cell regeneration in patients.
Functional and Structural Features of Sensory Epithelia
for their regeneration are the olfactory epithelium, the auditory
and vestibular epithelia of the inner ear, and the retina of the
eye. The details of the structure and function of these organs
are beyond the scope of this review, but a brief description of
their common features and their differences will place the
research on their regeneration in context.
The olfactory epithelium is contained within the nasal cavity
(Figure 1A). Most of the studies on regeneration have been
done in the main olfactory epithelium, but many vertebrates
also have additional sensory regions, like the vomeronasal
organ. The olfactory receptor neurons have a single dendrite
that extends to the apical surface of the epithelium and ends in
a terminal knob, which has many small cilia extending into the
Neuron 71, August 11, 2011 ª2011 Elsevier Inc.
mucosa. A single axon projects through the basal side of the
epithelium through the lamina cribosa to terminate in the olfac-
of over 1000 olfactory receptor proteins, G protein-coupled
receptor molecules,in theircilia(Kaupp, 2010)forrecentreview).
The neurons are surrounded by glial-like cells, called sustentac-
ular cells. Other cells in the epithelium contribute to the continual
production of the new receptor neurons and will be described
later in the review.
The vestibular and auditory epithelia in vertebrates have some
structural similarities to the olfactory epithelia (Figure 1B). The
mechanosensory receptor cells in these organs are called hair
cells. There are five distinct regions of vestibular epithelia in
the inner ear: the three cristae and the maculae of the utricle
and saccule. Like the olfactory receptor neurons, the hair cells
are surrounded on all sides by glial-like support cells but are
organized in a more regular mosaic than the olfactory receptor
cells. In addition to the inner ear sensory epithelia, aquatic
amphibians and fish have small mechanoreceptor organs
distributed along the body, called the lateral line organs. All
hair cells contain a mechanosensitive structure at their apical
surface called the hair bundle, consisting of a group of approxi-
mately 100 actin-containing sterocilia and a microtubule con-
taining kinocilium (for recent review, see Gillespie and Mu ¨ller,
In the auditory sensory epithelium of nonmammalian verte-
brates (the basilar papilla; BP), the hair cell and support cells
have a similar organization to that in the vestibular organs, with
alternating hair cells and support cells. However, in the mamma-
lian auditory sense organ (the cochlea) the hair cells are orga-
nized in a striking pattern, with a single row of ‘‘inner’’ hair cells
and three rows of ‘‘outer’’ hair cells, while the support cells
assume a variety of specialized morphologies. The inner hair
cells are the primary sensory receptors, while the outer hair cells
act to amplify sound at least in part through regulation of
ized support cells, the inner phalangeal cells. Lining the space
between the inner and outer hair cells, the tunnel of Corti, are
the pillar cells, which provide rigidity and structure to the epithe-
lium. Finally, the support cells associated with the outer hair cells
that reaches up around the outer hair cell and forms a contact
with its apical surface. It is thought that the development of the
tunnel of Corti and specializations of the cells may be an adapta-
tion necessary for higher frequency hearing (Dallos and Harris,
1978; Hudspeth, 1985).
The sensory receptors for visual information, the rod and cone
photoreceptor cells, arecontained in apart of the CNS called the
retina (Figure 1C). The retina is quite different in its embryology
from the olfactory and inner ear sensory epithelia in that the
former is derived from the neural plate with the rest of the
CNS, while the latter two are derived from ectodermal placodes
(Schlosser, 2010). There are several different types of cone
photoreceptors, and the different types are most sensitive to
aparticular wavelength. Inhumans,cones with peak sensitivities
to three different wavelengths (short, middle, and long) provide
us with trichromatic vision. Rods are specialized for high sensi-
tivity at low light levels and are responsible for nighttime vision.
All vertebrate retinas contain both rods and cones. The sensory
receptors are concentrated at the apical surface of the retinal
epithelium, organized in regular arrays and surrounded by glial
cells, the Mu ¨ller glia, that resemble the support cells and susten-
tacular cells of the inner ear and olfactory system, respectively.
Phototransduction in the sensory receptors is mediated by G
protein-coupled receptors, the opsins, which are concentrated
in specialized cilia, the so-called outer segments. In addition to
the sensory receptors and glia, the retina contains a group of
projection neurons, called retinal ganglion cells, somewhat
Figure 1. Simplified Schematic Diagrams of the Specialized Sensory Organs that Have Been Most Studied for Their Regeneration Potential
(A) The main olfactory epithelium (MOE) and the vomeronasal organ (VNO) contain specialized sensory receptor neurons (ORNs) and supporting cells, called
sustentacular cells. The axons of the ORNs project directly to the olfactory bulb (OB) in the brain.
Corti in mammals, and the vestibular epithelia—the three cristae, the utricle, and the saccule. The vestibular epithelia (middle) are organized with alternating hair
cells (red) and support cells (blue). In the organ of Corti (bottom), one row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs) alternate with various
types of supporting cells, the pillar cells (PCs) and the Deiters’ cells (DCs). The hair cells are innervated by afferent fibers from associated ganglia (spiral ganglia)
and from efferent fibers from the CNS.
(C) The neurosensory retina (red) lines the back of the eye; it contains the sensory receptors, the rods and cones (red), supporting Mu ¨ller glia (blue), and other
neurons (light red) that process and relay the light responses of the photoreceptors to the brain via the optic nerve.
Neuron 71, August 11, 2011 ª2011 Elsevier Inc.
analogous to the spiral ganglion neurons in the auditory system
as well as a diverse array of interneurons, more reminiscent of
other CNS regions than the other sensory epithelia.
Ongoing Sensory Receptor Cell Production
Although most of the neurons in the nervous system of verte-
brates are generated during a developmental period, some
regions of the nervous system continue to add new neurons
throughout life. For example, in mammals, neurons are gener-
ated in the hippocampus into adulthood (Hodge et al., 2008).
In many vertebrates, new receptor cells are also added to the
sensory organs. The cellular and molecular mechanisms that
enable ongoing genesis of receptor cells in different specialized
sensory epithelia in various species have some features in
common that provide insights into what factors might be critical
for regeneration (Figure 2).
The ongoing genesis of olfactory receptor cells is common to
all vertebrates (see Graziadei and Monti Graziadei, 1978 for
review) and the rate of production is quite high. The production
of new olfactory receptor cells is critical to the maintenance of
this system, as the olfactory receptor cells only last a few
months. The rate of production of new olfactory receptor cells
is balanced by their loss so that a relatively stable population
of these receptors is maintained. In the vestibular epithelium of
fish (Corwin, 1981), amphibians (Corwin, 1985), and birds
(Jørgensen and Mathiesen, 1988; Roberson et al., 1992), there
is also ongoing production of the hair cells. However, in fish
and amphibia, rather than the sensory receptor cell turnover
that occurs in the olfactory epithelium, the ongoing production
of new hair cells in vestibular epithelia results in an increase in
the overall number of these cells as the animal grows (Corwin,
1985). The macula neglecta of skates, for example, adds hair
cells continuously through at least six years increasing more
than 10-fold the number of hair cells with a 500-fold increase in
sensitivity. The number of hair cells appears to scale with overall
body size. In the toad sacculus, new hair cell addition occurs
primarily at the peripheral edges; as a result, the epithelium is
composed of concentric rings of progressively younger cells.
The situation is somewhat different in the vestibular epithelia of
birds. Although there is also good evidence for new hair cell
production throughout life, the newly generated hair cells are
frequently near apoptotic cells, and the number of hair cells
does not increase over the life of the animal as it does in fish.
Therefore, it is likely that the ongoing genesis of hair cells in birds
may serve a maintenance role to replace dying hair cells, much
like that in the olfactory epithelia (Jørgensen and Mathiesen,
1988; Roberson et al., 1992). In the retina of fish, there is also
ongoing production of one type of sensory receptor, the rod
photoreceptors (Johns and Easter, 1977; Raymond and Rivlin,
1987). Rod photoreceptor cells are not generated to replace
dying cells, but rather they are generated as the retina grows,
to keep the density of rod photoreceptors relatively constant
(Fernald, 1990). In fish and amphibians, the retina also grows
throughout life at its peripheral edge, adding new retinal cells
of all types that seamlessly integrate with the existing retina
(for review, see Lamba et al., 2008). This process also occurs
in birds to a limited extent (Fischer and Reh, 2000).
The continued production of sensory receptor cells in these
epithelia requires a mitotic cell population that can act like the
stem cells in nonneural epithelia. In the case of the olfactory
epithelium, there are at least two types of mitotic cells: the
globose basal cells (GBCs) and the horizontal basal cells
(HBCs). The GBCs are mitotically active in the normal, undam-
aged epithelium and act as a multipotent progenitor to generate
all of the other types of olfactory cells, including the sensory
receptors (Caggiano et al., 1994; Chen et al., 2004; Huard
et al., 1998). The more slowly cycling (or even quiescent) HBCs
are more like ‘‘stem cells’’ serving both to replenish the more
actively proliferating GBCs (Iwai et al., 2008) and as a reserve
pool after more extensive damage to the receptors (Leung
et al., 2007). The model of a slow-cycling stem cell (HBC) with
a more rapidly cycling, transit-amplifying progenitor cell (GBC)
has similarities with nonneural epithelia, like the epidermis
(Watt et al., 2006).The situation in the vestibular system of
nonmammals is somewhat different, in that there does not
appear to be a committed hair cell progenitor. Rather, it appears
that some or all of the support cells remain capable of mitotic
division and divide at a low rate to produce both additional hair
cells and support cells as the epithelium grows. In the retina,
the source of the new rods in the fish is a group of cells called
the rod precursors (Johns and Fernald, 1981), which typically
generate only rod photoreceptors under normal conditions and
are likely derived from the Mu ¨ller glia (more on this later).
The different progenitors/precursors in these systems also
share some common molecular expression patterns that are
similar to those expressed during initial development (see
Figure 3 and further discussion below). In the olfactory epithe-
lium, for example, at least some of the GBCs express Ascl1,
Neurog1, Sox2, and Pax6, genes critical during olfactory epithe-
lial development (Guo et al., 2010; Manglapus et al., 2004).
NeuroD1 is expressed at a slightly later stage, in the cells that
will differentiate into the olfactory receptor neurons. In the inner
ear, the support cells also express Sox2 (Oesterle et al., 2008),
and manyof thesupport cellsthat arein theS-phase or M-phase
of the cell cycle, as well as the newly generated postmitotic
daughters, express Atoh1 (Cafaro et al., 2007). In the retina,
the rod precursor expresses NeuroD1 (Hitchcock and Kakuk-
Atkins, 2004; Nelson and Reh, 2008), suggesting that these cells
are at a slightly ‘‘later’’ stage in their development, consistent
with their commitment to develop as rod photoreceptors and
their expression of other photoreceptor specific transcription
factors. The Mu ¨ller glia, which act as the ‘‘stem’’ cell that gives
rise to the rod precursors (Bernardos et al., 2007), express
Sox2 and Pax6 (and Ascl1 after damage, see below), similar to
From this overview, several common features of ongoing
sensory cell production emerge. First, the sensory receptor cells
are derived from what might be called a ‘‘persistent progenitor’’
lium and the retina of fish, the immediate precursor to the
receptor neurons/rods is a cell that seems to have a more limited
capacity for cell division than a true ‘‘stem cell.’’ The rod
precursor of fish is particularly committed to generating rod
photoreceptors, and the GBC of the olfactory epithelium can
generate most, though not all, of the cell types in the sensory
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