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(Sensorineural hearing loss is the most)Tj
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(sensory cell degeneration in the inner ear are also)Tj
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(Key words: )Tj
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(Cochlea, Hair cells, Auditory neurons,)Tj
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(Introduction)Tj
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[(W)80(orldwide, 500 million people are estimated to be)]TJ
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(Health Or)Tj
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(In the majority of the cases, the cause for hearing loss is)Tj
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(hearing \(Hilgert et al., 2009; Dror and A)Tj
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(vraham, 2010\).)Tj
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[(W)80(ork carried out using animal models has shown that)]TJ
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(of)Tj
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(ears, compared to uninjured controls \(Ulfendahl et al.,)Tj
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(2007; Matsuoka et al., 2007\). For example, Hu et al.)Tj
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T*
0.041 Tw
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T*
0.014 Tc
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(Ogita et al., 2010\). )Tj
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0.083 Tw
[(V)111(arious groups have also demonstrated that the)]TJ
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0.085 Tw
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0.125 Tw
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T*
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T*
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T*
0.023 Tc
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T*
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T*
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(al., 2005; Ulfendahl et al., 2007; Reyes et al., 2008\). )Tj
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(\(Pollock et al., 2006; Sekiya et al., 2007; Stevanato et)Tj
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(A)Tj
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(However)Tj
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0.041 Tc
0.084 Tw
(been suggested as one of the likely reasons for the)Tj
T*
0 Tc
0.078 Tw
(decline in the number of surviving cells observed at the)Tj
T*
0.008 Tc
0.117 Tw
(injection site \(Hildebrand et al., 2005; Coleman et al.,)Tj
T*
0 Tc
0.006 Tw
(2006\). In addition, injections of donor cells in the ST has)Tj
T*
0.004 Tc
0.121 Tw
[(yielded very low densities of exogenous cells in tar)19(get)]TJ
T*
0.001 Tc
0.124 Tw
[(areas such as Rosenthal\325)55(s Canal (RC), where the spiral)]TJ
T*
0 Tc
0.019 Tw
(ganglion cells are located, making this delivery route too)Tj
T*
0.017 Tw
[(inef)18(ficient for SGN replacement therapy \(Coleman et al.,)]TJ
T*
0.017 Tc
0.108 Tw
(2006; Matsuoka et al., 2006; Altschuler et al., 2008\).)Tj
T*
0.022 Tc
0.103 Tw
[(Consequently)65(, direct injection of donor cells into the)]TJ
T*
0.06 Tc
0.065 Tw
(auditory nerve has been very often adopted as an)Tj
T*
0.001 Tc
0.124 Tw
(alternative route, is it requires minimal sur)Tj
17.78831 0.00001 TD
(gical trauma)Tj
-17.78831 -1.01619 TD
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(and results in extensive migration of the exogenous)Tj
T*
0 Tc
0.011 Tw
(cells, not only along the entire nerve but also to the more)Tj
T*
0.106 Tw
(distal scala media, where the HCs reside \(Sekiya et al.,)Tj
T*
0 Tw
(2006; Lang et al., 2008\). )Tj
1.61905 -1.01619 TD
0.075 Tc
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(The route of implantation and subsequent)Tj
-1.61905 -1.01619 TD
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(distribution patterns of the injected cells are thought to)Tj
T*
0.026 Tc
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(play a role in the survival of donor cells. Overall, it)Tj
T*
0 Tc
0.058 Tw
(appears that cells implanted intra-neurally survive better)Tj
T*
0.038 Tc
0.087 Tw
(than those transplanted peri-neurally \(Sekiya et al.,)Tj
T*
0 Tc
0.091 Tw
(2006\). As mentioned before, in a number of studies the)Tj
0 -1.01618 TD
0.053 Tw
[(donor cells were transplanted into the ST)75(, with very low)]TJ
0 -1.01619 TD
0.015 Tw
(survival rates. An example of this is the work carried out)Tj
T*
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(by Ulfendahl et al. (2007) using ESCs. The authors)Tj
ET
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(h)Tj
0.49996 -0.00001 TD
0.029 Tw
(ypothesized that although the ST is an easily accessible)Tj
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T*
0.005 Tc
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[(the survival of transplanted cells. Importantly)67(, survival)]TJ
0 -1.01619 TD
0 Tc
0.029 Tw
(of the ESCs was greatly enhanced when these cells were)Tj
T*
0.085 Tw
(implanted together with small pieces of E13-E14 dorsal)Tj
T*
0.109 Tw
(root ganglion (DRG) tissue (Hu et al., 2005a), pointing)Tj
T*
0.013 Tc
0.111 Tw
(to the lack of some factor(s) in the adult cochlea that)Tj
0 -1.01618 TD
0 Tc
0.063 Tw
(might be critical for the survival of the exogenous cells.)Tj
0 -1.01619 TD
0.004 Tc
0.121 Tw
[(Additionally)65(, dif)18(ferent groups \(Hildebrand et al., 2005;)]TJ
0 -1.01618 TD
0.048 Tc
0.077 Tw
(Lang et al., 2008\) have shown that the survival of)Tj
0 -1.01619 TD
0.014 Tc
0.111 Tw
(implanted cells is higher in the perilymph than in the)Tj
0 -1.01618 TD
0 Tc
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(endolymph. )Tj
1.61905 -1.01619 TD
0.06 Tw
(Some studies have demonstrated that the location of)Tj
-1.61905 -1.01619 TD
0.015 Tc
0.11 Tw
[(the implanted cells within the tissue also af)20(fects their)]TJ
T*
0.011 Tc
0.114 Tw
[(dif)18(ferentiation. Parker and colleagues (2007) observed)]TJ
T*
0.044 Tc
0.081 Tw
(that NSCs transplanted into hearing-damaged mice)Tj
0 -1.01618 TD
0 Tc
0.033 Tw
[(dif)18(ferentially regulated their gene and protein expression)]TJ
0 -1.01619 TD
0.075 Tc
0.447 Tw
(depending on their location within the OC,)Tj
T*
0.051 Tc
0.074 Tw
(demonstrating an influence of the cochlear micro-)Tj
T*
0.075 Tc
0.249 Tw
[(environment on NSC dif)18(ferentiation. Dif)19(ferent)]TJ
T*
0.037 Tc
0.088 Tw
(morphology of neuralized ESCs depending on their)Tj
T*
0.034 Tc
0.091 Tw
(location within the host tissue was also reported by)Tj
T*
0 Tc
0.048 Tw
(Sekiya and co-workers in the inner ears of deafened rats)Tj
T*
0.041 Tw
((2006). Carrying out transplants of neuralized ESCs into)Tj
T*
0.031 Tc
0.094 Tw
(the cochleae of deafened gerbils, Lang et al. (2008))Tj
T*
0.021 Tc
0.104 Tw
(showed that a small number of donor cells that were)Tj
T*
0 Tc
0.066 Tw
(localised within the RC had dif)Tj
12.78174 0 TD
(ferentiated into cells that)Tj
-12.78174 -1.01619 TD
0.061 Tc
0.064 Tw
(expressed neurofilament-200, a marker of mature)Tj
T*
0 Tc
0.068 Tw
[(neurons, while no signs of neuronal dif)18(ferentiation were)]TJ
T*
0.064 Tc
0.061 Tw
(found outside this region. These are encouraging)Tj
T*
0.011 Tc
0.114 Tw
(observations in support of cell therapy approaches for)Tj
T*
0.01 Tc
0.115 Tw
(the treatment of hearing loss, as they indicate that the)Tj
T*
0.045 Tc
0.08 Tw
(mature mammalian cochlea, despite its inability to)Tj
T*
0 Tc
0.068 Tw
(regenerate lost cells, may retain the signals necessary to)Tj
T*
0.12 Tw
[(drive dif)18(ferentiation of stem cells towards cochlear cell)]TJ
T*
0 Tw
(phenotypes.)Tj
1.61905 -2.03238 TD
(Cell types used for cell therapy in the inner ear)Tj
T*
0.001 Tc
0.124 Tw
(Having outlined some of the most important issues)Tj
-1.61905 -1.01619 TD
0.074 Tc
0.051 Tw
(to be addressed when considering a cell therapy)Tj
T*
0 Tc
0.075 Tw
(approach for treating hearing loss, we will now proceed)Tj
T*
0.054 Tc
0.071 Tw
(to summarize the main findings obtained with the)Tj
T*
0 Tc
0 Tw
(various types of cells tested. )Tj
ET
Q
/GS3 gs
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((a) Embr)Tj
3.63721 0.00001 TD
(yonic stem cells (ESCs).)Tj
ET
Q
/GS3 gs
/GS2 gs
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BT
/F1 1 Tf
10.5 0 0 10.5 454.2465 194.3465 Tm
0 Tr
0 0 0 1 k
0.021 Tc
0.104 Tw
(In a series of studies)Tj
-13.875 -1.01619 TD
0.011 Tc
0.114 Tw
[(undif)18(ferentiated ESCs have been directly injected into)]TJ
T*
0 Tc
0.077 Tw
(the cochlea. One ar)Tj
7.93182 0.00001 TD
(gument in favour of this approach is)Tj
-7.93182 -1.0162 TD
0.069 Tw
(the plasticity of these cells, which might translate into a)Tj
0 -1.01619 TD
0.03 Tc
0.095 Tw
(better response to the dif)Tj
11.02585 0.00001 TD
(ferent micro-environmental)Tj
-11.02585 -1.01619 TD
0.043 Tc
0.082 Tw
(cues the implanted ESCs will encounter within the)Tj
T*
0.029 Tc
0.096 Tw
(various cochlear compartments; this would open the)Tj
T*
0.053 Tc
0.072 Tw
(door to a possible regeneration of several cellular)Tj
T*
0 Tc
0.04 Tw
(phenotypes, derived from the same transplant \(Shi et al.,)Tj
T*
0.039 Tc
0.086 Tw
[(2007\). Another advantage of using undif)18(ferentiated)]TJ
T*
0 Tc
0.103 Tw
[(ESCs is their low immunogenicity)66(, which makes a host)]TJ
0 -1.01618 TD
0 Tw
[(immune response less likely)66(.)]TJ
1.61905 -1.01619 TD
0.029 Tc
0.096 Tw
(Mouse ESCs transplanted into injured vestibulo-)Tj
-1.61905 -1.01619 TD
0 Tc
0.017 Tw
(cochlear nerves of adult rats and guinea pigs survived up)Tj
ET
0 0 0 0 k
45.354 729.071 504.567 14.1729 re
f
45.354 715.927 504.567 12.002 re
f
45.354 683.748 504.567 31.181 re
f
45.354 729.071 504.567 14.1729 re
f
Q
/GS3 gs
/GS2 gs
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/F3 1 Tf
7.7 0 0 7.7 46.3543 731.757 Tm
0 Tr
0 0 0 1 k
0 Tc
0 Tw
(926)Tj
ET
0 0 0 0 k
45.354 715.927 504.567 12.002 re
f
Q
/GS3 gs
/GS2 gs
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BT
/F4 1 Tf
10.5 0 2.23185 10.5 226.75 719.277 Tm
0 Tr
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(Approaches to inner ear repair)Tj
ET
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endstream
endobj
9 0 obj
<<
/Length 11419
>>
stream
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/GS1 gs
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45.354 51.023 242.363 631.654 re
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/GS2 gs
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/F1 1 Tf
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0 0 0 1 k
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(t)Tj
0.27796 -0.00001 TD
(o)Tj
0.81099 0 Td
0.061 Tw
(at least 9 weeks (Hu et al., 2004; Regala et al., 2005))Tj
-1.08895 -1.01618 TD
0.021 Tc
0.104 Tw
[(and a fraction of these cells dif)19(ferentiated into either)]TJ
T*
0.005 Tc
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[(glial or neuronal lineages. Importantly)67(, implanted cells)]TJ
0 -1.01619 TD
0.006 Tc
(were detected not only at the site of injection but also)Tj
T*
0 Tc
0.102 Tw
(within the brain stem. When ESCs were implanted into)Tj
T*
0.025 Tc
0.1 Tw
(the ST (Ulfendahl et al., 2007), surviving cells were)Tj
T*
0.001 Tc
0.124 Tw
(identified close to the spiral ganglion region and along)Tj
0 -1.01618 TD
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(the nerve fibers projecting to OC, as well as in the scala)Tj
0 -1.01619 TD
0.039 Tc
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(vestibuli, indicating migration towards functionally)Tj
0 -1.01618 TD
0 Tc
0.093 Tw
(relevant locations. Nevertheless, the survival rate of the)Tj
0 -1.01619 TD
0.048 Tc
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(transplanted cells was very low (1.1%-1.5%). Cell)Tj
0 -1.01618 TD
0 Tc
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[(survival and neuronal dif)18(ferentiation of ESCs injected in)]TJ
0 -1.01619 TD
0.009 Tc
0.116 Tw
(the cochlea was greatly enhanced when the stem cells)Tj
T*
0 Tc
0.053 Tw
(were implanted together with small pieces of embryonic)Tj
T*
0.068 Tc
0.057 Tw
[(mouse DRG tissue (Hu et al., 2005a). Moreover)40(,)]TJ
T*
0.005 Tc
0.12 Tw
(formation of neurite-like projections from \247III-tubulin-)Tj
0 -1.01618 TD
0.075 Tc
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(expressing donor cells towards peripheral SGN)Tj
0 -1.01619 TD
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0.023 Tw
(processes was only observed in the presence of the DRG)Tj
T*
0.028 Tc
0.097 Tw
[(co-graft. However)40(, no dif)18(ferentiation of the ESCs to)]TJ
T*
0 Tc
0.039 Tw
(myosin VIIa-positive cells \(a protein typically expressed)Tj
T*
0 Tw
(by HCs\) took place.)Tj
1.61905 -1.01619 TD
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(Altschuler et al. (2008) took the studies on survival)Tj
-1.61905 -1.01619 TD
0.005 Tc
0.12 Tw
(and dif)Tj
2.94248 0 TD
(ferentiation of ESCs implanted into the cochlea)Tj
-2.94248 -1.01619 TD
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0.077 Tw
(one step further and reported that continuous intrascalar)Tj
T*
0.029 Tc
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(administration of the neurotrophic factor (NF) glial-)Tj
T*
0 Tc
0.086 Tw
(derived neurotrophic factor (GDNF) following injection)Tj
T*
0.013 Tc
0.112 Tw
(of mouse ESCs into the cochleae of hearing-damaged)Tj
T*
0.072 Tc
0.053 Tw
(guinea pigs resulted in increased survival of the)Tj
T*
0.038 Tc
0.087 Tw
(implanted cells and a much higher rate of neuronal)Tj
T*
0 Tc
0.012 Tw
[(dif)18(ferentiation, compared to implants that did not receive)]TJ
T*
0.022 Tw
[(GDNF)79(. Moreover)39(, the ESC-derived neurons were mostly)]TJ
T*
0.005 Tc
0.12 Tw
(of an excitatory glutamater)Tj
11.27187 0 TD
(gic phenotype \(indicated by)Tj
-11.27187 -1.01619 TD
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0.077 Tw
(the expression of vesicular glutamate transporters,)Tj
T*
0.072 Tc
0.053 Tw
(VGLUT1/2\), and thus appropriate for functional)Tj
T*
0 Tc
0.105 Tw
(replacement of auditory neurons. Most of the processes)Tj
T*
0.031 Tc
0.094 Tw
(extended by the ESC-derived neurons were directed)Tj
T*
0.044 Tc
0.081 Tw
(towards the OC or towards remaining SGNs in the)Tj
T*
0.033 Tc
0.092 Tw
[(modiolus. Unfortunately)65(, no functional studies were)]TJ
T*
0 Tc
0 Tw
(conducted.)Tj
1.61905 -1.01619 TD
0.003 Tc
0.122 Tw
(The data obtained from the aforementioned studies)Tj
-1.61905 -1.01619 TD
0 Tc
0.107 Tw
(clearly indicate that successful dif)Tj
14.01459 0.00001 TD
(ferentiation and long-)Tj
-14.01459 -1.0162 TD
0.008 Tc
0.117 Tw
(term integration of implanted ESCs will likely require)Tj
0 -1.01619 TD
0.056 Tc
0.069 Tw
(either the co-grafting of some other tissue, or the)Tj
T*
0.075 Tc
0.411 Tw
(simultaneous application of appropriate NFs.)Tj
T*
0 Tc
0.106 Tw
[(Alternatively)66(, ESCs can be pre-dif)18(ferentiated )]TJ
ET
Q
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[(in vitr)37(o)]TJ
ET
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0 Tr
0 0 0 1 k
0 Tc
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(in)Tj
-22.1138 -1.01619 TD
0.03 Tc
0.095 Tw
(order to promote their final progression towards the)Tj
T*
0.006 Tc
0.119 Tw
(desired phenotypes following implantation. One of the)Tj
T*
0.013 Tc
0.112 Tw
(clear advantages of these latter methods, compared to)Tj
T*
0 Tc
0.123 Tw
(the implants of undif)Tj
8.70973 0.00001 TD
(ferentiated ESC, is the diminished)Tj
-8.70973 -1.01619 TD
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0.098 Tw
(risk of tumour formation )Tj
ET
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/GS2 gs
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/F5 1 Tf
10.5 0 0 10.5 164.3662 151.6665 Tm
0 Tr
0 0 0 1 k
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(in vivo)Tj
ET
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/GS2 gs
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0 0 0 1 k
0.0274 Tc
(.)Tj
0.65232 0 Td
0.027 Tc
0.098 Tw
(The appearance of)Tj
-14.87438 -1.01619 TD
0.032 Tc
0.093 Tw
(teratomas is always a major concern when injecting)Tj
T*
0.017 Tc
0.108 Tw
[(undif)18(ferentiated ESCs (Erdo et al., 2003; Sell, 2004),)]TJ
T*
0.001 Tc
0.124 Tw
(although it has not been reported by any of the groups)Tj
T*
0.048 Tc
0.077 Tw
(cited above \(Hu et al., 2005a; Regala et al., 2005;)Tj
T*
0.012 Tc
0.113 Tw
(Altschuler et al., 2008\). Other advantages are the fact)Tj
T*
0 Tc
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(that, unlike ESCs, ESC-derived populations may not be)Tj
0 -1.01618 TD
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(totally dependent on the cochlear environment for their)Tj
0 -1.01619 TD
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0.109 Tw
[(survival and correct dif)19(ferentiation. Additionally)66(, pre-)]TJ
T*
0.061 Tc
0.064 Tw
[(dif)18(ferentiation may allow the selection of a more)]TJ
ET
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10.5 0 0 10.5 308.559 674.4964 Tm
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0.0331 Tc
(h)Tj
0.53312 -0.00001 TD
0.033 Tc
0.092 Tw
(omogenous and appropriate population of cells for)Tj
-0.53312 -1.01618 TD
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0.117 Tw
(implants. Since lineage analysis studies have provided)Tj
T*
0.073 Tc
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(evidence that SGNs and HCs are derived from a)Tj
0 -1.01619 TD
0 Tc
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(common neural precursor cell, a very frequently adopted)Tj
T*
0.066 Tc
0.059 Tw
[(approach has been the dif)19(ferentiation of ESCs to)]TJ
T*
0.031 Tc
0.094 Tw
(neuroectodermal progenitors prior to transplantation)Tj
T*
0 Tc
0.109 Tw
(\(Hildebrand et al., 2005; Coleman et al., 2007; Lang et)Tj
0 -1.01618 TD
0.013 Tc
0.111 Tw
(al., 2008\). These cells, albeit committed to the neural)Tj
0 -1.01619 TD
0.04 Tc
0.085 Tw
(lineage, can still integrate into inner ear tissue and)Tj
0 -1.01618 TD
0.012 Tc
0.113 Tw
(respond to various signals present within the cochlear)Tj
0 -1.01619 TD
0.015 Tc
0.11 Tw
(environment (Corrales et al., 2006). Survival of these)Tj
0 -1.01618 TD
0.006 Tc
0.119 Tw
(cells after implantation into either the ST \(Coleman et)Tj
0 -1.01619 TD
0 Tc
0.057 Tw
(al., 2006\) or the auditory nerve \(Sekiya et al., 2006\) has)Tj
T*
0.075 Tc
0.588 Tw
(already been demonstrated. Regarding their)Tj
T*
0.031 Tc
0.094 Tw
[(dif)18(ferentiation, diver)19(gent results have been obtained)]TJ
T*
0.011 Tc
0.114 Tw
(using various animal models \(Hildebrand et al., 2005;)Tj
0 -1.01618 TD
0 Tc
0.113 Tw
(Sekiya et al., 2006\). Hildebrand and co-workers \(2005\))Tj
0 -1.01619 TD
0.001 Tc
0.124 Tw
[(failed to detect any further dif)19(ferentiation of ESCs that)]TJ
T*
[(were partially pre-dif)19(ferentiated to the neuroectodermal)]TJ
T*
0.05 Tc
0.075 Tw
(lineage following their implantation into deafened)Tj
T*
0.075 Tc
0.085 Tw
(guinea pigs, in spite of long survival times and)Tj
T*
0.049 Tc
0.076 Tw
(localization close to the damaged OC. In contrast,)Tj
T*
0.03 Tc
0.095 Tw
(Corrales and colleagues (2006) reported progressive)Tj
T*
0.015 Tc
0.11 Tw
(neuronal dif)Tj
5.13601 0 TD
(ferentiation of ESC-derived mouse neural)Tj
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(progenitor cells after injection into the cochlear nerve of)Tj
0 -1.01619 TD
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(immunosuppressed gerbils, with formation of abundant)Tj
T*
0 Tc
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(neuronal processes that traversed RC and grew towards)Tj
T*
0.031 Tc
0.094 Tw
(the HCs in the OC. The observed projection pattern)Tj
T*
0.035 Tc
0.09 Tw
(appeared to indicate that the newly formed neurites)Tj
T*
0.025 Tc
0.1 Tw
(followed the former pathways of degenerated SGNs,)Tj
T*
0.056 Tc
0.069 Tw
(reponding to cues probably sent to them from the)Tj
T*
0.04 Tc
0.085 Tw
(denervated OC. Moreover)Tj
11.51585 0 TD
0.0399 Tc
(,)Tj
0.66478 0 Td
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(these neurons expressed)Tj
-12.18063 -1.01619 TD
0.041 Tc
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(peripherin, a protein expressed in sensory neurons.)Tj
T*
0 Tc
0 Tw
(Unfortunately)Tj
5.54371 0 TD
(,)Tj
0.52683 0 Td
0.027 Tw
(the authors could not carry out any test to)Tj
-6.07054 -1.01619 TD
0.049 Tw
(assess functional recovery in the implanted animals, due)Tj
T*
0.014 Tw
(to the formation of thick scar tissue at the site of sur)Tj
20.92998 0 TD
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[(gery)65(.)]TJ
-20.92998 -1.01619 TD
0.075 Tc
0.158 Tw
(Promising results were obtained by Okano and)Tj
T*
0.009 Tc
0.116 Tw
(colleagues (2005), who implanted mouse ESC-derived)Tj
T*
0 Tc
0.101 Tw
(neural progenitors into the cochlear modiolus of guinea)Tj
T*
0.075 Tc
0.12 Tw
(pigs. This group confirmed survival and neural)Tj
T*
0 Tc
0 Tw
(dif)Tj
1.09278 0.00001 TD
0.118 Tw
(ferentiation of the donor cells, which were shown to)Tj
-1.09278 -1.0162 TD
0.086 Tw
(extend neurite projections toward peripheral and central)Tj
0 -1.01619 TD
0.051 Tc
0.074 Tw
(auditory tar)Tj
5.31006 0.00001 TD
(gets. Furthermore, auditory brain stem)Tj
-5.31006 -1.01619 TD
0 Tc
0.039 Tw
(response (ABR) measurements indicated the potential of)Tj
T*
0.034 Tc
0.09 Tw
(the transplanted cells for functional recovery of the)Tj
T*
0.033 Tc
0.092 Tw
(damaged cochleae, although no direct evidence was)Tj
T*
0.012 Tc
0.113 Tw
(presented for the establishment of synapses. Later on,)Tj
T*
0.03 Tc
0.095 Tw
(Matsumoto and co-workers (2008) demonstrated the)Tj
T*
0.046 Tc
0.079 Tw
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[(in vitr)37(o)]TJ
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[(dif)18(ferentiation of ESCs into HCs,)]TJ
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T*
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T*
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1.61905 -1.01619 TD
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T*
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[(dif)18(ferentiation )]TJ
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((b1) Neural stem cells)Tj
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0.039 Tc
0.086 Tw
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(In vivo)Tj
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0.62556 0 Td
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[(\(T)70(ateya et al., 2003; Hu et al., 2005c; Parker et al.,)]TJ
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0.004 Tc
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0.026 Tc
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45.354 683.748 504.567 31.181 re
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45.354 729.071 504.567 14.1729 re
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(928)Tj
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(Approaches to inner ear repair)Tj
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endstream
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(btained by Hu et al. (2005c), Parker and co-workers)Tj
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((2007) implanted a mouse clonal NSC line into sound-)Tj
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[(the dif)18(ferentiation of these cells into a wide range of)]TJ
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T*
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[(cochlea. T)71(wo to six weeks after implantation, a)]TJ
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(proportion of these cells was found in the spiral ganglion)Tj
0 -1.01618 TD
0.001 Tw
[(area and appeared to be dif)19(ferentiating into satellite cells,)]TJ
0 -1.01619 TD
0.082 Tw
[(Schwann cells, and even SGNs. V)110(ery importantly)66(, some)]TJ
0 -1.01618 TD
0.016 Tc
0.108 Tw
(of these cells also labelled for synapsin, suggesting a)Tj
0 -1.01619 TD
0.075 Tc
0.166 Tw
(possible competence for synaptic transmission.)Tj
0 -1.01618 TD
0 Tc
0.093 Tw
[(Altogether)40(, these data point towards an influence of the)]TJ
0 -1.01619 TD
0.005 Tc
0.12 Tw
[(microenvironment of the cochlea on the dif)20(ferentiation)]TJ
T*
0 Tc
0 Tw
(of the implanted cells.)Tj
1.61905 -1.01619 TD
0.028 Tc
0.097 Tw
(In another set of experiments Hu and colleagues)Tj
-1.61905 -1.01619 TD
0.015 Tc
0.11 Tw
((2005c) transduced NSCs with neurogenin2 (ngn2) to)Tj
0 -1.01618 TD
0 Tc
0.116 Tw
[(further promote their dif)19(ferentiation towards a neuronal)]TJ
0 -1.01619 TD
0.073 Tw
(phenotype. They observed better survival rates of ngn2-)Tj
T*
0.122 Tw
(expressing NSCs implanted into normal hearing guinea)Tj
T*
0.009 Tc
0.116 Tw
(pig cochleae, compared to control NSCs, although the)Tj
T*
0 Tc
0.001 Tw
(numbers of surviving cells were very low in both groups.)Tj
T*
0.021 Tc
0.103 Tw
(Neuronal dif)Tj
5.42466 0 TD
(ferentiation was also enhanced by ngn-2)Tj
-5.42466 -1.01619 TD
0.039 Tc
0.086 Tw
(transduction upon which NSC-derived \247III-tubulin-)Tj
T*
0.023 Tc
0.102 Tw
(expressing cells were identified in all inner ears that)Tj
T*
0.075 Tc
0.204 Tw
(contained surviving NSCs. On the other hand,)Tj
T*
0.001 Tc
0.124 Tw
(embryonic NSCs transduced with the Atoh1 gene gave)Tj
T*
0.075 Tc
0.212 Tw
(rise to both neurons and HCs, following their)Tj
T*
0 Tc
0.008 Tw
(implantation into normal guinea pig cochleae \(Han et al.,)Tj
T*
0 Tw
(2010\).)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
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0 0 0 1 k
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[((b2) Bone marr)37(ow stem cells)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 190.9664 365.0665 Tm
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0 0 0 1 k
0.075 Tc
(.)Tj
0.70809 0 Td
0.058 Tw
(Mesenchymal and)Tj
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0 Tc
0.041 Tw
(hematopoietic stem cells. Initially isolated from BM and)Tj
T*
0.031 Tc
0.094 Tw
(later on from other tissues such as muscle, synovial)Tj
T*
0 Tc
0.113 Tw
(membranes, peripheral blood, umbilical cord blood and)Tj
T*
0.015 Tc
0.11 Tw
(adipose tissue, mesenchymal stem cells (MSCs) are a)Tj
T*
0.004 Tc
0.121 Tw
(heterogeneous population of stem/progenitor cells with)Tj
T*
0 Tc
0.073 Tw
(pluripotent capacity to dif)Tj
10.55925 0 TD
(ferentiate into cell types of all)Tj
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0.122 Tw
(three embryonic layers (Krabbe et al., 2005). They are)Tj
T*
0 Tc
0.067 Tw
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ET
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(ex vivo)Tj
ET
Q
/GS3 gs
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0 Tr
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0 Tc
0.067 Tw
(than NSCs.)Tj
-18.26874 -1.01619 TD
0.09 Tw
[(Importantly)66(, they have been extensively used in clinical)]TJ
T*
0 Tw
(applications, so their safety is known.)Tj
1.61905 -1.01619 TD
0.001 Tw
(There have been a considerable number of reports on)Tj
-1.61905 -1.01619 TD
0.009 Tc
0.116 Tw
[(the neural dif)18(ferentiation of MSCs \(S\207nchez-Ramos et)]TJ
T*
0.021 Tc
0.104 Tw
(al., 2000; W)Tj
5.32456 0.00001 TD
(oodbury et al., 2000; Deng et al., 2001\).)Tj
-5.32456 -1.01619 TD
0 Tc
0.117 Tw
(Interpretation of these data must nonetheless be carried)Tj
T*
0.037 Tw
(out with caution, as it has been shown in some instances)Tj
T*
0.001 Tw
(that rapid phenotypic changes of treated MSCs towards a)Tj
T*
0.099 Tw
(neuronal morphology are often the result of a cytotoxic)Tj
T*
0.014 Tc
0 Tw
(ef)Tj
0.78724 0.00001 TD
0.111 Tw
(fect (Jin et al., 2003; Lu et al., 2004). Furthermore,)Tj
-0.78724 -1.0162 TD
0 Tc
0.002 Tw
(expression of neuronal or glial proteins \(e.g. \247III-tubulin,)Tj
0 -1.01619 TD
0.028 Tw
(MAP-2, GF)Tj
4.73104 0.00001 TD
(AP\) has been demonstrated in standard MSC)Tj
-4.73104 -1.01619 TD
0.06 Tc
0.065 Tw
(cultures, in the absence of any specific induction)Tj
T*
0 Tc
0.08 Tw
[(protocol \(T)70(ondreau et al., 2004\). In addition, cell fusion)]TJ
T*
0.019 Tc
0.106 Tw
(phenomena have been observed between transplanted)Tj
T*
0 Tc
0.03 Tw
[(MSCs and host tissue. Consequently)65(, confirmation that a)]TJ
T*
0.03 Tc
0.094 Tw
[(transdif)18(ferentiation process of MSCs towards neural)]TJ
T*
0.048 Tc
0.077 Tw
(lineages has taken place requires not only that the)Tj
0 -1.01618 TD
0 Tc
0.026 Tw
(possibility of cell fusion has been excluded, but also that)Tj
0 -1.01619 TD
0.06 Tc
0.065 Tw
(morphological, immunocytochemical and electro-)Tj
T*
0.016 Tc
0.109 Tw
(physiological studies are carried out \(Jin et al., 2003;)Tj
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(K)Tj
0.72195 -0.00001 TD
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(rabbe et al., 2005\). )Tj
0.8971 -1.01618 TD
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(The use of MSCs as donor cells for transplantations)Tj
-1.61905 -1.01618 TD
0.09 Tw
(is further complicated by the fact that it is not yet clear)Tj
0 -1.01619 TD
0.02 Tc
0.105 Tw
(which cell population is responsible for the observed)Tj
T*
0.01 Tc
0.115 Tw
[(cases of MSC transdif)17(ferentiation \(Song and S\207nchez-)]TJ
T*
0 Tc
0.092 Tw
(Ramos, 2003\). There is some evidence for the presence)Tj
T*
0.001 Tw
(of a set of quiescent primordial stem cells in adult tissues)Tj
0 -1.01618 TD
0.092 Tw
[(such as the BM and the brain that can dif)19(ferentiate into)]TJ
0 -1.01619 TD
0.046 Tc
0.079 Tw
(mesodermal, neuroectodermal and endodermal cell)Tj
0 -1.01618 TD
0.075 Tc
0.117 Tw
(types, and thus might lead to an assumption of)Tj
0 -1.01619 TD
0.078 Tw
[(transdif)18(ferentiation of the cell cultures they are)]TJ
0 -1.01618 TD
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0 Tw
(contaminating (Jiang et al., 2002b; Krabbe et al., 2005). )Tj
0 -1.01619 TD
0.023 Tc
0.102 Tw
(These stem cells have been termed multipotent adult)Tj
T*
0.031 Tc
0.094 Tw
(progenitor cells (MAPCs) (Jiang et al., 2002a). In a)Tj
T*
0.005 Tc
0.12 Tw
(recent publication, Kuroda and colleagues (2010) have)Tj
T*
0 Tc
0.062 Tw
(also reported the isolation of a type of human MSC that)Tj
0 -1.01618 TD
0.013 Tc
0.112 Tw
(can give rise to cells corresponding to the three germ)Tj
0 -1.01619 TD
0 Tc
0.033 Tw
(layers. These cells are present at very low frequencies in)Tj
T*
0.099 Tw
(primary cultures of BM aspirates and have been named)Tj
T*
0.039 Tw
[(multilineage dif)19(ferentiating stress enduring (Muse) cells,)]TJ
T*
0.048 Tc
0.076 Tw
(as their numbers increase during passaging of BM)Tj
T*
0 Tc
0.01 Tw
(cultures and exposure to stress conditions. An alternative)Tj
T*
0.009 Tc
0.116 Tw
(hypothesis that has been proposed is that adult tissues)Tj
T*
0.031 Tc
0.094 Tw
(might contain mixed populations of progenitor cells)Tj
T*
0 Tc
0 Tw
(derived from distinct embryonic germ layers.)Tj
1.61905 -1.01619 TD
0.102 Tw
(Regarding the transplants of BM-derived stem cells)Tj
-1.61905 -1.01619 TD
0.012 Tc
0.113 Tw
(into the cochlea, survival and migration of these cells)Tj
T*
0 Tc
0.036 Tw
(have been demonstrated \(Naito et al., 2004; Matsuoka et)Tj
T*
0.075 Tc
0.293 Tw
(al., 2007\) and there are some reports on the)Tj
T*
0 Tc
0.079 Tw
[(dif)18(ferentiation of injected MSCs into neuronal-like cells)]TJ
ET
Q
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(in vivo)Tj
ET
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/GS3 gs
/GS2 gs
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10.5 0 0 10.5 342.5614 354.3965 Tm
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0.007 Tc
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((Naito et al., 2004). In order to investigate the)Tj
-3.23833 -1.01619 TD
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0.119 Tw
(potential for transdif)Tj
8.56514 0 TD
(ferentation of BM-derived cells in)Tj
-8.56514 -1.01619 TD
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0.12 Tw
(the cochlea, T)Tj
5.87013 0 TD
(an et al. (2008) isolated these cells from)Tj
-5.87013 -1.01619 TD
0.031 Tc
0.094 Tw
(GFP-transgenic donor mice and engrafted them into)Tj
T*
0.011 Tc
0.114 Tw
(lethally irradiated mice. Shortly after acoustic trauma,)Tj
T*
0 Tc
0.048 Tw
(prominent GFP-positive cell infiltration was observed in)Tj
T*
0.109 Tw
(the cochlea, outside the sensory epithelial regions. This)Tj
T*
0.113 Tw
(infiltration was most intense during the first week after)Tj
T*
0.008 Tc
0.117 Tw
(deafening, coinciding with an up-regulation of SDF-1.)Tj
T*
0 Tc
0.095 Tw
[(However)39(, most of the infiltrated BM-derived cells were)]TJ
T*
0.005 Tw
(identified as macrophages and GFP-positive cells did not)Tj
T*
0.021 Tc
0.104 Tw
(exhibit any cochlear characteristics. No sign of ABR)Tj
T*
(threshold recovery was observed up to 8 weeks after)Tj
T*
0 Tc
0.008 Tw
(deafening. The main conclusion from this work was that,)Tj
T*
0.071 Tw
(although acoustic damage resulted in a clear increase of)Tj
T*
0.057 Tc
0.068 Tw
(the homing ability of the BM-derived cells to the)Tj
T*
0.011 Tc
0.114 Tw
(cochlea, compared to control cochleae, these cells did)Tj
T*
0 Tc
0.066 Tw
(not transdif)Tj
4.63035 0.00001 TD
(ferentiate into any cochlear cell type and did)Tj
-4.63035 -1.0162 TD
0.088 Tw
(not contribute to its repair)Tj
10.68215 0.00001 TD
-0.0001 Tc
(.)Tj
0.5878 0 Td
0 Tc
(As possible explanations for)Tj
-11.26996 -1.01619 TD
0.02 Tc
0.105 Tw
(these results, the authors suggested that the damaged)Tj
T*
0.024 Tc
0.101 Tw
(cochlea might not be sending out the necessary cues)Tj
T*
0 Tc
0.109 Tw
(needed to attract pluripotent cells from the BM-derived)Tj
T*
0.016 Tc
(cell pool and/or it might not provide the regenerative)Tj
T*
0.075 Tc
0.149 Tw
(signals required for BM-derived cells to trans-)Tj
T*
0.006 Tc
0.119 Tw
[(dif)18(ferentiate into appropriate cell types. Similar results)]TJ
T*
0.031 Tc
0.094 Tw
(were obtained by Lang and co-workers (2006), who)Tj
0 -1.01618 TD
0 Tc
0.113 Tw
(confirmed homing of BM-derived cells to the inner ear)Tj
0 -1.01619 TD
0.062 Tc
0.063 Tw
(of irradiated mice, outside the epithelial regions;)Tj
T*
0 Tc
0.011 Tw
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45.354 716.262 504.567 12 re
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45.354 683.748 504.567 31.181 re
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45.354 729.071 504.567 14.1729 re
f
Q
/GS3 gs
/GS2 gs
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/F3 1 Tf
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0 Tr
0 0 0 1 k
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0 Tw
(929)Tj
ET
0 0 0 0 k
45.354 716.262 504.567 12 re
f
Q
/GS3 gs
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/F4 1 Tf
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(Approaches to inner ear repair)Tj
ET
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endstream
endobj
12 0 obj
<<
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>>
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W n
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(o)Tj
0.50856 -0.00001 TD
(f)Tj
0.71651 0 Td
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(specialized fibrocytes involved in ion transport, the)Tj
-1.22507 -1.01618 TD
0 Tc
0.04 Tw
[(authors did not observe transdif)18(ferentiation of any donor)]TJ
T*
0 Tw
(cell into either HCs or neurons.)Tj
1.61905 -1.01619 TD
0.005 Tc
0.12 Tw
(Overall, MSCs have been shown to survive in and)Tj
-1.61905 -1.01619 TD
0.013 Tc
0.112 Tw
(migrate to multiple sites within the cochlea following)Tj
T*
0 Tc
0.043 Tw
[(implantation (Matsuoka et al., 2007). However)41(, the rates)]TJ
T*
0.004 Tc
0.121 Tw
[(of neuronal dif)18(ferentiation of these cells are reportedly)]TJ
0 -1.01618 TD
0 Tc
0.02 Tw
[(very low)65(, both in normal and in hearing-damaged animal)]TJ
0 -1.01619 TD
0.031 Tc
0.094 Tw
(models. In light of these results, Ogita et al. (2010))Tj
0 -1.01618 TD
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0.05 Tw
(adopted a method for the neural induction of BM-MSCs)Tj
0 -1.01619 TD
0.011 Tw
(isolated from adult guinea pigs prior to their transfer into)Tj
0 -1.01618 TD
0.075 Tc
0.36 Tw
(the modiolus of adult guinea pigs. Neuronal)Tj
0 -1.01619 TD
0 Tc
0.007 Tw
[(dif)18(ferentiation of the MSCs was observed in 18,6 \261)-257(6,4%)]TJ
T*
0.034 Tc
0.091 Tw
(and 24.1\2615.3% of the transplants in the normal and)Tj
T*
0 Tc
0.072 Tw
[(damaged cochleae, respectively)67(. However)39(, no dif)18(ference)]TJ
T*
0.125 Tw
(was found between transplanted and control animals in)Tj
0 -1.01618 TD
0.059 Tc
0.066 Tw
(the number of surviving SGNs following ouabain)Tj
0 -1.01619 TD
0.005 Tc
0.12 Tw
(treatment, indicating that the transplanted cells did not)Tj
T*
0 Tc
0.081 Tw
(promote the survival of host SGNs. This was consistent)Tj
T*
0.055 Tc
0.07 Tw
(with the ABR results, showing that no significant)Tj
T*
0.062 Tc
0.063 Tw
(functional recovery of the damaged cochleae had)Tj
T*
0 Tc
0.056 Tw
(occurred. This result dif)Tj
9.757 0 TD
(fered from the recovery of ABR)Tj
-9.757 -1.01619 TD
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0.085 Tw
(thresholds observed by the same group when using)Tj
T*
0.02 Tc
0.105 Tw
(mouse ESC-derived neural progenitors \(Okano et al.,)Tj
T*
0 Tc
0.095 Tw
[(2005\). It is possible that the MSCs did not dif)18(ferentiate)]TJ
T*
0.014 Tc
0.111 Tw
[(into the appropriate neuronal subtype \(glutamater)20(gic\),)]TJ
T*
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0.124 Tw
(and thus lacked the characteristics of auditory neurons.)Tj
T*
0.003 Tc
0.122 Tw
[(The ability of MSCs to dif)18(ferentiate into glutamater)20(gic)]TJ
T*
0.062 Tc
0.063 Tw
(neurons was demonstrated )Tj
ET
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[(in vitr)37(o)]TJ
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(by Kondo and)Tj
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0.011 Tw
(colleagues (2005). These authors observed that, although)Tj
0.0693 Tc
(a)'
0.88827 0 Td
0.069 Tc
0.056 Tw
(marked up-regulation of neuronal markers was)Tj
-0.88827 -1.01619 TD
0.074 Tc
0.051 Tw
(observed in mouse BM-MSCs exposed to bFGF/)Tj
T*
0.003 Tc
0.122 Tw
(Forskolin, expression of sensory neuronal markers was)Tj
T*
0.016 Tc
0.109 Tw
(only detected when the cells were also treated with a)Tj
T*
0.029 Tc
0.096 Tw
(combination of Shh and RA, two molecules that are)Tj
T*
0.023 Tc
0.102 Tw
(secreted in the vicinity of peripheral sensory ganglia)Tj
T*
0 Tc
0.047 Tw
(during embryogenesis. Co-culture experiments with pre-)Tj
T*
0.013 Tc
0.112 Tw
(natal mouse OC explants revealed that the BM-MSC-)Tj
T*
0 Tc
0 Tw
(derived neurons extended processes towards HCs. )Tj
1.61905 -1.01619 TD
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0.399 Tw
(Not only have BM-MSCs been shown to)Tj
-1.61905 -1.01619 TD
0 Tc
0 Tw
(dif)Tj
1.09277 0.00001 TD
0.044 Tw
(ferentiate into glutamater)Tj
10.1753 0.00001 TD
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(in vitr)Tj
2.42309 0.00001 TD
0 Tw
(o, )Tj
ET
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/GS3 gs
/GS2 gs
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0.044 Tw
(but also)Tj
-19.7095 -1.01619 TD
0.008 Tc
0.117 Tw
(into HC-like cells, as reported by Jeon and colleagues)Tj
T*
0 Tc
0.026 Tw
((2007). This group used a combination of growth factors)Tj
T*
0.075 Tc
0.192 Tw
(to drive mouse BM-MSCs into a neurosensory)Tj
T*
0 Tc
0.012 Tw
[(progenitor phenotype. As observed by Heller)-3655(s group \(Li)]TJ
0.0082 Tc
(et)'
1.11338 0 Td
0.008 Tc
0.117 Tw
(al., 2003b\) with ESCs, further dif)Tj
14.23283 0.00001 TD
(ferentiation of the)Tj
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0.029 Tw
(progenitors into a mature HC phenotype \(e.g. expression)Tj
T*
0.085 Tw
(of markers such as myosin VIIa, espin, and presence of)Tj
T*
0.057 Tc
0.068 Tw
(protrusions resembling stereociliary bundles\) was)Tj
T*
0.001 Tc
0.124 Tw
(observed when these cells were either co-cultured with)Tj
T*
0 Tc
0.097 Tw
(embryonic day 3 (E3) chick otocyst cells or injected )Tj
ET
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(ex)Tj
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(vivo)Tj
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0.055 Tc
0.07 Tw
[(into E3 chick otocysts. Alternatively)66(, further)]TJ
-2.26203 -1.01619 TD
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0.11 Tw
(maturation of the progenitors was achieved by forced)Tj
T*
0 Tc
0.026 Tw
(expression of the transcription factor Atoh1, required for)Tj
T*
0 Tw
[(HC formation in the inner ear)56(. )]TJ
ET
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[((b3) Olfactory bulb pr)37(ecursor cells.)]TJ
ET
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(The olfactory)Tj
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0.022 Tc
0.103 Tw
(neuroepithelium is the only tissue in the body where)Tj
0 -1.01619 TD
0.004 Tc
0.121 Tw
(damaged or dead neurons are replaced throughout life,)Tj
T*
0 Tc
0.073 Tw
(and this is due to the presence of multipotent stem cells)Tj
ET
0 0 0 0 k
307.559 51.023 242.362 631.654 re
f
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/F1 1 Tf
10.5 0 0 10.5 308.559 674.4964 Tm
0 0 0 1 k
0.0048 Tc
(\()Tj
0.3378 -0.00001 TD
0.005 Tc
0.12 Tw
(Roisen et al., 2001; Othman et al., 2005\). These cells)Tj
-0.3378 -1.01618 TD
0.038 Tc
0.087 Tw
(can be easily and abundantly obtained, making this)Tj
T*
0.075 Tc
0.082 Tw
(tissue a very important source of stem cells for)Tj
0 -1.01619 TD
0.002 Tc
0.123 Tw
(autologous transplantation. Following culture of mouse)Tj
T*
0 Tc
0.125 Tw
(olfactory precursor cells in the presence of conditioned)Tj
T*
0.015 Tc
0.11 Tw
(medium from adult mouse cochlear cultures or in co-)Tj
T*
0.018 Tc
0.107 Tw
(culture with these cells, Doyle and colleagues (2007))Tj
0 -1.01618 TD
0.075 Tc
0.062 Tw
[(reported dif)18(ferentiation of a proportion of these)]TJ
0 -1.01619 TD
0.02 Tc
0.105 Tw
(precursors into cells that expressed proteins found in)Tj
0 -1.01618 TD
0 Tc
0.101 Tw
(HCs (i.e. myosin VIIa, espin, calretinin, prestin). These)Tj
0 -1.01619 TD
0.122 Tw
(results pointed to the presence of soluble factors in the)Tj
0 -1.01618 TD
0.003 Tc
[(cochlear cultures capable of inducing dif)20(ferentiation of)]TJ
0 -1.01619 TD
0 Tc
0 Tw
(non-auditory cells. )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 308.559 535.7866 Tm
0 Tr
0 0 0 1 k
0 Tc
0.041 Tw
((b4) Ependymal cells.)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 404.3233 535.7866 Tm
0 Tr
0 0 0 1 k
-0.0001 Tc
(A)Tj
1.01332 0 Td
0 Tc
0.041 Tw
(population of proliferative cells)Tj
-10.13373 -1.01619 TD
0.063 Tw
(that exhibit morphological and functional characteristics)Tj
T*
0.022 Tc
0.103 Tw
[(similar to those of HCs was isolated by W)80(ei and co-)]TJ
0 -1.01618 TD
0 Tc
0.113 Tw
(workers (2008) from the ependymal layer of the lateral)Tj
0 -1.01619 TD
0.067 Tw
(brain ventricle of adult rodents and humans. These cells)Tj
T*
0.057 Tc
0.068 Tw
(expressed various HC proteins \(e.g. myosin VIIa,)Tj
T*
0.006 Tc
0.119 Tw
[(myosin VI, the HC synaptic protein ribeye\) and lar)19(ge-)]TJ
T*
0.029 Tc
0.096 Tw
(conductance FM1-43 permeable channels, possessed)Tj
T*
0.003 Tc
0.122 Tw
(stereociliary and kinociliary bundles, and were capable)Tj
T*
0.002 Tc
0.123 Tw
(of establishing functional synapses with primary SGNs)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 308.559 429.0865 Tm
0 Tr
0 0 0 1 k
0 Tc
0.115 Tw
(in vitr)Tj
2.49472 0 TD
0 Tw
(o. )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 346.4642 429.0865 Tm
0 Tr
0 0 0 1 k
0 Tc
0 Tw
(Interestingly)Tj
4.98852 0 TD
(,)Tj
0.61522 0 Td
0.115 Tw
(these cells incorporated well into)Tj
-9.21376 -1.0162 TD
0.117 Tw
(the sensory epithelia of explanted cochleae from which)Tj
0 -1.01619 TD
0.02 Tc
0.105 Tw
(HCs had been eliminated. The authors thus proposed)Tj
T*
0.016 Tc
0.109 Tw
(ependymal cells as candidates to take over functional)Tj
T*
0 Tc
0 Tw
[(roles of HCs in the damaged inner ear)56(.)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 308.559 375.7365 Tm
0 Tr
0 0 0 1 k
0.02 Tc
0.105 Tw
((b5) Inner ear stem cells. )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 428.1173 375.7365 Tm
0 Tr
0 0 0 1 k
0.02 Tc
0.105 Tw
(Stem cells of the inner ear)Tj
-11.38651 -1.01619 TD
0 Tc
0 Tw
[(have been isolated from the vestibular or)19(gans of mice \(Li)]TJ
T*
0.093 Tw
(et al., 2003a; Oshima et al., 2007\), from the mouse OC)Tj
T*
0.004 Tw
((Oshima et al., 2007; Savary et al., 2007, 2008) and from)Tj
T*
0.053 Tw
(the spiral ganglion \(Rask-Andersen et al., 2005; Oshima)Tj
T*
0.002 Tw
(et al., 2007\), applying a sphere-formation assay routinely)Tj
T*
0.015 Tc
0.11 Tw
(used with CNS stem cells \(Mart\222nez-Monedero et al.,)Tj
T*
0 Tc
0.102 Tw
(2007\). Li and colleagues \(2003a\) showed that inner ear)Tj
T*
0.011 Tc
0.114 Tw
(stem cells isolated from the adult mouse utricle could)Tj
T*
0 Tc
0.119 Tw
(give rise to cells from the three germ layers. Moreover)Tj
T*
0.007 Tc
0.118 Tw
[(they could also dif)18(ferentiate into auditory neurons and)]TJ
T*
0.046 Tc
0.078 Tw
(HC-like cells that expressed multiple HC markers,)Tj
T*
0.021 Tc
0.104 Tw
(presented hair)Tj
6.0127 0.00001 TD
(-bundle-like protrusions, and expressed)Tj
-6.0127 -1.0162 TD
0.015 Tc
0.11 Tw
(functional ion channels similar to those of embryonic)Tj
0 -1.01619 TD
0.069 Tc
0.056 Tw
(HCs. Mart\222nez-Monedero and co-workers (2008))Tj
T*
0.058 Tc
0.067 Tw
[(demonstrated that this dif)19(ferentiation could occur)]TJ
T*
0.035 Tc
0 Tw
(spontaneously)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 377.3231 205.0166 Tm
0 Tr
0 0 0 1 k
0.035 Tc
0.09 Tw
[(in vitr)37(o, )]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 418.3572 205.0166 Tm
0 Tr
0 0 0 1 k
0.035 Tc
0.09 Tw
(in the absence of any added)Tj
-10.45697 -1.01619 TD
0 Tc
0.1 Tw
(growth factor)Tj
5.45891 0.00001 TD
-0.0001 Tc
(.)Tj
0.60013 0 Td
0 Tc
(Inner ear stem cells gave rise to HC-like)Tj
-6.05905 -1.01619 TD
0.005 Tc
0.12 Tw
(and glial cells, as well as to auditory-like neurons that)Tj
T*
0 Tc
0.113 Tw
(responded to glutamate, fired action potentials and sent)Tj
T*
0.043 Tc
0.082 Tw
(out processes towards explants of denervated OCs,)Tj
T*
0 Tc
0.123 Tw
(where they formed contacts with HCs. V)Tj
16.98221 0.00001 TD
(ery relevant is)Tj
-16.98221 -1.01619 TD
0.051 Tc
0.074 Tw
(also the finding by Rask-Andersen and colleagues)Tj
T*
0 Tc
0.113 Tw
((2005) who described a stem/progenitor cell population)Tj
T*
0.016 Tc
0.109 Tw
(present in adult human and guinea pig spiral ganglia.)Tj
T*
0.02 Tc
0.105 Tw
(These cells formed nestin-expressing spheres )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 516.1289 108.9865 Tm
0 Tr
0 0 0 1 k
0.02 Tc
0.105 Tw
[(in vitr)37(o)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 308.559 98.3165 Tm
0 Tr
0 0 0 1 k
0 Tc
0.097 Tw
[(and could dif)18(ferentiate into neurons and glial cells. The)]TJ
0 -1.01619 TD
0.047 Tc
0.078 Tw
[(newly emer)18(ged neurons expressed T)35(rkB and T)35(rkC,)]TJ
0 -1.01618 TD
0 Tc
0.047 Tw
[(receptors for the NFs BDNF and neurotrophin-3 \(NT)91(-3\).)]TJ
0 -1.01619 TD
0.004 Tc
0.121 Tw
(These data support the notion that inner ear stem cells)Tj
T*
0 Tc
0.059 Tw
(keep some kind of memory of their tissue of origin, and)Tj
ET
0 0 0 0 k
45.354 729.071 504.567 14.1729 re
f
45.354 715.927 504.567 12.002 re
f
45.354 683.748 504.567 31.181 re
f
45.354 729.071 504.567 14.1729 re
f
Q
/GS3 gs
/GS2 gs
q
BT
/F3 1 Tf
7.7 0 0 7.7 46.3543 731.757 Tm
0 Tr
0 0 0 1 k
0 Tc
0 Tw
(930)Tj
ET
0 0 0 0 k
45.354 715.927 504.567 12.002 re
f
Q
/GS3 gs
/GS2 gs
q
BT
/F4 1 Tf
10.5 0 2.23185 10.5 226.75 719.277 Tm
0 Tr
0 0 0 1 k
0 Tc
0 Tw
(Approaches to inner ear repair)Tj
ET
Q
endstream
endobj
13 0 obj
<<
/Length 12256
>>
stream
/GS0 gs
q
0 0.929 595 782 re
W n
1 g
0 782.929 0 0 re
f
Q
/GS1 gs
q
/GS2 gs
0 0 0 0 k
45.354 51.023 242.363 631.654 re
f
Q
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 46.3543 674.4964 Tm
0 Tr
0 0 0 1 k
0.0586 Tc
(s)Tj
0.44759 -0.00001 TD
0.059 Tc
0.066 Tw
[(eem to follow an innate program to dif)19(ferentiate)]TJ
-0.44759 -1.01618 TD
0 Tc
0.058 Tw
(towards the corresponding auditory phenotypes. Oshima)Tj
T*
0.001 Tc
0.124 Tw
[(and co-workers (2007) pointed out intrinsic dif)19(ferences)]TJ
0 -1.01619 TD
0 Tc
0.06 Tw
(in the potential of stem cells isolated from distinct inner)Tj
T*
0.075 Tc
0.125 Tw
(ear tissues to give rise to auditory phenotypes.)Tj
T*
0.007 Tc
0.118 Tw
[(Accordingly)65(, spiral ganglion-derived spheres appear to)]TJ
T*
0.01 Tc
0.115 Tw
(give rise mostly to neurons and glial cell types, while)Tj
0 -1.01618 TD
0.046 Tc
0.079 Tw
(spheres derived from the OC or vestibular sensory)Tj
0 -1.01619 TD
0 Tc
0 Tw
(epithelia most frequently give rise to HCs. )Tj
1.61905 -1.01618 TD
0.022 Tc
0.103 Tw
(An interesting population of auditory progenitors)Tj
-1.61905 -1.01619 TD
0.02 Tc
0.105 Tw
(was identified by Rivolta and his group \(Chen et al.,)Tj
0 -1.01618 TD
0.031 Tc
0.094 Tw
[(2007, 2009\) in cochleae from 9-1)37(1-week-old human)]TJ
0 -1.01619 TD
0 Tc
0.084 Tw
[(fetuses \(human fetal auditory stem cells or hF)75(ASCs\). In)]TJ
T*
0.032 Tc
0.093 Tw
(contrast to some of the progenitors described above)Tj
T*
0 Tc
0.102 Tw
((Rask-Andersen et al., 2005; Savary et al., 2007), these)Tj
T*
0.035 Tc
0.09 Tw
[(cells were capable of under)19(going long-term )]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 252.9757 514.4465 Tm
0 Tr
0 0 0 1 k
0.035 Tc
0.09 Tw
[(in vitr)37(o)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 46.3543 503.7766 Tm
0 Tr
0 0 0 1 k
0.008 Tc
0.117 Tw
(expansion (i.e. for at least up to 1 year). Furthermore,)Tj
0 -1.01619 TD
0.022 Tc
0.103 Tw
[(hF)73(ASCs could dif)18(ferentiate into HC-like and sensory)]TJ
T*
0.075 Tc
0.206 Tw
(neuron-like cells that exhibited functional and)Tj
T*
0.054 Tc
0.071 Tw
(electrophysiological properties similar to those of)Tj
T*
0 Tc
0.125 Tw
(developing cochlear HCs and auditory neurons )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 254.2115 461.0965 Tm
0 Tr
0 0 0 1 k
0 Tc
0.125 Tw
(in vivo)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 283.7992 461.0965 Tm
0 Tr
0 0 0 1 k
0 Tc
(;)Tj
-22.6138 -1.01619 TD
0.018 Tc
0.107 Tw
(cells expressing SC markers were also obtained from)Tj
T*
0 Tc
0 Tw
(hF)Tj
0.98193 0 TD
(ASCs. )Tj
0.63711 -1.01619 TD
0.022 Tw
(The presence of stem cells in the post-natal inner ear)Tj
-1.61905 -1.01619 TD
0.075 Tc
0.075 Tw
(appears contradictory with the observed lack of)Tj
T*
0.058 Tc
0.067 Tw
(regeneration in the mature cochlea following otic)Tj
T*
0.025 Tc
0.1 Tw
(damage. However)Tj
7.71458 0 TD
0.0253 Tc
(,)Tj
0.65022 0 Td
0.025 Tc
(lower numbers of sphere-forming)Tj
-8.3648 -1.01619 TD
0 Tc
0.061 Tw
(cells in early postnatal cochleae compared to embryonic)Tj
T*
0.028 Tc
0.097 Tw
(tissue have been reported by Savary and co-workers)Tj
T*
0.039 Tc
0.086 Tw
((2008), and Oshima and colleagues (2007) recently)Tj
T*
0 Tc
0.079 Tw
(demonstrated that there is a radical loss of stem cells in)Tj
T*
0.006 Tc
0.119 Tw
(the mammalian cochlea during postnatal maturation of)Tj
T*
0 Tc
0.002 Tw
(the auditory system. While cochlear tissues isolated from)Tj
T*
0.031 Tc
0.094 Tw
(mice not older than 3 weeks of age harbour sphere-)Tj
T*
0.026 Tc
0.099 Tw
(forming cells, this capacity appears to be practically)Tj
T*
0 Tc
0.006 Tw
(absent in the cochlea of older mice. This seems to be due)Tj
T*
0.023 Tw
(to either death of these stem/progenitor types or to a loss)Tj
T*
0.075 Tc
0.056 Tw
(of their stem cell features. Regarding this latter)Tj
T*
0 Tc
0.033 Tw
[(possibility)65(, in the young mammalian cochlea it is not yet)]TJ
T*
0.082 Tw
(clear which cell population stem cells are derived from.)Tj
T*
0.05 Tw
(Zhai and co-workers (2005) isolated a population of HC)Tj
T*
0.025 Tc
0.1 Tw
(progenitors from the lesser epithelial ridge (LER) of)Tj
T*
0 Tc
(neonatal rats. This tissue is juxtaposed to the outer hair)Tj
T*
0.029 Tc
0.096 Tw
(cells and, together with the medially located greater)Tj
T*
0.062 Tc
0.063 Tw
(epithelial ridge (GER), it has been proposed as a)Tj
T*
0.021 Tc
0.104 Tw
(potential source for HC progenitors, as both of these)Tj
T*
0.022 Tc
0.103 Tw
(tissues may give rise to HCs when forced to express)Tj
T*
0 Tc
0.054 Tw
(Atoh1 \(Zheng and Gao, 2000; Shou et al., 2003; Zhai et)Tj
T*
0.041 Tw
(al., 2005\). Zhai and colleagues \(2005\) demonstrated that)Tj
T*
0.122 Tw
(isolated LER cells grown as spheres in the presence of)Tj
T*
0.017 Tc
0.108 Tw
(EGF proliferated and could dif)Tj
13.25128 0.00001 TD
(ferentiate into HC-like)Tj
-13.25128 -1.0162 TD
0.058 Tc
0.067 Tw
(and SC-like cells when co-cultured with utricular)Tj
0 -1.01619 TD
0.047 Tc
0.078 Tw
(mesenchymal cells, in a pattern reminiscent of the)Tj
T*
0.075 Tc
0.292 Tw
(sensory epithelium )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 149.673 108.9865 Tm
0 Tr
0 0 0 1 k
0.075 Tc
0.292 Tw
(in vivo. )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 196.4187 108.9865 Tm
0 Tr
0 0 0 1 k
0.075 Tc
0.292 Tw
(In another set of)Tj
-14.29185 -1.01619 TD
0 Tc
0.103 Tw
(experiments, Malgrange and colleagues (2002) detected)Tj
T*
0.066 Tw
(nestin expression in the GER region and below the IHC)Tj
0 -1.01618 TD
0.005 Tc
0.12 Tw
(of rats between embryonic day 19 (E19) and postnatal)Tj
0 -1.01619 TD
0.028 Tc
0.097 Tw
(day 7 (P7); they observed that )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 190.5111 66.3066 Tm
0 Tr
0 0 0 1 k
0.028 Tc
0.097 Tw
[(in vitr)37(o)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 228.069 66.3066 Tm
0 Tr
0 0 0 1 k
0.028 Tc
0 Tw
(non-adherent)Tj
-17.30616 -1.01619 TD
0 Tc
0.006 Tw
(culture of nestin-positive cells isolated from the newborn)Tj
ET
0 0 0 0 k
307.559 51.023 242.362 631.654 re
f
BT
/F1 1 Tf
10.5 0 0 10.5 308.559 674.4964 Tm
0 0 0 1 k
-0.0001 Tc
(r)Tj
0.33294 -0.00001 TD
0 Tc
0.099 Tw
[(at OC led to their dif)19(ferentiation into HC-like and SC-)]TJ
-0.33294 -1.01618 TD
0.121 Tw
[(like cells. Interestingly)66(, nearly one third of the HC-like)]TJ
T*
0.024 Tc
0.101 Tw
(cells present after 2 days of suspension culture were)Tj
0 -1.01619 TD
0 Tc
0.025 Tw
(produced following cell division, as indicated by myosin)Tj
T*
0 Tw
(VIIa/BrdU double labeling. )Tj
1.61905 -1.01619 TD
0.022 Tc
0.103 Tw
(It has also been hypothesized that HC progenitor)Tj
-1.61905 -1.01619 TD
0 Tc
0.098 Tw
(cells in the early postnatal period might in fact be SCs,)Tj
0 -1.01618 TD
0.018 Tc
0.107 Tw
(as it has been shown that SCs isolated from neonatal)Tj
0 -1.01619 TD
0 Tc
0.064 Tw
[(mice can divide and transdif)19(ferentiate into HC-like cells)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 308.559 578.4666 Tm
0 Tr
0 0 0 1 k
0.017 Tc
0.108 Tw
[(in vitr)37(o)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 345.2876 578.4666 Tm
0 Tr
0 0 0 1 k
0.017 Tc
0.108 Tw
[((White et al., 2006). Interestingly)66(, an Abcg2-)]TJ
-3.49796 -1.01619 TD
0.003 Tc
0.122 Tw
(expressing side population (SP) of progenitor cells has)Tj
0 -1.01618 TD
0.005 Tc
0.119 Tw
(been identified within the population of SCs in the P3)Tj
0 -1.01619 TD
0.028 Tc
0.097 Tw
[(mouse cochlea and can be isolated by F)75(ACS sorting)]TJ
T*
0.009 Tc
0.116 Tw
((Savary et al., 2007). These cells also express another)Tj
T*
0 Tc
0.104 Tw
[(stem cell marker)41(, Musashi1, proliferate and give rise to)]TJ
T*
0.067 Tw
(HCs and SCs )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 369.3035 514.4465 Tm
0 Tr
0 0 0 1 k
0 Tc
0.067 Tw
[(in vitr)37(o)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 400.2431 514.4465 Tm
0 Tr
0 0 0 1 k
0 Tc
(.)Tj
0.56715 0 Td
0.067 Tw
(Of note, they have a very limited)Tj
-9.29898 -1.01618 TD
0.025 Tc
0.1 Tw
(capacity for self-renewal (i.e. only two passages), in)Tj
0 -1.01619 TD
0.055 Tc
0.07 Tw
(contrast to stem cells isolated from the vestibular)Tj
T*
0 Tc
0.074 Tw
(system, where a limited amount of HC regeneration has)Tj
T*
0.063 Tw
(been observed. Intrinsic changes in the ability of SCs to)Tj
T*
0.031 Tc
0.094 Tw
(give rise to HCs over time have also been reported.)Tj
T*
0.026 Tc
0.099 Tw
(White and co-workers (2006) demonstrated that SCs)Tj
T*
0.048 Tc
0.076 Tw
(isolated from P14 mouse cochleae failed to down-)Tj
T*
0.043 Tc
0.082 Tw
(regulate the cyclin-dependent kinase inhibitor p27,)Tj
T*
0.036 Tc
0.089 Tw
(compared to cultures of SCs isolated from neonatal)Tj
T*
0.056 Tc
0.068 Tw
(mice. This inability to re-enter the cell cycle was)Tj
T*
0.075 Tc
0.257 Tw
(associated with lower numbers of cells trans-)Tj
T*
0.07 Tc
0.055 Tw
[(dif)18(ferentiating into HCs. In addition to a loss of)]TJ
T*
0.075 Tc
0.113 Tw
(phenotypic plasticity of progenitor cells during)Tj
T*
0 Tc
0.034 Tw
(maturation of the mammalian cochlea, the observed lack)Tj
T*
0.091 Tw
(of regeneration of lost cell types in the injured auditory)Tj
T*
0.123 Tw
(system might also be related to the presence of )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 519.3456 343.7265 Tm
0 Tr
0 0 0 1 k
0 Tc
0.123 Tw
(in vivo)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 308.559 333.0565 Tm
0 Tr
0 0 0 1 k
0.025 Tc
0.1 Tw
(mechanisms that are inhibitory for cell proliferation.)Tj
0 -1.01619 TD
0 Tc
0.019 Tw
(Data from dif)Tj
5.46135 0 TD
(ferent groups \(White et al., 2006; Savary et)Tj
-5.46135 -1.01619 TD
0.004 Tc
0.121 Tw
(al., 2007\) point to the existence of pools of progenitor)Tj
T*
0.018 Tc
0.107 Tw
(cells present in the OC of post-natal animals that are)Tj
T*
0.015 Tc
0.11 Tw
(capable of proliferating under the appropriate )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 516.432 290.3765 Tm
0 Tr
0 0 0 1 k
0.015 Tc
0.11 Tw
(in vitr)Tj
2.59411 0.00001 TD
0 Tc
(o)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
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0 Tr
0 0 0 1 k
0.03 Tc
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(culture conditions following their isolation from the)Tj
0 -1.01619 TD
0 Tc
0 Tw
(original tissue.)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F4 1 Tf
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0 Tr
0 0 0 1 k
0 Tc
0 Tw
(Regeneration by endogenous cell types)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 325.559 226.3565 Tm
0 Tr
0 0 0 1 k
0.064 Tc
0.061 Tw
(As already mentioned above, one of the main)Tj
-1.61905 -1.01619 TD
0.005 Tc
0.12 Tw
(hurdles when approaching inner ear cell therapy is the)Tj
T*
0 Tc
0.071 Tw
(correct integration of the transplanted cells into the host)Tj
T*
0.099 Tw
(tissue. T)Tj
3.45229 0.00001 TD
0 Tw
(ransdif)Tj
2.7583 0.00001 TD
0.099 Tw
(ferentiation of endogenous inner ear cell)Tj
-6.21058 -1.0162 TD
0.069 Tc
0.056 Tw
(types might overcome this problem \(Shibata and)Tj
0 -1.01619 TD
0.058 Tc
0.067 Tw
(Raphael, 2010\). Studies on avians and other non-)Tj
T*
0.073 Tc
0.052 Tw
(mammalian systems \(Stone and Cotanche, 2007;)Tj
T*
0.019 Tc
0.106 Tw
(Cotanche, 2008; Y)Tj
7.94579 0.00001 TD
0.0187 Tc
(u)Tj
0.8936 0 Td
0.019 Tc
(et al., 2010\), and the similarities)Tj
-8.8394 -1.01619 TD
0 Tc
0.02 Tw
(found with embryonic and neonatal mammalian auditory)Tj
T*
0.064 Tw
[(or)17(gans \(Fekete and W)41(u, 2002; Daudet and Lewis, 2005\))]TJ
T*
0.042 Tw
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T*
0.029 Tw
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0.0225 Tc
(a)'
0.84151 0 Td
0.023 Tc
0.102 Tw
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-0.84151 -1.01619 TD
0.052 Tc
0.073 Tw
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0 -1.01618 TD
0.016 Tc
0.109 Tw
(expression of the cell cycle inhibitor p27 in HCs and)Tj
0 -1.01619 TD
0 Tc
0.105 Tw
[(SCs of the mature avian sensory or)18(gan does not appear)]TJ
T*
0.029 Tc
0.096 Tw
[(to inhibit regeneration \(Cotanche and Kaiser)42(, 2010\),)]TJ
ET
0 0 0 0 k
45.354 729.071 504.567 14.1729 re
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45.354 716.262 504.567 12 re
f
45.354 683.748 504.567 31.181 re
f
45.354 729.071 504.567 14.1729 re
f
Q
/GS3 gs
/GS2 gs
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BT
/F3 1 Tf
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0 Tr
0 0 0 1 k
0 Tc
0 Tw
(931)Tj
ET
0 0 0 0 k
45.354 716.262 504.567 12 re
f
Q
/GS3 gs
/GS2 gs
q
BT
/F4 1 Tf
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0 Tr
0 0 0 1 k
0 Tc
0 Tw
(Approaches to inner ear repair)Tj
ET
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endstream
endobj
14 0 obj
<<
/Length 11095
>>
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/GS0 gs
q
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W n
1 g
0 782.929 0 0 re
f
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/GS1 gs
q
/GS2 gs
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45.354 51.023 242.363 631.654 re
f
Q
/GS2 gs
q
BT
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0 Tr
0 0 0 1 k
-0.0001 Tc
(f)Tj
0.33295 -0.00001 TD
0 Tc
0.122 Tw
(ailure of the adult mammalian SCs to re-enter the cell)Tj
-0.33295 -1.01618 TD
0.106 Tw
(cycle has been attributed, among other reasons, to their)Tj
T*
0.009 Tc
0.116 Tw
(inability to suppress this inhibitor \(White et al., 2006;)Tj
0 -1.01619 TD
0.017 Tc
0.108 Tw
(Ono et al., 2009\). Therefore, some of the attempts to)Tj
T*
0 Tc
0.036 Tw
(obtain new HCs have focused on the down-regulation of)Tj
T*
0.017 Tc
0.108 Tw
(this and other inhibitors such as retinoblastoma (Rb),)Tj
T*
0.01 Tc
0.115 Tw
(which also plays a role in maintaining the postmitotic)Tj
0 -1.01618 TD
0.013 Tc
0.112 Tw
(state of SCs and HCs \(Sage et al., 2005; Laine et al.,)Tj
0 -1.01619 TD
0.065 Tc
0.06 Tw
(2007\). Indeed, inactivation of these proliferation)Tj
0 -1.01618 TD
0.013 Tc
0.112 Tw
(inhibitors in mammalian SCs has led to cell cycle re-)Tj
0 -1.01619 TD
0 Tc
0.041 Tw
(entry of some SC populations \(Minoda et al., 2007; Ono)Tj
0 -1.01618 TD
0.028 Tc
0.097 Tw
[(et al., 2009; Y)111(u et al., 2010\). Moreover)40(, while some)]TJ
0 -1.01619 TD
0.032 Tc
0.093 Tw
[(groups have not observed transdif)18(ferentiation of the)]TJ
T*
0.075 Tc
0.106 Tw
(cycling SCs into HCs, others have reported the)Tj
T*
0 Tc
0.043 Tw
(production of excess SCs as well as supernumerary HCs)Tj
T*
0.049 Tw
[(\(Chen et al., 2003; Sage et al., 2005, 2006; W)81(eber et al.,)]TJ
0 -1.01618 TD
0.062 Tc
0.063 Tw
[(2008\) following mitosis. However)40(, this abnormal)]TJ
0 -1.01619 TD
0.032 Tc
0.093 Tw
(proliferation of SCs ultimately resulted in markedly)Tj
T*
0.014 Tc
0.11 Tw
(increased apoptotic rates of the newly generated cells)Tj
T*
0.075 Tc
0.075 Tw
(which in turn led to a disruption of the sensory)Tj
T*
0.03 Tc
0.095 Tw
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T*
0 Tc
0.081 Tw
(2005; Laine et al., 2007; W)Tj
11.29636 0 TD
(eber et al., 2008; Ono et al.,)Tj
-11.29636 -1.01619 TD
0.019 Tc
0.106 Tw
(2009; Groves, 2010\). Similarly)Tj
13.29786 0 TD
0.0192 Tc
(,)Tj
0.64414 0 Td
0.019 Tc
(inactivation of Rb in)Tj
-13.942 -1.01619 TD
0.015 Tc
0.11 Tw
(postmitotic HCs was shown to result in cell cycle re-)Tj
T*
0 Tc
0.05 Tw
[(entry)65(, although these cells died at dif)19(ferent stages before)]TJ
T*
0 Tw
[(mitosis was complete \(W)81(eber et al., 2008\).)]TJ
1.61905 -1.01619 TD
0.084 Tw
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-1.61905 -1.01619 TD
0.034 Tw
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T*
0.109 Tw
(factors are required. A main candidate is Math1/Atoh1,)Tj
T*
0.021 Tc
0.104 Tw
(encoding a basic helix-loop-helix transcription factor)Tj
T*
0 Tc
0.073 Tw
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T*
0.041 Tw
(of the HC lineage \(W)Tj
8.69107 0 TD
(oods et al., 2004; Jeon et al., 2007;)Tj
-8.69107 -1.01619 TD
0.1 Tw
(Han et al., 2010\). Absence of Atoh1 in knock-out mice)Tj
T*
0.084 Tw
(results in the loss of HCs in the sensory epithelium and)Tj
T*
0.004 Tc
0.121 Tw
[(disrupted dif)18(ferentiation of cochlear SCs \(Bermingham)]TJ
T*
0 Tc
0.125 Tw
(et al., 1999; W)Tj
6.21533 0 TD
(oods et al., 2004\). On the other hand, it)Tj
-6.21533 -1.01619 TD
0.074 Tw
(has been reported that over)Tj
11.10195 0.00001 TD
(-expression of this gene may)Tj
-11.10195 -1.01619 TD
0.018 Tc
0.107 Tw
(lead to the formation of supernumerary HC-like cells)Tj
T*
0.004 Tc
0.121 Tw
(\(Zheng and Gao, 2000; Zheng et al., 2000; Gubbels et)Tj
T*
0 Tc
0.015 Tw
(al., 2008\) both )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
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0 Tr
0 0 0 1 k
0 Tc
0.015 Tw
[(in vitr)37(o )]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 143.8834 258.3665 Tm
0 Tr
0 0 0 1 k
0 Tc
0 Tw
(and )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 161.8301 258.3665 Tm
0 Tr
0 0 0 1 k
0 Tc
0.015 Tw
(in vivo)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 190.2716 258.3665 Tm
0 Tr
0 0 0 1 k
0 Tc
(,)Tj
0.51529 0 Td
0.015 Tw
(and this may occur in)Tj
-14.2217 -1.01619 TD
0.008 Tc
0.117 Tw
(the absence of proliferation (Shou et al., 2003). These)Tj
T*
0.006 Tc
0.119 Tw
(cells have been shown to express HC proteins such as)Tj
T*
0 Tc
0.077 Tw
(myosin VIIa and calretinin and display HC morphology)Tj
T*
0.021 Tw
(and stereociliary bundles \(Zheng et al., 2000; Kawamoto)Tj
T*
0.093 Tw
(et al., 2003; Shou et al., 2003; Izumikawa et al., 2005\).)Tj
T*
0.062 Tc
0.062 Tw
(In some cases, the newly emer)Tj
14.32367 0.00001 TD
(ged HCs exhibited)Tj
-14.32367 -1.01619 TD
0.054 Tc
0.071 Tw
(electrophysiological properties similar to those of)Tj
T*
0.047 Tc
0.078 Tw
(already existing HCs and some appeared to attract)Tj
T*
0.004 Tc
0.12 Tw
(neurofilament-bearing processes from either the OC or)Tj
T*
0 Tc
0.029 Tw
(the cochlear nucleus \(Kawamoto et al., 2003; Gubbels et)Tj
T*
0.037 Tc
0.088 Tw
(al., 2008\). Furthermore, Izumikawa and co-workers)Tj
T*
0.003 Tc
0.122 Tw
((2005) reported reduced ABR thresholds in the ears of)Tj
T*
0.063 Tc
0.062 Tw
(hearing-damaged adult guinea pigs that had been)Tj
T*
0.006 Tc
0.118 Tw
(transduced with an Atoh1-GFP construct, compared to)Tj
T*
0 Tc
0.002 Tw
(non-inoculated control ears. This was associated with the)Tj
T*
0.008 Tc
0.117 Tw
(appearance of a substantial number of mature HC-like)Tj
0 -1.01618 TD
0 Tc
0.075 Tw
(cells in the deafened cochlea. The same group observed)Tj
0 -1.01619 TD
0.088 Tw
(that, while novel HCs detected within the OC exhibited)Tj
T*
0.047 Tc
0.078 Tw
(normal HC-like morphology and orientation, these)Tj
ET
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f
BT
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(f)Tj
0.35112 -0.00001 TD
0.018 Tc
0.107 Tw
(eatures were not maintained in neighbouring ectopic)Tj
-0.35112 -1.01618 TD
0.032 Tc
0.093 Tw
(HCs. In fact, some of these cells displayed a mixed)Tj
T*
0.075 Tc
0.271 Tw
(phenotype between HCs and SCs, pointing to)Tj
0 -1.01619 TD
0.377 Tw
[(transdif)18(ferentiation of SCs to HCs following)]TJ
T*
0.019 Tc
0.106 Tw
(misexpression of Atoh1 (Izumikawa et al., 2005). As)Tj
T*
0 Tc
0.073 Tw
(mentioned above, other non-sensory inner ear cell types)Tj
T*
0.028 Tc
0.097 Tw
(have been shown to give rise to new HCs following)Tj
0 -1.01618 TD
0 Tc
0.101 Tw
[(Atoh1 over)20(-expression; this is the case for cells present)]TJ
0 -1.01619 TD
0.008 Tc
0.117 Tw
(in the GER and LER \(Zheng et al., 2000; Shou et al.,)Tj
0 -1.01618 TD
0 Tc
0 Tw
(2003\).)Tj
1.61905 -1.01619 TD
0.008 Tc
0.117 Tw
[(W)40(ith regards to transdif)18(ferentiation of non-sensory)]TJ
-1.61905 -1.01618 TD
0.021 Tc
0.104 Tw
(cells to HCs via their genetic manipulation it is very)Tj
0 -1.01619 TD
0.028 Tc
0.097 Tw
(important to bear in mind the status of the damaged)Tj
T*
0 Tc
0.094 Tw
(tissue before its repair (Izumikawa et al., 2005). SCs in)Tj
T*
0.075 Tc
0.221 Tw
[(damaged cochleae under)19(go a series of marked)]TJ
T*
0.02 Tc
0.105 Tw
(morphological changes, expanding and forming scars)Tj
0 -1.01618 TD
0 Tc
0.085 Tw
(that prevent the perilymph and endolymph from mixing)Tj
0 -1.01619 TD
0.014 Tw
((Oesterle and Campbell, 2009). Extensive otic injury can)Tj
T*
0.016 Tc
0.109 Tw
[(ultimately result in the absence of dif)20(ferentiated SCs,)]TJ
T*
0 Tc
0.029 Tw
(which are replaced by a simple epithelium with cuboidal)Tj
T*
0.013 Tc
0.112 Tw
(or flat appearance; forced expression of Atoh1 in this)Tj
T*
0 Tc
0.116 Tw
(epithelium does not lead to any morphological changes)Tj
T*
0.005 Tw
(and HCs are not regenerated, indicating that the presence)Tj
T*
0.062 Tc
0.062 Tw
(of dif)Tj
2.61323 0 TD
(ferentiated SCs is a prerequisite for Atoh1-)Tj
-2.61323 -1.0162 TD
0 Tc
0 Tw
[(mediated transdif)19(ferentiation (Izumikawa et al., 2008).)]TJ
1.61905 -1.01619 TD
0.118 Tw
[(T)70(ogether with Atoh1, the Notch signalling pathway)]TJ
-1.61905 -1.01619 TD
0.112 Tw
(also plays a key role in regulating the numbers of HCs)Tj
T*
0.036 Tw
(that form in the OC. It has been shown that inhibition of)Tj
T*
0.015 Tc
0.11 Tw
(this pathway in the mammalian inner ear leads to the)Tj
T*
0 Tc
0.022 Tw
(formation of supernumerary HCs derived from either the)Tj
T*
0.075 Tc
0.124 Tw
[(transdif)18(ferentiation of SCs into HCs and/or the)]TJ
T*
0 Tc
0 Tw
(dif)Tj
1.09278 0 TD
0.056 Tw
(ferentiation of sensory progenitor cells still present in)Tj
-1.09278 -1.01619 TD
0.002 Tw
(early postnatal cochlear tissue \(Zine et al., 2000; Kiernan)Tj
T*
0.125 Tw
(et al., 2005; Y)Tj
5.97165 0 TD
(amamoto et al., 2006; Doetzlhofer et al.,)Tj
-5.97165 -1.01619 TD
0.084 Tw
[(2009; Groves, 2010\). Nevertheless, this ef)18(fect gradually)]TJ
T*
0.037 Tw
(diminishes during development in mammals \(Zine et al.,)Tj
T*
0.044 Tc
0.081 Tw
(2000\) and it is practically absent in adults. This is)Tj
T*
0.037 Tc
0.088 Tw
(thought to result from changes in the expression of)Tj
T*
0.001 Tc
0.124 Tw
(Notch pathway components \(Hori et al., 2007; Batts et)Tj
T*
0 Tc
0.007 Tw
[(al., 2009; Groves, 2010\). W)80(ork carried out by Ito\325)55(s group)]TJ
T*
0.041 Tc
0.084 Tw
((Hori et al., 2007) has revealed very low or absent)Tj
T*
0.001 Tc
0.123 Tw
(Notch1 and Jagged1 expression in the cochlea of adult)Tj
T*
0 Tc
0.026 Tw
(guinea pigs, in contrast with the higher expression levels)Tj
T*
0.056 Tc
0.069 Tw
(found in the GER and SCs of embryonic auditory)Tj
T*
0 Tc
0.105 Tw
(epithelia. In addition, and in agreement with the results)Tj
T*
0.04 Tc
0.085 Tw
(obtained by Batts and co-workers (2009), Hori and)Tj
T*
0 Tc
0.104 Tw
(colleagues (2007) observed up-regulation of both genes)Tj
T*
0.025 Tc
0.1 Tw
(in the inner sulcus region of the auditory epithelium)Tj
T*
0.024 Tc
0.101 Tw
(following ototoxic treatment of adult animals. Notch)Tj
T*
0.049 Tc
0.076 Tw
(inhibition in these animals led to the formation of)Tj
T*
0 Tc
0.061 Tw
(ectopic HCs, in contrast to its ef)Tj
13.20741 0.00001 TD
(fects on the cochleae of)Tj
-13.20741 -1.0162 TD
0.09 Tw
(normal-hearing control animals. Damage prior to Notch)Tj
0 -1.01619 TD
0.069 Tc
0.056 Tw
(inhibition was therefore required for ectopic HC)Tj
T*
0 Tc
0.03 Tw
[(formation to take place. Importantly)67(, a time window was)]TJ
T*
0.023 Tc
0.102 Tw
(identified in mammals when interference with Notch)Tj
T*
0.052 Tc
0.073 Tw
(pathway activation may lead to an increase in HC)Tj
0 -1.01618 TD
0.001 Tc
0.124 Tw
(production in damaged auditory epithelia. This appears)Tj
0 -1.01619 TD
0 Tc
0.039 Tw
(to be dependent on the species as well as on the severity)Tj
T*
0 Tw
(of the lesion (Oesterle et al., 2008; Batts et al., 2009).)Tj
ET
0 0 0 0 k
45.354 729.071 504.567 14.1729 re
f
45.354 715.927 504.567 12.002 re
f
45.354 683.748 504.567 31.181 re
f
45.354 729.071 504.567 14.1729 re
f
Q
/GS3 gs
/GS2 gs
q
BT
/F3 1 Tf
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0 Tr
0 0 0 1 k
0 Tc
0 Tw
(932)Tj
ET
0 0 0 0 k
45.354 715.927 504.567 12.002 re
f
Q
/GS3 gs
/GS2 gs
q
BT
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0 Tr
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0 Tw
(Approaches to inner ear repair)Tj
ET
Q
endstream
endobj
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<<
/Length 11768
>>
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/GS0 gs
q
0 0.929 595 782 re
W n
1 g
0 782.929 0 0 re
f
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/GS1 gs
q
/GS2 gs
0 0 0 0 k
45.354 51.023 242.363 631.654 re
f
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/GS2 gs
q
BT
/F0 1 Tf
9.5 0 0 9.5 46.3543 674.7535 Tm
0 Tr
0 0 0 1 k
0.011 Tc
0.128 Tw
(Promoting the survival of cell types that remain in)Tj
0 -1.12316 TD
-0.0001 Tc
(t)Tj
0.3329 -0.00001 TD
0 Tc
0 Tw
(he cochlea following otic injury)Tj
ET
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/GS3 gs
/GS2 gs
q
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/F4 1 Tf
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0 Tr
0 0 0 1 k
0 Tc
0 Tw
(Cell therapy approaches: Introduction of exogenous cells)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
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0 Tr
0 0 0 1 k
-0.0001 Tc
(A)Tj
0.98631 0 Td
0 Tc
0.014 Tw
(very important aspect of inner ear therapy consists)Tj
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0.044 Tc
0.081 Tw
(in promoting the survival of cell types that remain)Tj
0 -1.01618 TD
0.015 Tc
0.11 Tw
[(following otic injury)66(. This is especially critical in the)]TJ
0 -1.01619 TD
0.052 Tc
0.073 Tw
(case of SGNs, given the requirement for a certain)Tj
T*
0 Tc
0.045 Tw
[(population size of healthy SGNs that ensure the ef)19(ficacy)]TJ
T*
0.053 Tc
0.072 Tw
(of cochlear implants in hearing-damaged patients.)Tj
T*
0.043 Tc
0.082 Tw
(Several NFs have been identified that can promote)Tj
0 -1.01618 TD
0 Tc
0.061 Tw
(regeneration and enhance the function of surviving cells)Tj
0 -1.01619 TD
0.026 Tw
((see below). Maintenance of SGNs in the damaged inner)Tj
T*
0.054 Tc
0.071 Tw
(ear may require long-term administration of these)Tj
T*
0.045 Tc
0.08 Tw
[(f)1(a)1(c)1(t)1(o)1(r)1(s)1(;)1( )1(h)1(o)1(w)1(e)1(v)1(e)1(r)41(, the osmotic pumps employed for)]TJ
0 -1.01618 TD
0.03 Tc
0.095 Tw
(intracochlear infusion of NFs have a finite life-span)Tj
0 -1.01619 TD
0 Tc
0.088 Tw
((Gillespie et al., 2003; Shepherd et al., 2008). Repeated)Tj
T*
0.099 Tw
(replacement of these pumps conveys the serious risk of)Tj
T*
0.065 Tw
(infection within the cochlea, which makes these devices)Tj
T*
0.006 Tc
0.119 Tw
(unsuitable for clinical applications. On the other hand,)Tj
T*
0 Tc
0.029 Tw
(use of viral vectors to deliver therapeutic molecules may)Tj
T*
0.046 Tc
0.079 Tw
(yield high and sustained expression of the gene of)Tj
T*
0.038 Tc
0.087 Tw
(interest (Liu et al., 2005; Konishi et al., 2008), but)Tj
T*
0.054 Tc
0.071 Tw
[(carries the risk of potential toxicity)67(. )]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 225.3446 418.6736 Tm
0 Tr
0 0 0 1 k
0.054 Tc
0.071 Tw
(Ex vivo)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 265.1906 418.6736 Tm
0 Tr
0 0 0 1 k
0.054 Tc
0 Tw
(gene)Tj
-20.84155 -1.01619 TD
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0.062 Tw
(manipulation of appropriate cell types and their)Tj
T*
0.05 Tc
0.075 Tw
(subsequent use as a source of NFs following their)Tj
T*
0.032 Tc
0.093 Tw
[(transplantation into the inner ear has emer)20(ged as an)]TJ
T*
0.014 Tc
0.111 Tw
[(alternative therapeutic option. V)113(arious cell types have)]TJ
T*
0.018 Tc
0.107 Tw
(already been tested, such as HSCs, NSCs, fibroblasts)Tj
T*
0.002 Tc
0.123 Tw
(and Schwann cells; the latter are especially interesting,)Tj
T*
0 Tc
0.068 Tw
(since they are amenable to genetic manipulation, can be)Tj
T*
0.106 Tw
(easily obtained and used autologously)Tj
15.57921 0 TD
-0.0001 Tc
(.)Tj
0.60629 0 Td
0 Tc
0 Tw
(Importantly)Tj
4.65588 0 TD
(,)Tj
0.60637 0 Td
(and)Tj
-21.44775 -1.0162 TD
0.042 Tc
(dif)Tj
1.22004 0 TD
0.083 Tw
(ferently from the setting when dif)Tj
15.30389 0 TD
(ferentiation of)Tj
-16.52392 -1.0162 TD
0.037 Tc
0.088 Tw
(exogenous cells into specific inner ear cell types is)Tj
0 -1.01619 TD
0.002 Tc
0.123 Tw
[(sought-after)40(, the implantation of donor cells that act as)]TJ
T*
0.022 Tc
0.103 Tw
(delivery vectors for the production of trophic factors)Tj
T*
0.001 Tc
0.124 Tw
(should not require precise morphological integration of)Tj
T*
0.029 Tc
0.095 Tw
(these cells into the host tissue (Sekiya et al., 2006).)Tj
T*
0.043 Tc
0.082 Tw
(Additional support for the use of cell/gene therapy)Tj
T*
0.006 Tc
0.119 Tw
(versus the direct infusion of relevant trophic factors is)Tj
T*
0.065 Tc
0.059 Tw
(underlined by studies such as that carried out by)Tj
T*
0 Tc
0.09 Tw
(Pettingill and colleagues (2008), who demonstrated that)Tj
T*
0.038 Tc
0.087 Tw
[(Schwann cells genetically modified to over)22(-)1(e)1(x)1(p)1(r)1(e)1(s)1(s)]TJ
T*
0.026 Tc
0.099 Tw
[(BDNF elicited a greater ef)19(fect on the survival of rat)]TJ
T*
0 Tw
(SGNs )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
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0.026 Tc
0.099 Tw
[(in vitr)37(o)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 109.9547 194.6036 Tm
0 Tr
0 0 0 1 k
0.0263 Tc
(,)Tj
0.65122 0 Td
0.026 Tc
0.099 Tw
(compared to the direct application of)Tj
-6.7084 -1.01619 TD
0 Tc
0.038 Tw
[(recombinant BDNF)80(. These results indicate that Schwann)]TJ
T*
0.058 Tc
0.067 Tw
(cells produce some additional factor(s) that acted)Tj
T*
0 Tc
0 Tw
[(syner)18(gistically with the secreted BDNF)80(. )]TJ
1.61905 -1.01619 TD
0.006 Tc
0.119 Tw
(Okano and colleagues (2006) demonstrated for the)Tj
-1.61905 -1.01619 TD
0.01 Tc
0.115 Tw
(first time the possibility of using genetically modified)Tj
T*
0.008 Tc
0.117 Tw
(cells as vectors for the local and sustained delivery of)Tj
T*
0.075 Tc
0.373 Tw
(therapeutic agents into the cochlea. Prior to)Tj
T*
0 Tc
0.09 Tw
(transplantation, this group transfected the fibroblast cell)Tj
T*
0.004 Tc
0.121 Tw
(line NIH3T3 with the BDNF gene, whose product had)Tj
T*
0.015 Tc
0.11 Tw
[(previously been shown to ef)18(ficiently protect HCs and)]TJ
T*
0.036 Tc
0.089 Tw
(SGNs from various ototoxic insults. Okano and co-)Tj
T*
0.061 Tc
0.064 Tw
(workers confirmed survival and settlement of the)Tj
T*
0.053 Tc
0.072 Tw
(engineered cells in the perilymphatic space of the)Tj
ET
0 0 0 0 k
307.559 51.023 242.362 631.654 re
f
BT
/F1 1 Tf
10.5 0 0 10.5 308.559 674.4964 Tm
0 0 0 1 k
0.0464 Tc
(c)Tj
0.49043 -0.00001 TD
0.046 Tc
0.079 Tw
(ochlea and vestibule and a significant increase in)Tj
-0.49043 -1.01618 TD
0 Tc
0.116 Tw
[(BDNF protein levels in the inner ear)56(. Subsequent work)]TJ
T*
0.01 Tc
0.115 Tw
(by Pettingill and co-workers (2008) demonstrated that)Tj
0 -1.01619 TD
0.005 Tc
0.12 Tw
[(rat Schwann cells genetically modified to over)22(-express)]TJ
T*
0.043 Tc
0.082 Tw
[(BDNF or NT)91(-3 enhanced rat SGN survival )]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 514.6601 631.8165 Tm
0 Tr
0 0 0 1 k
0.043 Tc
0.082 Tw
[(in vitr)37(o)]TJ
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 308.559 621.1465 Tm
0 Tr
0 0 0 1 k
0 Tc
0.069 Tw
(compared to both control Schwann cells or recombinant)Tj
0 -1.01619 TD
0 Tw
(neurotrophin proteins. )Tj
1.61905 -1.01618 TD
0.048 Tc
0.077 Tw
[(Interestingly)65(, it has been observed that besides)]TJ
-1.61905 -1.01619 TD
0 Tc
0.03 Tw
(genetically modified cells, also normal, unmodified cells)Tj
0 -1.01618 TD
0.026 Tc
0.099 Tw
(such as stem cells of various types, e.g. HSCs, BM-)Tj
0 -1.01619 TD
0.047 Tc
0.078 Tw
(MSCs or NSCs may contribute to the survival and)Tj
0 -1.01618 TD
0 Tc
0.042 Tw
(function of remaining inner ear cell types \(Krabbe et al.,)Tj
0 -1.01619 TD
0.058 Tw
[(2005; Y)100(oshida et al., 2007; Whitlon et al., 2009\). In this)]TJ
T*
0.068 Tc
0.057 Tw
[(regard, the beneficial ef)19(fects observed following)]TJ
T*
0.013 Tc
0.112 Tw
(transplantation of MSCs into injured tissue may be at)Tj
T*
(least partially mediated by their production of trophic)Tj
0 -1.01618 TD
0.004 Tc
0.121 Tw
(and protective factors \(Krabbe et al., 2005; Caddick et)Tj
0 -1.01619 TD
0 Tc
0.028 Tw
[(al., 2006\). In line with this ar)19(gument are also the data by)]TJ
T*
0.055 Tc
0.069 Tw
[(Y)99(oshida and colleagues (2007), who reported that)]TJ
T*
0.06 Tc
0.065 Tw
(treatment with HSCs ameliorated progressive HC)Tj
T*
0 Tc
0.061 Tw
(damage caused by transient cochlear ischemia in gerbils)Tj
T*
0.041 Tc
0.084 Tw
(and prevented a shift in ABR thresholds. While no)Tj
T*
0.003 Tc
0 Tw
(transdif)Tj
3.0633 0 TD
0.122 Tw
(ferentiation of the implanted cells into cochlear)Tj
-3.0633 -1.01619 TD
0.03 Tc
0.095 Tw
(cells or fusion events were observed, HSC injection)Tj
T*
0 Tc
0.113 Tw
(appeared to up-regulate the expression of GDNF in the)Tj
T*
0 Tw
(OC following ischemia.)Tj
1.61905 -1.01619 TD
0.071 Tc
0.054 Tw
(Hakuba and co-workers (2005) observed that)Tj
-1.61905 -1.01619 TD
0 Tc
0.118 Tw
(injection of NSCs into the inner ear of gerbils that had)Tj
T*
0.054 Tc
0.071 Tw
[(suf)17(fered cochlear ischemia resulted in a markedly)]TJ
T*
0.074 Tc
0.051 Tw
(reduced injury-induced ABR threshold shift and)Tj
T*
0.045 Tc
0.08 Tw
(decreased inner HC damage, compared to the non-)Tj
T*
0 Tc
0.1 Tw
(transplanted side. These ef)Tj
10.94314 0 TD
(fects were also considered to)Tj
-10.94314 -1.01619 TD
0.017 Tw
(be the result of increased production of NFs or cytokines)Tj
T*
0.012 Tc
0.113 Tw
(by the implanted cells. In an )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F5 1 Tf
10.5 0 0 10.5 441.1036 322.3865 Tm
0 Tr
0 0 0 1 k
0.012 Tc
0.113 Tw
(in vitr)Tj
2.57782 0 TD
0 Tc
(o)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 477.4867 322.3865 Tm
0 Tr
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0.012 Tc
0 Tw
(study)Tj
2.16299 0 TD
0.0122 Tc
(,)Tj
0.6372 0 Td
0.012 Tc
0.113 Tw
(Chen and)Tj
-18.88855 -1.01619 TD
0.033 Tc
0.092 Tw
(colleagues (2010) showed increased proliferation of)Tj
T*
0.067 Tc
0.058 Tw
(auditory cell cultures grown in NSC-conditioned)Tj
T*
0 Tc
0.04 Tw
(medium, compared to controls, and correlated this ef)Tj
21.39335 0.00001 TD
0 Tw
(fect)Tj
-21.39335 -1.01619 TD
0.002 Tw
(with higher concentrations of leukaemia inhibitory factor)Tj
T*
0.056 Tc
0.069 Tw
((LIF) in the NSC-conditioned medium, leading to)Tj
T*
0 Tc
0.03 Tw
[(activation of the LIF/JAK/ST)81(A)111(T)-1( s)1(i)-1(gnalling pathway)66(. LIF)]TJ
T*
0.101 Tw
(had already been previously shown to improve survival)Tj
T*
0.009 Tc
0.116 Tw
(of SGNs (Marzella et al., 1999; Whitlon et al., 2006).)Tj
T*
0.052 Tc
0.073 Tw
(Regarding the use of NSCs for repair of inner ear)Tj
T*
0.075 Tc
0.057 Tw
(damage, it is also worth taking into account the)Tj
T*
0 Tc
0.006 Tw
(observations made by Ourednik and colleagues (2002) in)Tj
T*
0.075 Tc
0.05 Tw
(the CNS. They observed that transplanted NSCs)Tj
T*
0.054 Tc
0.071 Tw
(appeared to have an inherent ability to migrate to)Tj
T*
0.045 Tc
0.08 Tw
(damaged areas and, rather than dif)Tj
15.67902 0.00001 TD
(ferentiating into)Tj
-15.67902 -1.0162 TD
0.013 Tc
0.112 Tw
(\322replacement\323 cells, rescue the damaged host neurons)Tj
0 -1.01619 TD
0.041 Tc
0.084 Tw
(from under)Tj
4.94932 0.00001 TD
(going permanent functional impairment.)Tj
-4.94932 -1.01619 TD
0.014 Tc
0.111 Tw
(They attributed this positive ef)Tj
13.14877 0.00001 TD
(fect of undif)Tj
5.32809 0.00001 TD
0 Tw
(ferentiated)Tj
-18.47686 -1.01621 TD
0.054 Tc
0.071 Tw
(NSCs to the secretion of important trophic and/or)Tj
0 -1.01619 TD
0.022 Tc
0.103 Tw
[(neuroprotective factors, such as GDNF)80(. On the other)]TJ
T*
0 Tc
0.076 Tw
(hand, work carried out by Ito and co-workers \(Iguchi et)Tj
T*
0.017 Tc
0.108 Tw
(al., 2003\) showed that a population of NSCs injected)Tj
T*
0.003 Tc
0.122 Tw
[(into mouse inner ears spontaneously dif)19(ferentiated into)]TJ
0 -1.01618 TD
0.024 Tc
0.101 Tw
[(glial cells, and started expressing GDNF and BDNF)80(,)]TJ
0 -1.01619 TD
0 Tc
0 Tw
(thereby contributing to SGN survival. )Tj
1.61905 -1.01619 TD
0.038 Tc
0.087 Tw
(In addition to the production of trophic factors,)Tj
ET
0 0 0 0 k
45.354 729.071 504.567 14.1729 re
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45.354 716.262 504.567 12 re
f
45.354 683.748 504.567 31.181 re
f
45.354 729.071 504.567 14.1729 re
f
Q
/GS3 gs
/GS2 gs
q
BT
/F3 1 Tf
7.7 0 0 7.7 536.0798 731.757 Tm
0 Tr
0 0 0 1 k
0 Tc
0 Tw
(933)Tj
ET
0 0 0 0 k
45.354 716.262 504.567 12 re
f
Q
/GS3 gs
/GS2 gs
q
BT
/F4 1 Tf
10.5 0 2.23185 10.5 226.75 719.6104 Tm
0 Tr
0 0 0 1 k
0 Tc
0 Tw
(Approaches to inner ear repair)Tj
ET
Q
endstream
endobj
16 0 obj
<<
/Length 11134
>>
stream
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0 0.929 595 782 re
W n
1 g
0 782.929 0 0 re
f
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/GS1 gs
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/GS2 gs
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45.354 51.023 242.363 631.654 re
f
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/GS2 gs
q
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0 Tr
0 0 0 1 k
0.0344 Tc
(i)Tj
0.31243 -0.00001 TD
0.034 Tc
0.091 Tw
[(mplanted cells may also exert beneficial ef)21(fects on)]TJ
-0.31243 -1.01618 TD
0 Tc
0.057 Tw
(remaining auditory cell types through other means, such)Tj
T*
0.113 Tw
(as the secretion of extracellular matrix proteins and the)Tj
0 -1.01619 TD
0.003 Tc
0.122 Tw
(expression of cell adhesion molecules on their surface.)Tj
T*
0.033 Tc
0.092 Tw
(Whitlon et al. (2006) reported improved survival of)Tj
T*
0 Tc
0.095 Tw
(SGNs that had been co-cultured with Schwann cells, as)Tj
T*
0.06 Tc
0.065 Tw
(compared to controls, and attributed this positive)Tj
0 -1.01618 TD
0 Tc
0.106 Tw
(outcome not only to the production of NFs by the glial)Tj
0 -1.01619 TD
0.091 Tw
(cells (Hansen et al., 2001) but also to the establishment)Tj
0 -1.01618 TD
0.09 Tw
(of direct cell-cell contacts. The Schwann cells appeared)Tj
0 -1.01619 TD
0.056 Tc
0.068 Tw
(to provide a favourable microenvironment for the)Tj
0 -1.01618 TD
0.065 Tc
0.06 Tw
(regeneration of auditory neurons and served as a)Tj
0 -1.01619 TD
0.003 Tc
0.122 Tw
(substrate for neuronal attachment and growth \(Whitlon)Tj
T*
0.016 Tc
0.109 Tw
(et al., 2009\). Similar observations have been recently)Tj
T*
0.075 Tc
0.17 Tw
(made with olfactory ensheathing cells (OECs):)Tj
T*
0.043 Tc
0.082 Tw
(conditioned medium from these cells promoted the)Tj
0 -1.01618 TD
0.001 Tc
0.124 Tw
(survival and proliferation of cultured SGNs \(Liu et al.,)Tj
0 -1.01619 TD
0 Tc
0.076 Tw
[(2010; Y)111(u et al., 2010\), in agreement with the reports on)]TJ
T*
0.014 Tc
0.111 Tw
[(the ability of these cells to secrete NFs such as NGF)81(,)]TJ
T*
0.008 Tc
0.117 Tw
[(BDNF)79(, NT)92(-3 and GDNF)78(. Nevertheless, survival of the)]TJ
T*
0.025 Tc
0.099 Tw
(plated SGNs was most markedly enhanced when the)Tj
T*
0.004 Tc
0.121 Tw
(neurons were cultured in direct contact with the OECs)Tj
T*
0 Tc
0.015 Tw
(themselves (Liu et al., 2010). Interestingly)Tj
17.00309 0 TD
-0.0001 Tc
(,)Tj
0.51466 0 Td
0 Tc
(expression of)Tj
-17.51775 -1.01619 TD
0.048 Tw
(adhesion molecules implicated in neuronal survival \(e.g.)Tj
T*
0 Tw
(NCAM\) was detected in OECs \(Liu et al., 2010\). )Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F4 1 Tf
9.5 0 2.01929 9.5 46.3543 397.0765 Tm
0 Tr
0 0 0 1 k
0 Tc
0 Tw
(Protection via administration of survival factors)Tj
ET
Q
/GS3 gs
/GS2 gs
q
BT
/F1 1 Tf
10.5 0 0 10.5 63.3543 375.7365 Tm
0 Tr
0 0 0 1 k
0.054 Tc
0.071 Tw
(As mentioned above, maintenance of a certain)Tj
-1.61905 -1.01619 TD
0.01 Tc
0.115 Tw
(population of functional SGNs is necessary for CIs to)Tj
T*
0.063 Tc
0.061 Tw
[(e)-1(x)-1(e)-1(r)-1(t)-1( )-1(a)-1( )-1(b)-1(e)-1(n)-1(e)-1(f)-1(i)-1(c)-1(i)-1(a)-1(l)-1( )-1(e)-1(f)18(fect following HC loss. SGN)]TJ
T*
0 Tc
0.117 Tw
(development and survival is dependent on the presence)Tj
-0.0001 Tc
(of)'
1.13645 0 Td
0 Tc
0.054 Tw
(various NFs as well as neural activity \(Schimmang et)Tj
-1.13645 -1.01619 TD
0.019 Tc
0.106 Tw
(al., 2003; Alam et al., 2007; Hildebrand et al., 2008;)Tj
T*
0.018 Tc
0.107 Tw
[(Shepherd et al., 2008\), which are provided to a lar)19(ge)]TJ
T*
0.057 Tc
0.068 Tw
(extent by HCs and SCs within the OC. While HC)Tj
T*
0.036 Tc
0.089 Tw
(degeneration is mostly irreversible by the time it is)Tj
T*
0 Tc
0.053 Tw
(detected, SGN loss is usually a slow process in humans,)Tj
T*
0.075 Tc
0.1 Tw
[(of)18(fering a reasonably wide therapeutic window)66(.)]TJ
T*
0 Tc
0.064 Tw
[(Regarding HC loss, factors such as GDNF and NT)91(-3, as)]TJ
T*
0.002 Tc
0.122 Tw
(well as anti-oxidants have been identified \(Shoji et al.,)Tj
T*
0 Tc
0.02 Tw
(2000a,b; Hakuba et al., 2003; Liu et al., 2008\) that could)Tj
T*
0.122 Tw
(exert a prophylactic ef)Tj
9.31459 0.00001 TD
(fect on the survival and function)Tj
-9.31459 -1.01619 TD
-0.0001 Tc
(of)Tj
1.10844 0 Td
0 Tc
0.026 Tw
(HCs if administered prior to otic damage. Application)Tj
-1.10844 -1.01619 TD
0.05 Tc
0.074 Tw
(of these factors may be useful for some groups of)Tj
T*
0.033 Tc
0.092 Tw
(patients who require aminoglycoside treatment \(e.g.)Tj
T*
0.009 Tc
0.116 Tw
(gentamicin\) and are at risk of developing hearing loss)Tj
T*
0.039 Tc
0 Tw
(\(T)Tj
0.9517 0.00001 TD
0.086 Tw
(alaska et al., 2006; Bitner)Tj
11.59497 0.00001 TD
(-Glindzicz et al., 2010;)Tj
-12.54667 -1.0162 TD
0.034 Tc
0.091 Tw
(Prayle and Smyth, 2010\). Regarding the protection/)Tj
0 -1.01619 TD
0 Tc
0.122 Tw
(regeneration of SGNs, administration of NFs, electrical)Tj
T*
0.075 Tc
0.08 Tw
(stimulation and anti-oxidative treatment are the)Tj
T*
0.017 Tc
0.108 Tw
(approaches most extensively studied \(Pettingill et al.,)Tj
T*
0.002 Tc
0.123 Tw
(2007; Shepherd et al., 2008\). It has been demonstrated)Tj
T*
0.001 Tc
0.124 Tw
(that expression of NF receptors is maintained in SGNs)Tj
T*
0 Tc
0.023 Tw
(of deafened animals \(Gillespie et al., 2004; Hurley et al.,)Tj
T*
0.007 Tc
0.118 Tw
(2004\) and NF administration has resulted in improved)Tj
0 -1.01618 TD
0.027 Tc
0.098 Tw
(survival of auditory neurons (Meen et al., 2009). Of)Tj
0 -1.01619 TD
0.02 Tc
0.105 Tw
(note, improved SGN survival was also obtained with)Tj
T*
0.075 Tc
0.399 Tw
(some NF combinations in studies where the)Tj
ET
0 0 0 0 k
307.559 51.023 242.362 631.654 re
f
BT
/F1 1 Tf
10.5 0 0 10.5 308.559 674.4964 Tm
0 0 0 1 k
0.0693 Tc
(a)Tj
0.51332 -0.00001 TD
0.069 Tc
0.056 Tw
(dministration of the treatment was delayed to a)Tj
-0.51331 -1.01618 TD
0.02 Tc
0.105 Tw
(timepoint when degenerative and apoptotic processes)Tj
T*
0 Tc
0.125 Tw
[(were already ongoing \(Y)100(amagata et al., 2004; Miller et)]TJ
0 -1.01619 TD
0.025 Tw
(al., 2007; Pettingill et al., 2007\). In addition to improved)Tj
T*
0.075 Tc
0.198 Tw
(survival, some studies have reported enhanced)Tj
T*
0 Tc
0.108 Tw
(resprouting of auditory peripheral processes \(Altschuler)Tj
T*
0.002 Tw
[(et al., 1999; W)41(ise et al., 2005\). A considerable a)-1(mount of)]TJ
0 -1.01618 TD
0.005 Tw
[(work has been done on the delivery of BDNF and/or NT)92(-)]TJ
0 -1.01619 TD
0.0103 Tc
(3)Tj
0.88521 0 Td
0.01 Tc
0.115 Tw
(into hearing-damaged animal models, using osmotic)Tj
-0.88521 -1.01618 TD
0.075 Tc
0.073 Tw
(pumps or alginate beads \(Gillespie et al., 2004;)Tj
0 -1.01619 TD
0 Tc
0.009 Tw
[(Y)100(amagata et al., 2004; Noushi et al., 2005; Richardson et)]TJ
0 -1.01618 TD
0.008 Tw
[(al., 2005; W)40(ise et al., 2005\). Other factors that have been)]TJ
0 -1.01619 TD
0.064 Tw
[(administered are NGF)80(, GDNF)79(, CNTF)79(, LIF)80(, transforming)]TJ
T*
0.013 Tc
0.112 Tw
[(growth factor)20(-\247 (TGF-\247), and fibroblast growth factor)]TJ
T*
0.007 Tc
0.118 Tw
[((FGF), alone or in dif)18(ferent combinations \(Marzella et)]TJ
T*
0.02 Tc
0.105 Tw
(al., 1999; Shoji et al., 2000b; Shinohara et al., 2002;)Tj
0 -1.01618 TD
0.024 Tc
0.101 Tw
(Gillespie et al., 2004; Gillespie and Shepherd, 2005;)Tj
0 -1.01619 TD
0 Tc
0.094 Tw
(Miller et al., 2007\). Some studies used viral vectors for)Tj
T*
0.125 Tw
[(NF expression \(Y)99(agi et al., 2000; Kanzaki et al., 2002;)]TJ
T*
0.015 Tc
0.11 Tw
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((2009). Enhanced survival of spiral ganglion cells after cessation of)Tj
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0.087 Tw
(treatment with brain-derived neurotrophic factor in deafened guinea)Tj
0 -1.42266 TD
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(pigs. J. Assoc. Res. Otolaryngol. 10, 355-367. )Tj
-1.65544 -1.42266 TD
0.021 Tw
(Alam S.A., Robinson B.K., Huang J. and Green S.H. (2007). Prosurvival)Tj
1.65544 -1.42268 TD
0.028 Tw
(and proapoptotic intracellular signaling in rat spiral ganglion neurons)Tj
0 -1.42267 TD
0 Tw
(in vivo after the loss of hair cells. J. Comp. Neurol. 503, 832-852. )Tj
-1.65544 -1.42267 TD
0.055 Tw
(Altschuler R.A., Cho Y., Ylikoski J., Pirvola U., Magal E. and Miller J.M.)Tj
1.65544 -1.42267 TD
0.083 Tc
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((1999). Rescue and regrowth of sensory nerves following)Tj
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(deafferentation by neurotrophic factors. Ann. N. Y. Acad. Sci. 884,)Tj
0 -1.42266 TD
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(305-311. )Tj
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0.068 Tc
0.071 Tw
(Altschuler R.A., O'Shea K.S. and Miller J.M. (2008). Stem cell)Tj
1.65544 -1.42267 TD
0 Tc
0.021 Tw
(transplantation for auditory nerve replacement. Hear. Res. 242, 110-)Tj
T*
0 Tw
(116. )Tj
-1.65544 -1.42266 TD
0.012 Tc
0.127 Tw
(Batts S.A., Shoemaker C.R. and Raphael Y. (2009). Notch signaling)Tj
1.65544 -1.42266 TD
0.003 Tc
0.136 Tw
(and Hes labeling in the normal and drug-damaged organ of Corti.)Tj
0 -1.42267 TD
0 Tc
0 Tw
(Hear. Res. 249, 15-22. )Tj
-1.65544 -1.42267 TD
0.079 Tw
(Bermingham N.A., Hassan B.A., Price S.D., Vollrath M.A., Ben-Arie N.,)Tj
1.65544 -1.42266 TD
0.012 Tc
0.127 Tw
(Eatock R.A., Bellen H.J., Lysakowski A. and Zoghbi H.Y. (1999).)Tj
0 -1.42267 TD
0 Tc
0.116 Tw
(Math1: an essential gene for the generation of inner ear hair cells.)Tj
0 -1.42266 TD
0 Tw
(Science 284, 1837-1841. )Tj
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0.083 Tc
0.109 Tw
(Bermingham-McDonogh O. and Rubel E.W. (2003). Hair cell)Tj
1.65544 -1.42266 TD
0 Tc
0.13 Tw
(regeneration: winging our way towards a sound future. Curr. Opin.)Tj
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(935)Tj
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(Approaches to inner ear repair)Tj
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(eurobiol. 13, 119-126. )Tj
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(Bitner-Glindzicz M., Osei-Lah V., Colvin I., Sirimanna T., Lucas D., Mac)Tj
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(N)Tj
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(at. Neurosci. 12, 679-685. )Tj
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0.134 Tw
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0.083 Tc
0.122 Tw
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(454, 350-360. )Tj
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0.017 Tc
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1.65544 -1.42266 TD
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0 Tw
(mature guinea pigs in vivo. J. Neurosci. 23, 4395-4400. )Tj
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0.088 Tw
(Kelley M.W., Talreja D.R. and Corwin J.T. (1995). Replacement of hair)Tj
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(c)Tj
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0 Tc
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(ells after laser microbeam irradiation in cultured organs of corti from)Tj
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(132, 4353-4362. )Tj
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0.0268 Tc
(K)Tj
0.69382 0.00001 TD
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(e)Tj
0.55582 0.00001 TD
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(pithelial integrity in the deafened auditory epithelium. Cell. Cycle 6,)Tj
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(612-619. )Tj
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(K)Tj
0.70283 0.00001 TD
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(ondo T., Johnson S.A., Yoder M.C., Romand R. and Hashino E.)Tj
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((2005). Sonic hedgehog and retinoic acid synergistically promote)Tj
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(ensory fate specification from bone marrow-derived pluripotent)Tj
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(K)Tj
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0.98862 -1.42267 TD
0 Tw
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0.0833 Tc
(K)Tj
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(uroda Y., Kitada M., Wakao S., Nishikawa K., Tanimura Y.,)Tj
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(Makinoshima H., Goda M., Akashi H., Inutsuka A., Niwa A.,)Tj
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0.105 Tw
(Y. and Dezawa M. (2010). Unique multipotent cells in adult human)Tj
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0.027 Tc
0.112 Tw
(mesenchymal cell populations. Proc. Natl. Acad. Sci. USA 107,)Tj
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0 Tc
0 Tw
(8639-8643. )Tj
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0.014 Tw
(Laine H., Doetzlhofer A., Mantela J., Ylikoski J., Laiho M., Roussel M.F.,)Tj
1.65544 -1.42267 TD
0.006 Tw
(Segil N. and Pirvola U. (2007). p19(Ink4d) and p21(Cip1) collaborate)Tj
T*
0.064 Tc
0.074 Tw
(to maintain the postmitotic state of auditory hair cells, their)Tj
T*
0 Tc
0.09 Tw
(codeletion leading to DNA damage and p53-mediated apoptosis. J.)Tj
T*
0 Tw
(Neurosci. 27, 1434-1444. )Tj
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0.088 Tw
(Lang H., Ebihara Y., Schmiedt R.A., Minamiguchi H., Zhou D., Smythe)Tj
1.65544 -1.42267 TD
0.075 Tw
(N., Liu L., Ogawa M. and Schulte B.A. (2006). Contribution of bone)Tj
T*
0.07 Tc
0.068 Tw
(marrow hematopoietic stem cells to adult mouse inner ear:)Tj
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(mesenchymal cells and fibrocytes. J. Comp. Neurol. 496, 187-201. )Tj
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0.125 Tw
(Lang H., Schulte B.A., Goddard J.C., Hedrick M., Schulte J.B., Wei L.)Tj
1.65544 -1.42266 TD
0.023 Tc
0.116 Tw
(and Schmiedt R.A. (2008). Transplantation of mouse embryonic)Tj
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0.055 Tw
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0 -1.42266 TD
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(effects of timing after injury. J. Assoc. Res. Otolaryngol. 9, 225-240. )Tj
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1.65544 -1.42267 TD
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(mouse inner ear. Nat. Med. 9, 1293-1299. )Tj
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0.011 Tw
(Li H., Roblin G., Liu H. and Heller S. (2003b). Generation of hair cells by)Tj
1.65544 -1.42267 TD
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0.133 Tw
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(Sci. USA 100, 13495-13500. )Tj
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1.65544 -1.42266 TD
0.048 Tc
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(478, 37-41. )Tj
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(Liu Y., Okada T., Sheykholeslami K., Shimazaki K., Nomoto T.,)Tj
1.65544 -1.42266 TD
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(Muramatsu S., Kanazawa T., Takeuchi K., Ajalli R., Mizukami H.,)Tj
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0.137 Tw
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T*
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0.13 Tw
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(associated virus type 3 vector. Mol. Ther. 12, 725-733. )Tj
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(Liu Y., Okada T., Shimazaki K., Sheykholeslami K., Nomoto T.,)Tj
1.65544 -1.42267 TD
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(Muramatsu S., Mizukami H., Kume A., Xiao S., Ichimura K. and)Tj
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0.003 Tc
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(Lu P., Blesch A. and Tuszynski M.H. (2004). Induction of bone marrow)Tj
1.65544 -1.42266 TD
0.037 Tc
0.102 Tw
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(artifact? J. Neurosci. Res. 77, 174-191. )Tj
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0.55577 0.00001 TD
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(Martinez-Monedero R., Yi E., Oshima K., Glowatzki E. and Edge A.S.)Tj
1.65544 -1.42266 TD
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(aruyama J., Yamagata T., Ulfendahl M., Bredberg G., Altschuler R.A.)Tj
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(09-318. )Tj
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1.65544 -1.42266 TD
0.0679 Tc
(n)Tj
0.62394 0.00001 TD
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0.138 Tw
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0.033 Tw
(Marzella P.L., Gillespie L.N., Clark G.M., Bartlett P.F. and Kilpatrick T.J.)Tj
1.65544 -1.42267 TD
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T*
0.028 Tw
(of the TGF-beta superfamily to promote the survival of spiral ganglia)Tj
T*
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-1.65544 -1.42267 TD
0.049 Tw
(Matsumoto M., Nakagawa T., Kojima K., Sakamoto T., Fujiyama F. and)Tj
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0.135 Tw
(Ito J. (2008). Potential of embryonic stem cell-derived neurons for)Tj
T*
0.019 Tc
0.12 Tw
(synapse formation with auditory hair cells. J. Neurosci. Res. 86,)Tj
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0.029 Tw
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0.133 Tw
(and in vitro characterization of bone marrow-derived stem cells in)Tj
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0 Tw
(the cochlea. Laryngoscope 116, 1363-1367. )Tj
-1.65544 -1.42267 TD
0.044 Tc
0.095 Tw
(Matsuoka A.J., Kondo T., Miyamoto R.T. and Hashino E. (2007).)Tj
1.65544 -1.42267 TD
0 Tc
0.087 Tw
(Enhanced survival of bone-marrow-derived pluripotent stem cells in)Tj
0 -1.42266 TD
0.117 Tw
(an animal model of auditory neuropathy. Laryngoscope 117, 1629-)Tj
0 -1.42267 TD
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0.049 Tw
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1.65544 -1.42267 TD
0.097 Tw
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(119, 1590-1593. )Tj
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0.06 Tw
(Meyers J.R. and Corwin J.T. (2007). Shape change controls supporting)Tj
1.65544 -1.42267 TD
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0.103 Tw
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-1.65544 -1.42266 TD
0.018 Tc
0.121 Tw
(Miller J. and Altschuler R. (2004). Neurotrophic factor and electrical)Tj
1.65544 -1.42266 TD
0 Tc
0.087 Tw
(stimulation promotes auditory nerve survival and regrowth following)Tj
0 -1.42267 TD
0 Tw
(deafness. ARO Midwinter meeting, 90. )Tj
-1.65544 -1.42267 TD
0.018 Tc
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1.65544 -1.42267 TD
0.044 Tc
0.095 Tw
((2006). Auditory nerve survival remains enhanced four weeks)Tj
0 -1.42266 TD
0.077 Tc
0.062 Tw
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0 -1.42267 TD
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0 Tw
(neurotrophic factor. ARO Midwinter meeting, Abstract 891. )Tj
-1.65544 -1.42267 TD
0.055 Tw
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1.65544 -1.42266 TD
0.102 Tw
((2007). Delayed neurotrophin treatment following deafness rescues)Tj
T*
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T*
0 Tc
0 Tw
(factor and fibroblast growth factor. J. Neurosci. Res. 85, 1959-1969. )Tj
-1.65544 -1.42267 TD
0.022 Tc
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0.12 Tw
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1.65544 -1.42266 TD
0.116 Tw
(T.S., Hiratsuka Y., Tamura T., Kanemaru S., Shimizu Y. and Ito J.)Tj
0 -1.42267 TD
0.045 Tc
0.094 Tw
((2004). Transplantation of bone marrow stromal cells into the)Tj
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0.49982 0.00001 TD
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(Nakaizumi T., Kawamoto K., Minoda R. and Raphael Y. (2004).)Tj
1.65544 -1.42266 TD
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(A)Tj
0.70718 0.00001 TD
0.04 Tc
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(factor protects spiral ganglion neurons from ototoxic damage.)Tj
0 -1.42266 TD
-0.0002 Tc
(A)Tj
0.66681 0.00001 TD
0 Tc
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(udiol. Neurootol. 9, 135-143. )Tj
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0.129 Tw
(Nicholl A.J., Kneebone A., Davies D., Cacciabue-Rivolta D.I., Rivolta)Tj
1.65544 -1.42267 TD
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0.83284 0.00001 TD
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-0.55583 -1.42267 TD
0 Tw
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0.72186 0.00001 TD
0 Tc
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0.93358 -1.42267 TD
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(m)Tj
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(20, 1250-1254. )Tj
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(oushi F., Richardson R.T., Hardman J., Clark G. and O'Leary S.)Tj
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0.87761 -1.42267 TD
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0.127 Tw
(long-deafened aged mouse ears. J. Assoc. Res. Otolaryngol. 10,)Tj
0 -1.42266 TD
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-2.21121 -1.42268 TD
0.029 Tc
0.11 Tw
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1.65544 -1.42267 TD
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0.108 Tw
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(Transplantation of bone marrow-derived neurospheres into guinea)Tj
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(pig cochlea. Laryngoscope 120, 576-581. )Tj
-1.65544 -1.42267 TD
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0.085 Tw
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1.65544 -1.42267 TD
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(Matsumoto M., Ohno T., Sakamoto T., Iguchi F. and Ito J. (2005).)Tj
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0.053 Tc
0.086 Tw
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