How to Bury the Dead: Elimination of Apoptotic Hair Cells from the Hearing Organ of the Mouse

Anttonen, Tommi; Belevich, Ilya; Kirjavainen, Anna; Laos, Maarja; Brakebusch, Cord; Jokitalo, Eija; Pirvola, Ulla

doi:10.1007/s10162-014-0480-x

Cited by 52 publications

(57 citation statements)

References 50 publications

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“…These data are supported by previous reports of HC nuclei or debris within SCs after damage. 15,[35][36][37] Our data are consistent with a model in which glia-like SCs remove dead HCs from the mature mammalian inner ear (Figure 8). SCs completely surround healthy HCs (Figure 8a).…”

Section: Discussionsupporting

confidence: 88%

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Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

et al. 2015

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Hearing loss and balance disorders affect millions of people worldwide. Sensory transduction in the inner ear requires both mechanosensory hair cells (HCs) and surrounding glia-like supporting cells (SCs). HCs are susceptible to death from aging, noise overexposure, and treatment with therapeutic drugs that have ototoxic side effects; these ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic drug cisplatin. Although both classes of drugs are known to kill HCs, their effects on SCs are less well understood. Recent data indicate that SCs sense and respond to HC stress, and that their responses can influence HC death, survival, and phagocytosis. These responses to HC stress and death are critical to the health of the inner ear. Here we have used live confocal imaging of the adult mouse utricle, to examine the SC responses to HC death caused by aminoglycosides or cisplatin. Our data indicate that when HCs are killed by aminoglycosides, SCs efficiently remove HC corpses from the sensory epithelium in a process that includes constricting the apical portion of the HC after loss of membrane integrity. SCs then form a phagosome, which can completely engulf the remaining HC body, a phenomenon not previously reported in mammals. In contrast, cisplatin treatment results in accumulation of dead HCs in the sensory epithelium, accompanied by an increase in SC death. The surviving SCs constrict fewer HCs and display impaired phagocytosis. These data are supported by in vivo experiments, in which cochlear SCs show reduced capacity for scar formation in cisplatin-treated mice compared with those treated with aminoglycosides. Together, these data point to a broader defect in the ability of the cisplatin-treated SCs, to preserve tissue health in the mature mammalian inner ear. . 4 SCs perform many functions, including providing critical trophic factors, preventing excitotoxicity, and mediating regeneration in those systems (non-mammalian vertebrates) capable of replacing lost HCs. 5-11 When HCs die, SCs also preserve the integrity and function of the remaining tissue by forming scars and clearing dead HCs. 2,12-17 Maintaining a fluid barrier at the surface of the sensory epithelium after damage is necessary to preserve the electro-chemical gradient that drives HC depolarization and therefore sensory transduction after the onset of hearing (reviewed in Wangemann). 18 Several major stressors cause HC death, 19-22 including aging, noise trauma, and exposure to therapeutic drugs with ototoxic side effects. When a HC is killed by noise or aminoglycoside antibiotics, surrounding SCs form a filamentous actin (F-actin) cable that constricts the HC at its apex. 2,[12][13][14][15][16][17] This process separates the apical portion of the cell, including the stereocilia bundle, from the HC body and preserves a sealed reticular lamina. 23 In the chick utricle, following the apical constriction of dead HCs, the SCs engulf and phagocytose the remaining HC corpse. 15 Additional data from the chick indicate that the ototoxi...

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Section: Discussionsupporting

confidence: 88%

“…These data suggest that HC shrinkage occurred independently of SC activity, consistent with recent data reported in the mammalian cochlea. 35 The slow shrinkage that precedes HC death may thus represent the initiation of a cell death program that began hours before any SC activity was observed.…”

Section: Discussionmentioning

confidence: 99%

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

et al. 2015

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“…The OHC base is docked by a cup-like subdomain (DC cup) that differentiates from the DC soma2. We did not observe the DC cup in either controls or Atoh1-Brg1 −/− OC at P6 (data not shown).…”

Section: Resultsmentioning

confidence: 86%

“…The SCs project phalangeal cellular processes toward the lumen of the cochlear duct. The apex of HCs form tight cellular contacts with the flattened ends of phalangeal processes of SCs through a special tight junction hybridized with the adherens junction1, and the OHC base is encapsulated by a cup-like subdomain that differentiates from the DC soma2. The tight junctions play an important role in compartmentalizing the endolymph and perilymph, the compositionally distinct inner ear fluids34.…”

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confidence: 99%

Deletion of Brg1 causes abnormal hair cell planer polarity, hair cell anchorage, and scar formation in mouse cochlea

Jin

Ren

et al. 2016

Sci Rep

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Hair cells (HCs) are mechanosensors that play crucial roles in perceiving sound, acceleration, and fluid motion. The precise architecture of the auditory epithelium and its repair after HC loss is indispensable to the function of organ of Corti (OC). In this study, we showed that Brg1 was highly expressed in auditory HCs. Specific deletion of Brg1 in postnatal HCs resulted in rapid HC degeneration and profound deafness in mice. Further experiments showed that cell-intrinsic polarity of HCs was abolished, docking of outer hair cells (OHCs) by Deiter’s cells (DCs) failed, and scar formation in the reticular lamina was deficient. We demonstrated that Brg1 ablation disrupted the Gαi/Insc/LGN and aPKC asymmetric distributions, without overt effects on the core planer cell polarity (PCP) pathway. We also demonstrated that Brg1-deficient HCs underwent apoptosis, and that leakage in the reticular lamina caused by deficient scar formation shifted the mode of OHC death from apoptosis to necrosis. Together, these data demonstrated a requirement for Brg1 activity in HC development and suggested a role for Brg1 in the proper cellular structure formation of HCs.

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“…1 and 2). Extant accounts of rapid hair cell death after exposure to noise (Oesterle, 2013) and ototoxins (Anttonen et al, 2012, 2014; Astbury and Read, 1982; Forge, 1985; Leonova and Raphael, 1997; McDowell et al, 1989; Raphael and Altschuler, 1991; Taylor et al, 2008) in guinea pig, rat, and mouse favor a general principle where scar formation coincides with hair cell elimination from the reticular lamina, and holes are prevented. Prior to the current study, exceptions have been limited to knockout mouse models (Cohen-Salmon et al, 2002; Jin et al, 2016) and focal hair cell loss in chinchillas for relatively low-level noise exposures reported by Bohne and colleagues (Harding and Bohne, 2004).…”

Section: Discussionmentioning

confidence: 99%

The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice

et al. 2018

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The endocochlear potential (EP) provides part of the electrochemical drive for sound-driven currents through cochlear hair cells. Intense noise exposure (110 dB SPL, 2 h) differentially affects the EP in three inbred mouse strains (C57BL/6 [B6], CBA/J [CBA], BALB/cJ [BALB]) (Ohlemiller and Gagnon, 2007, Hearing Research 224:34–50; Ohlemiller et al., 2011, JARO 12:45–58). At least for mice older than 3 mos, B6 mice are unaffected, CBA mice show temporary EP reduction, and BALB mice may show temporary or permanent EP reduction. EP reduction was well correlated with histological metrics for injury to stria vascularis and spiral ligament, and little evidence was found for holes or tears in the reticular lamina that might ‘short out’ the EP. Thus we suggested that the genes and processes that underlie the strain EP differences primarily impact cochlear lateral wall, not the organ of Corti. Our previous work did not test the range of noise exposure conditions over which strain differences apply. It therefore remained possible that the relation between exposure severity and acute EP reduction simply has a higher exposure threshold in B6 mice compared to CBA and BALB. We also did not test for age dependence. It is well established that young adult animals are especially vulnerable to noise-induced permanent threshold shifts (NIPTS). It is unknown, however, whether heightened vulnerability of the lateral wall contributes to this condition. The present study extends our previous work to multiple noise exposure levels and durations, and explicitly compares young adult (6–7 wks) and older mice (>4 mos). We find that the exposure level-versus-acute EP relation is dramatically strain-dependent, such that B6 mice widely diverge from both CBA and BALB. For all three strains, however, acute EP reduction is greater in young mice. Above 110 dB SPL, all mice exhibited rapid and severe EP reduction that is likely related to tearing of the reticular lamina. By contrast, EP-versus-noise duration examined at 104 dB suggested that different processes contribute to EP reduction in young and older mice. The average EP falls to a constant level after ~7.5 min in older mice, but progressively decreases with further exposure in young mice. Confocal microscopy of organ of Corti surface preparations stained for phalloidin and zonula occludens-1 (ZO-1) indicated this corresponds to rapid loss of outer hair cells (OHCs) and formation of both holes and tears in the reticular lamina of young mice. In addition, when animals exposed at 119 dB were allowed to recover for 1 mo, only young B6 mice showed collapse of the EP to ≤5 mV. Confocal analysis suggested novel persistent loss of tight junctions in the lateral organ of Corti. This may allow paracellular leakage that permanently reduces the EP. From our other findings, we propose that noise-related lateral wall pathology in young CBA and BALB mice promotes hair cell loss and opening of the reticular lamina. The heightened vulnerability of young adult animals to noise exposure may in part reflect sp...

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How to Bury the Dead: Elimination of Apoptotic Hair Cells from the Hearing Organ of the Mouse

Cited by 52 publications

References 50 publications

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

Deletion of Brg1 causes abnormal hair cell planer polarity, hair cell anchorage, and scar formation in mouse cochlea

The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice

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