Inhibition Of Notch Activity Promotes Nonmitotic Regeneration of Hair Cells in the Adult Mouse Utricles

Lin, Vincent; Golub, Justin S.; Nguyen, Tot Bui; Hume, Clifford R.; Oesterle, Elizabeth C.; Stone, Jennifer S.

doi:10.1523/jneurosci.2057-11.2011

Cited by 148 publications

(203 citation statements)

References 62 publications

(89 reference statements)

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“…Other utricle studies suggested that hair cell damage is required for Notchmediated regeneration in the adult (Wang et al 2010;Lin et al 2011;Jung et al 2013), consistent with what has been shown in the zebrafish lateral line and the FIG. 7.…”

Section: Discussionsupporting

confidence: 79%

“…Overall, at P30, there was a 34.1 % loss due to culture, which is consistent with that seen in other adult cultures of vestibular organs (e.g. Lin et al 2011). Generally, this loss appeared as an overall thinning of the hair cell density throughout the sensory epithelium ( Fig.…”

Section: Fig 1 Aa′supporting

confidence: 88%

“…Cristae were analyzed by counting the total number of Gfi1 + hair cells. This concentration of DAPT is lower than that used in similar studies in the utricle (Collado et al 2011;Lin et al 2011) and was chosen based on a concentration curve performed on P7 explants cultured for 5 DIV with 1, 10, or 30 μM DAPT with DMSO as a vehicle control. This is in contrast to the postnatal cochlea where 5 μM DAPT is sufficient to inhibit lateral inhibition (Hayashi et al 2008).…”

Section: ) Error On Reported Values Is Standard Deviation the Exmentioning

confidence: 99%

“…Therefore, while the PLP transgene limited our analysis to the peripheral zone, within this region there was not a particular area of regenerative competence in the adult. In the mature regenerating utricle, there does appear to be regional regeneration (Collado et al 2011;Lin et al 2011;Golub et al 2012;Jung et al 2013). However, there is no consensus on which regions are competent for regeneration as the regionalization found varied between studies.…”

Section: Fig 8 Examples Of Lineage Traced Transitional Cells (Tc)mentioning

confidence: 99%

“…In the developing maculae, lateral inhibition is mediated through expression of the effectors Hes1 and Hes5 (Zheng et al 2000;Zine et al 2001). In the utricle, this Notch-mediated lateral inhibition is required into the second postnatal week and also plays a role in regeneration after damage (Wang et al 2010;Collado et al 2011;Lin et al 2011;Jung et al 2013). However, no studies have investigated Notch-mediated regeneration in the cristae.…”

Section: Introductionmentioning

confidence: 99%

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Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Slowik

Bermingham‐McDonogh

2013

JARO

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Balance disorders caused by hair cell loss in the sensory organs of the vestibular system pose a significant health problem worldwide, particularly in the elderly. Currently, this hair cell loss is permanent as there is no effective treatment. This is in stark contrast to nonmammalian vertebrates who robustly regenerate hair cells after damage. This disparity in regenerative potential highlights the need for further manipulation in order to stimulate more robust hair cell regeneration in mammals. In the utricle, Notch signaling is required for maintaining the striolar support cell phenotype into the second postnatal week. Notch signaling has further been implicated in hair cell regeneration after damage in the mature utricle. Here, we investigate the role of Notch signaling in the mature mammalian cristae in order to characterize the Notch-mediated regenerative potential of these sensory organs. For these studies, we used the γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-Lalanyl]-S-phenylglycine t-butyl ester (DAPT), in conjunction with a method we developed to culture cristae in vitro. In postnatal and adult cristae, we found that 5 days of DAPT treatment resulted in a downregulation of the Notch effectors Hes1 and Hes5 and also an increase in the total number of Gfi1 + hair cells. Hes5, as reported by Hes5-GFP, was downregulated specifically in peripheral support cells. Using lineage tracing with proteolipid protein (PLP)/CreER;mTmG mice, we found that these hair cells arose through transdifferentiation of support cells in cristae explanted from mice up to 10 weeks of age. These transdifferentiated cells arose without proliferation and were capable of taking on a hair cell morphology, migrating to the correct cell layer, and assembling what appears to be a stereocilia bundle with a long kinocilium. Overall, these data show that Notch signaling is active in the mature cristae and suggest that it may be important in maintaining the support cell fate in a subset of peripheral support cells.

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Section: Discussionsupporting

confidence: 79%

Section: Fig 1 Aa′supporting

confidence: 88%

Section: ) Error On Reported Values Is Standard Deviation the Exmentioning

confidence: 99%

Section: Fig 8 Examples Of Lineage Traced Transitional Cells (Tc)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Slowik

Bermingham‐McDonogh

2013

JARO

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Ultrastructural Characterization of Stem Cell‐Derived Replacement Vestibular Hair Cells Within Ototoxin‐Damaged Rat Utricle Explants

Werner

Water

Stenlund

et al. 2019

The Anatomical Record

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The auditory apparatus of the inner ear does not show turnover of sensory hair cells (HCs) in adult mammals; in contrast, there are many observations supporting low‐level turnover of vestibular HCs within the balance organs of mammalian inner ears. This low‐level renewal of vestibular HCs exists during normal conditions and it is further enhanced after trauma‐induced loss of these HCs. The main process for renewal of HCs within mammalian vestibular epithelia is a conversion/transdifferentiation of existing supporting cells (SCs) into replacement HCs.In earlier studies using long‐term organ cultures of postnatal rat macula utriculi, HC loss induced by gentamicin resulted in an initial substantial decline in HC density followed by a significant increase in the proportion of HCs to SCs indicating the production of replacement HCs. In the present study, using the same model of ototoxic damage to study renewal of vestibular HCs, we focus on the ultrastructural characteristics of SCs undergoing transdifferentiation into new HCs. Our objective was to search for morphological signs of SC plasticity during this process. In the utricular epithelia, we observed immature HCs, which appear to be SCs transdifferentiating into HCs. These bridge SCs have unique morphological features characterized by formation of foot processes, basal accumulation of mitochondria, and an increased amount of connections with nearby SCs. No gap junctions were observed on these transitional cells. The tight junction seals were morphologically intact in both control and gentamicin‐exposed explants. Anat Rec, 303:506–515, 2020. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

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Historical Aspects of Gene Therapy and Stem Cell Therapy in the Treatment of Hearing and Balance Disorder

Water

2020

The Anatomical Record

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This review presents many but not all the major historical events that have led to our current understanding of gene and stem cell therapies for the treatment of hearing and balance disorders in animal models of these disorders. In order to better understand the application of these emerging therapies to the treatment of inner ear disorders in a clinical setting, it has been necessary to provide some genetic and pathobiology backgrounds from both animal models and clinical disorders. The current focus and goal of gene and stem cell therapies are directed toward understanding the effective treatment of animal models that mimic human disorders of hearing and balance. This approach not only addresses the most effective ways to deliver the gene or stem cell therapies to affected inner ears, it also provides an assessment of the efficacy of the applied therapy(s) in achieving either partial or full restoration of either hearing and/or balance within the animal models receiving these therapeutic interventions. This review also attempts to present a realistic assessment of how close the research fields of gene and stem cell therapies are to application for the treatment of human disorders in a clinical setting. Progress made in developing these novel therapies toward clinical applications would not have been possible without the many pioneering studies and discoveries achieved by the investigators cited in this review. There were also many other excellent studies performed by gifted investigators that were not able to be included within this review. Anat Rec, 303:390–407, 2020. © 2019 American Association for Anatomy

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Inhibition Of Notch Activity Promotes Nonmitotic Regeneration of Hair Cells in the Adult Mouse Utricles

Cited by 148 publications

References 62 publications

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Ultrastructural Characterization of Stem Cell‐Derived Replacement Vestibular Hair Cells Within Ototoxin‐Damaged Rat Utricle Explants

Historical Aspects of Gene Therapy and Stem Cell Therapy in the Treatment of Hearing and Balance Disorder

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