Atoh1 is required in supporting cells for regeneration of vestibular hair cells in adult mice

Hicks, Kelli L.; Wisner, Serena R.; Cox, Brandon C.; Stone, Jennifer S.

doi:10.1016/j.heares.2019.107838

“…Furthermore, it needs to be emphasized that our study was conducted in vitro and was limited to immature, early postnatal stages. While recent studies showed promise in regenerating vestibular hair cells in adult mice (9,87), the regeneration of cochlear hair cells in adult mice has proven thus far an impossible task (67; reviewed in ref. 88).…”

Section: Discussionmentioning

confidence: 99%

“…The transcription factor SOX2 is essential for the establishment and maintenance of prosensory cells (4) and plays a critical role in the induction of Atoh1 during hair cell formation (5,6). The transcriptional activator ATOH1 is required for hair cell formation in the developing inner ear (7) and its reactivation in supporting cells is an essential step in the process of hair cell regeneration (8,9).…”

mentioning

confidence: 99%

LIN28B/ let-7 control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

Li

¹

,

Doetzlhofer

²

2020

Proc. Natl. Acad. Sci. U.S.A.

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Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells. However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mammalian target of rapamycin (mTOR) activity. Employing murine cochlear organoid and explant cultures to model mitotic and nonmitotic mechanisms of hair cell generation, we show that loss of LIN28B function, due to its conditional deletion, or due to overexpression of the antagonistic miRNA let-7g, suppressed Akt-mTOR complex 1 (mTORC1) activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and nonmitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner.

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“…Furthermore, it needs to be emphasized that our study was conducted in vitro and was limited to immature, early postnatal stages. While recent studies showed promise in regenerating vestibular hair cells in adult mice (9,82), the regeneration of cochlear hair cells in adult mice has proven thus far an impossible task (65) and reviewed in (83).…”

Section: Discussionmentioning

confidence: 99%

“…The transcription factor SOX2 is essential for the establishment and maintenance of pro-sensory cells (4) and plays a critical role in the induction of Atoh1 during hair cell formation (5,6). ATOH1, a bHLH transcriptional activator, is required for hair cell formation in the developing inner ear (7) and its reactivation in supporting cells is an essential step in the process of hair cell regeneration (8,9).…”

mentioning

confidence: 99%

LIN28B controls the regenerative capacity of neonatal murine auditory supporting cells through activation of mTOR signaling

Li

¹

,

Doetzlhofer

²

2020

Preprint

0

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Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells.However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mTOR activity. Employing murine cochlear organoid and explant cultures to model mitotic and non-mitotic mechanisms of hair cell generation, we show that loss of Lin28b function, due to its conditional deletion, or due to overexpression of the antagonistic miRNA let-7g, suppressed Akt-mTORC1 activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and non-mitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner. SIGNIFICANCE STATEMENTCochlear hair cell loss is a leading cause of deafness in humans and other mammals. In the immature cochlea lost hair cells are regenerated by neighboring glia-like supporting cells. However, for reasons unknown, such regenerative capacity is rapidly lost as supporting cells undergo maturation. Here we identify a direct link between LIN28B-mTOR activity and supporting cell plasticity. Mimicking later developmental stages, we found that loss of the RNA binding protein LIN28B attenuated mTOR signaling and rendered young, immature supporting cells incapable of producing hair cells. Conversely, we found Recent studies uncovered that as early as postnatal day 5/6 (P5/P6) murine cochlear supporting cells fail to regenerate hair cells in response to injury (14), inhibition of Notch signaling (26), or over-activation of Wnt/β-catenin signaling (27). What causes the rapid decline in supporting cell plasticity during the first postnatal week is currently unknown. We previously demonstrated that a regulatory circuit consisting of LIN28B and let-7 miRNAs modulates the production of new hair cells in stage P2 murine cochlear explants, with LIN28B promoting new hair cell production and let-7 miRNAs suppressing it (28). The closely related RNA binding proteins LIN28A and LIN28B (LIN28A/B) and members of the let-7 family of miRNAs belong to an evolutionary highly conserved network of genes, initially identified in C-elegans for their role in d...

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“…The basic helix-loop-helix (bHLH) transcription factor, atonal homolog 1 or Atoh1, is critical for the differentiation of HCs ( Bermingham et al, 1999 ). Atoh1 overexpression activates the HC differentiation in murine vestibular epithelia both in vitro ( Zheng and Gao, 2000 ; Huang et al, 2009 ; Qian et al, 2021 ) and in vivo ( Staecker et al, 2007 ; Schlecker et al, 2011 ; Gao et al, 2016 ; Sayyid et al, 2019 ), which can be enhanced by injury ( Staecker et al, 2007 ; Schlecker et al, 2011 ; Sayyid et al, 2019 ; Hicks et al, 2020 ; Qian et al, 2021 ) and depressed by aging ( Gao et al, 2016 ). On the other hand, Atoh1 deletion inhibits the spontaneous returning of HCs significantly ( Hicks et al, 2020 ).…”

Section: Regeneration Of Human Vestibular Hair Cellsmentioning

confidence: 99%

Regeneration of Hair Cells in the Human Vestibular System

Huang

¹

,

Mao

²

,

Chen

³

2022

Front. Mol. Neurosci.

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The vestibular system is a critical part of the human balance system, malfunction of this system will lead to balance disorders, such as vertigo. Mammalian vestibular hair cells, the mechanical receptors for vestibular function, are sensitive to ototoxic drugs and virus infection, and have a limited restorative capacity after damage. Considering that no artificial device can be used to replace vestibular hair cells, promoting vestibular hair cell regeneration is an ideal way for vestibular function recovery. In this manuscript, the development of human vestibular hair cells during the whole embryonic stage and the latest research on human vestibular hair cell regeneration is summarized. The limitations of current studies are emphasized and future directions are discussed.

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Atoh1 is required in supporting cells for regeneration of vestibular hair cells in adult mice

Cited by 22 publications

References 73 publications

LIN28B/ let-7 control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

LIN28B/ let-7 control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

LIN28B controls the regenerative capacity of neonatal murine auditory supporting cells through activation of mTOR signaling

Regeneration of Hair Cells in the Human Vestibular System

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