Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells

White, Patricia M.; Doetzlhofer, Angelika; Lee, Yun Shain; Groves, Andrew K.; Segil, Neil

doi:10.1038/nature04849

Cited by 381 publications

(428 citation statements)

References 27 publications

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“…Such loss is permanent, because mammalian inner ear hair cells do not regenerate. The inability of mammals to restore sensory hair cells after injury is intriguing given that (i) mammalian vestibular support cells exhibit low levels of proliferation after injury; (ii) cochlear support cells of newborn mice are able to proliferate subsequent to hair cell death in cell culture (1); and (iii) other vertebrates such as birds, amphibians, and fish replace their sensory hair cells continuously and, importantly, are capable of regenerating hair cells after damage (2)(3)(4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

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

133

152

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Deafness caused by the terminal loss of inner ear hair cells is one of the most common sensory diseases. However, nonmammalian animals (e.g., birds, amphibians, and fish) regenerate damaged hair cells. To understand better the reasons underpinning such disparities in regeneration among vertebrates, we set out to define at high resolution the changes in gene expression associated with the regeneration of hair cells in the zebrafish lateral line. We performed RNA-Seq analyses on regenerating support cells purified by FACS. The resulting expression data were subjected to pathway enrichment analyses, and the differentially expressed genes were validated in vivo via whole-mount in situ hybridizations. We discovered that cell cycle regulators are expressed hours before the activation of Wnt/β-catenin signaling following hair cell death. We propose that Wnt/β-catenin signaling is not involved in regulating the onset of proliferation but governs proliferation at later stages of regeneration. In addition, and in marked contrast to mammals, our data clearly indicate that the Notch pathway is significantly down-regulated shortly after injury, thus uncovering a key difference between the zebrafish and mammalian responses to hair cell injury. Taken together, our findings lay the foundation for identifying differences in signaling pathway regulation that could be exploited as potential therapeutic targets to promote either sensory epithelium or hair cell regeneration in mammals.signaling pathway analysis | RNA sequencing | neuromast | Jak/Stat3 | cdkn1b

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mentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

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

133

152

View full text Add to dashboard Cite

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“…Recently, mice with transgenic expression of a green fluorescent protein (GFP) under the regulation of general supporting cell-specific (p27 kip1 ) or hair cell-specific (Atoh1) promoters were used to isolate these mixed cell populations, respectively White et al 2006). Similarly, mice with cell type-specific GFP expression have been used to isolate and characterize the transcriptomes of specific cell populations from the brain and the retina (Ivanov et al 2008;Lobo et al 2006;Marsh et al 2008).…”

Section: Discussionmentioning

confidence: 99%

CD44 is a Marker for the Outer Pillar Cells in the Early Postnatal Mouse Inner Ear

Hertzano

Puligilla

Chan

et al. 2010

JARO

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Cluster of differentiation antigens (CD proteins) are classically used as immune cell markers. However, their expression within the inner ear is still largely undefined. In this study, we explored the possibility that specific CD proteins might be useful for defining inner ear cell populations. mRNA expression profiling of microdissected auditory and vestibular sensory epithelia revealed 107 CD genes as expressed in the early postnatal mouse inner ear. The expression of 68 CD genes was validated with real-time RT-PCR using RNA extracted from microdissected sensory epithelia of cochleae, utricles, saccules, and cristae of newborn mice. Specifically, CD44 was identified as preferentially expressed in the auditory sensory epithelium. Immunohistochemistry revealed that within the early postnatal organ of Corti, the expression of CD44 is restricted to outer pillar cells. In order to confirm and expand this finding, we characterized the expression of CD44 in two different strains of mice with loss-and gain-of-function mutations in Fgfr3 which encodes a receptor for FGF8 that is essential for pillar cell development. We found that the expression of CD44 is abolished from the immature pillar cells in homozygous Fgfr3 knockout mice. In contrast, both the outer pillar cells and the aberrant Deiters' cells in the Fgfr3 P244R/+ mice express CD44. The deafness phenotype segregating in DFNB51 families maps to a linkage interval that includes CD44. To study the potential role of CD44 in hearing, we characterized the auditory system of CD44 knockout mice and sequenced the entire open reading frame of CD44 of affected members of DFNB51 families. Our results suggest that CD44 does not underlie the deafness phenotype of the DFNB51 families. Finally, our study reveals multiple potential new cell type-specific markers in the mouse inner ear and identifies a new marker for outer pillar cells.

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“…Additionally, SCs impact the extent of damage in the auditory epithelium through scar formation and clearance of HC debris (18). Furthermore, SCs are considered a potential source of cells for HC replacement in mammals, because SCs are a documented source of new HCs in cultured neonatal cochlea (19) and in adult utricles (20). Additionally, nonmammalian vertebrates regenerate HCs and SCs after damage and recover hearing, with the SCs being the source of the regenerative response (21)(22)(23).…”

mentioning

confidence: 99%

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Lagarde

Wan

Zhang

et al. 2014

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

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Supporting cells in the cochlea play critical roles in the development, maintenance, and function of sensory hair cells and auditory neurons. Although the loss of hair cells or auditory neurons results in sensorineural hearing loss, the consequence of supporting cell loss on auditory function is largely unknown. In this study, we specifically ablated inner border cells (IBCs) and inner phalangeal cells (IPhCs), the two types of supporting cells surrounding inner hair cells (IHCs) in mice in vivo. We demonstrate that the organ of Corti has the intrinsic capacity to replenish IBCs/IPhCs effectively during early postnatal development. Repopulation depends on the presence of hair cells and cells within the greater epithelial ridge and is independent of cell proliferation. This plastic response in the neonatal cochlea preserves neuronal survival, afferent innervation, and hearing sensitivity in adult mice. In contrast, the capacity for IBC/IPhC regeneration is lost in the mature organ of Corti, and consequently IHC survival and hearing sensitivity are impaired significantly, demonstrating that there is a critical period for the regeneration of cochlear supporting cells. Our findings indicate that the quiescent neonatal organ of Corti can replenish specific supporting cells completely after loss in vivo to guarantee mature hearing function.deafness | cell ablation | hair cell | organ of Corti | glia

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Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells

Cited by 381 publications

References 27 publications

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

CD44 is a Marker for the Outer Pillar Cells in the Early Postnatal Mouse Inner Ear

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

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