Direct transdifferentiation gives rise to the earliest new hair cells in regenerating avian auditory epithelium

Roberson, David W.; Alosi, Julie A.; Cotanche, Douglas A.

doi:10.1002/jnr.20271

Cited by 156 publications

(197 citation statements)

References 44 publications

(57 reference statements)

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“…2). Such cells resembled early regenerated HCs in vivo between 3 and 4 days postgentamicin (Stone and Rubel 2000;Mangiardi et al 2004;Roberson et al 2004). They had very immature morphologies, with nuclei positioned in the SC nuclear layer and long constricted necks that extended from the nucleus toward the lumenal surface.…”

Section: Supporting Cell Reentry Into Cell Cycle After Aminoglycosidementioning

confidence: 84%

“…These observations suggest many HCs were regenerated by direct transdifferentiation, during which an SC converts phenotypically into an HC without dividing. Further evidence for this phenomenon, which was proposed in the mid-1990s (Baird et al 1996;Adler and Raphael 1996;Roberson et al 1996), was recently provided by the observation that SCs upregulate the HC-specific protein Atoh1 shortly after HC damage is initiated in chickens in vivo (Cafaro et al 2007). We provide additional evidence for "transitional" cells here.…”

Section: Hair Cells Are Regenerated By Mitotic and Nonmitotic Meansmentioning

confidence: 95%

“…In support of this, we found that BrdU-negative HCs appeared more highly differentiated (had developed stereociliary bundles) at 8 days than BrdU-positive HCs. In addition, during in vivo avian auditory HC regeneration, direct transdifferentiation precedes cell division by 24-48 h (Roberson et al 2004;Cafaro et al 2007). Alternative explanations for these findings are that differentiation of postmitotic cells into HCs is delayed in culture and/ or that incorporated BrdU specifically delays or inhibits HC differentiation.…”

Section: Hair Cells Are Regenerated By Mitotic and Nonmitotic Meansmentioning

confidence: 99%

“…This process contributes to HC regeneration in cultured saccules of frogs and salamanders after aminoglycoside-induced injury (Baird et al 1996(Baird et al , 2000Taylor and Forge 2005). In chickens, some regenerated auditory HCs are unlabeled for a proliferation marker ( 3 H-thymidine or bromodeoxyuridine (BrdU)) despite its continual perfusion into the inner ear after damage (Roberson et al 1996(Roberson et al , 2004. Cells with features of both HCs and SCs were seen in regenerating BPs, suggesting such cells were SCs converting into HCs (Adler et al 1997;Cafaro et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Shang

Cafaro

Nehmer

et al. 2010

JARO

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In chickens, nonsensory supporting cells divide and regenerate auditory hair cells after injury. Anatomical evidence suggests that supporting cells can also transdifferentiate into hair cells without dividing. In this study, we characterized an organ culture model to study auditory hair cell regeneration, and we used these cultures to test if direct transdifferentiation alone can lead to significant hair cell regeneration. Control cultures (organs from posthatch chickens maintained without streptomycin) showed complete hair cell loss in the proximal (high-frequency) region by 5 days. In contrast, a 2-day treatment with streptomycin induced loss of hair cells from all regions by 3 days. Hair cell regeneration proceeded in culture, with the time course of supporting cell division and hair cell differentiation generally resembling in vivo patterns. The degree of supporting cell division depended upon the presence of streptomycin, the epithelial region, the type of culture media, and serum concentration. On average, 87% of the regenerated hair cells lacked the cell division marker BrdU despite its continuous presence, suggesting that most hair cells were regenerated via direct transdifferentiation. Addition of the DNA polymerase inhibitor aphidicolin to culture media prevented supporting cell division, but numerous hair cells were regenerated nonetheless. These hair cells showed signs of functional maturation, including stereociliary bundles and rapid uptake of FM1-43. These observations demonstrate that direct transdifferentiation is a significant mechanism of hair cell regeneration in the chicken auditory after streptomycin damage in vitro.

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Section: Supporting Cell Reentry Into Cell Cycle After Aminoglycosidementioning

confidence: 84%

Section: Hair Cells Are Regenerated By Mitotic and Nonmitotic Meansmentioning

confidence: 95%

Section: Hair Cells Are Regenerated By Mitotic and Nonmitotic Meansmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Shang

Cafaro

Nehmer

et al. 2010

JARO

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“…As HCs are lost, function deteriorates. Nonmammalian vertebrates are able to replace the lost HCs via two processes: the cell division of resident progenitor/stem cells and the direct conversion of another cell type (e.g., support cells [SCs]) into HCs without an intervening mitosis (Corwin and Cotanche 1988;Ryals and Rubel 1988;Adler and Raphael 1996;Baird et al 1996;Roberson et al 1996Roberson et al , 2004Taylor and Forge 2005). Humans and other mammals, in contrast, are unable to replace lost auditory HCs and have limited ability to regenerate vestibular HCs (reviewed in Bermingham-McDonogh and Rubel 2003;Oesterle and Stone 2008).…”

Section: Introductionmentioning

confidence: 99%

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Oesterle

Campbell

Taylor³

et al. 2007

JARO

215

245

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Inner ear hair cells detect environmental signals associated with hearing, balance, and body orientation. In humans and other mammals, significant hair cell loss leads to irreversible hearing and balance deficits, whereas hair cell loss in nonmammalian vertebrates is repaired by the spontaneous generation of replacement hair cells. Research in mammalian hair cell regeneration is hampered by the lack of in vivo damage models for the adult mouse inner ear and the paucity of cell-type-specific markers for nonsensory cells within the sensory receptor epithelia. The present study delineates a protocol to drug damage the adult mouse auditory epithelium (organ of Corti) in situ and uses this protocol to investigate Sox2 and Jagged1 expression in damaged inner ear sensory epithelia. In other tissues, the transcription factor Sox2 and a ligand member of the Notch signaling pathway, Jagged1, are involved in regenerative processes. Both are involved in early inner ear development and are expressed in developing support cells, but little is known about their expressions in the adult. We describe a nonsurgical technique for inducing hair cell damage in adult mouse organ of Corti by a single high-dose injection of the aminoglycoside kanamycin followed by a single injection of the loop diuretic furosemide. This drug combination causes the rapid death of outer hair cells throughout the cochlea. Using immunocytochemical techniques, Sox2 is shown to be expressed specifically in support cells in normal adult mouse inner ear and is not affected by drug damage. Sox2 is absent from auditory hair cells, but is expressed in a subset of vestibular hair cells. Double-labeling experiments with Sox2 and calbindin suggest Sox2-positive hair cells are Type II. Jagged1 is also expressed in support cells in the adult ear and is not affected by drug damage. Sox2 and Jagged1 may be involved in the maintenance of support cells in adult mouse inner ear.

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WDR1 colocalizes with ADF and actin in the normal and noise‐damaged chick cochlea

Adler

Raphael

et al. 2002

J of Comparative Neurology

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Auditory hair cells of birds, unlike hair cells in the mammalian organ of Corti, can regenerate following sound-induced loss. We have identified several genes that are upregulated following such an insult. One gene, WDR1, encodes the vertebrate homologue of actin-interacting protein 1, which interacts with actin depolymerization factor (ADF) to enhance the rate of actin filament cleavage. We examined WDR1 expression in the developing, mature, and noise-damaged chick cochlea by in situ hybridization and immunocytochemistry. In the mature cochlea, WDR1 mRNA was detected in hair cells, homogene cells, and cuboidal cells, all of which contain high levels of F-actin. In the developing inner ear, WDR1 mRNA was detected in homogene cells and cuboidal cells by embryonic day 7, in the undifferentiated sensory epithelium by day 9, and in hair cells at embryonic day 16. We also demonstrated colocalization of WDR1, ADF, and F-actin in all three cell types in the normal and noise-damaged cochlea. Immediately after acoustic overstimulation, WDR1 mRNA was seen in supporting cells. These cells contribute to the structural integrity of the basilar papilla, the maintenance of the ionic barrier at the reticular lamina, and the generation of new hair cells. These results indicate that one of the immediate responses of the supporting cell after noise exposure is to induce WDR1 gene expression and thus to increase the rate of actin filament turnover. These results suggest that WDR1 may play a role either in restoring cytoskeletal integrity in supporting cells or in a cell signaling pathway required for regeneration.

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Direct transdifferentiation gives rise to the earliest new hair cells in regenerating avian auditory epithelium

Cited by 156 publications

References 44 publications

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

WDR1 colocalizes with ADF and actin in the normal and noise‐damaged chick cochlea

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