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1.
Cell Rep ; 35(3): 109016, 2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33882317

RESUMEN

The mammalian cochlea cannot regenerate functional hair cells (HCs) spontaneously. Atoh1 overexpression as well as other strategies are unable to generate functional HCs. Here, we simultaneously upregulated the expression of Gfi1, Pou4f3, and Atoh1 in postnatal cochlear supporting cells (SCs) in vivo, which efficiently converted SCs into HCs. The newly regenerated HCs expressed HC markers Myo7a, Calbindin, Parvalbumin, and Ctbp2 and were innervated by neurites. Importantly, many new HCs expressed the mature and terminal marker Prestin or vesicular glutamate transporter 3 (vGlut3), depending on the subtypes of the source SCs. Finally, our patch-clamp analysis showed that the new HCs in the medial region acquired a large K+ current, fired spikes transiently, and exhibited signature refinement of ribbon synapse functions, in close resemblance to native wild-type inner HCs. We demonstrated that co-upregulating Gfi1, Pou4f3, and Atoh1 enhances the efficiency of HC generation and promotes the functional maturation of new HCs.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Unión al ADN/genética , Células Ciliadas Auditivas/metabolismo , Proteínas de Homeodominio/genética , Células Laberínticas de Soporte/metabolismo , Organogénesis/genética , Factor de Transcripción Brn-3C/genética , Factores de Transcripción/genética , Potenciales de Acción/fisiología , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Calbindinas/genética , Calbindinas/metabolismo , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Proteínas de Unión al ADN/metabolismo , Regulación del Desarrollo de la Expresión Génica , Células Ciliadas Auditivas/citología , Proteínas de Homeodominio/metabolismo , Transporte Iónico , Células Laberínticas de Soporte/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Motoras Moleculares/genética , Proteínas Motoras Moleculares/metabolismo , Miosina VIIa/genética , Miosina VIIa/metabolismo , Neuritas/metabolismo , Neuritas/ultraestructura , Parvalbúminas/genética , Parvalbúminas/metabolismo , Técnicas de Placa-Clamp , Potasio/metabolismo , Transducción de Señal , Factor de Transcripción Brn-3C/metabolismo , Factores de Transcripción/metabolismo
2.
J Assoc Res Otolaryngol ; 10(4): 525-44, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19644644

RESUMEN

Significant sensory hair cell loss leads to irreversible hearing and balance deficits in humans and other mammals. Future therapeutic strategies to repair damaged mammalian auditory epithelium may involve inserting stem cells into the damaged epithelium, inducing non-sensory cells remaining in the epithelium to transdifferentiate into replacement hair cells via gene therapy, or applying growth factors. Little is currently known regarding the status and characteristics of the non-sensory cells that remain in the deafened auditory epithelium, yet this information is integral to the development of therapeutic treatments. A single high-dose injection of the aminoglycoside kanamycin coupled with a single injection of the loop diuretic furosemide was used to kill hair cells in adult mice, and the mice were examined 1 year after the drug insult. Outer hair cells are lost throughout the entire length of the cochlea and less than a third of the inner hair cells remain in the apical turn. Over 20% and 55% of apical organ of Corti support cells and spiral ganglion cells are lost, respectively. We examined the expression of several known support cell markers to investigate for possible support cell dedifferentiation in the damaged ears. The support cell markers investigated included the microtubule protein acetylated tubulin, the transcription factor Sox2, and the Notch signaling ligand Jagged1. Non-sensory epithelial cells remaining in the organ of Corti retain acetylated tubulin, Sox2 and Jagged1 expression, even when the epithelium has a monolayer-like appearance. These results suggest a lack of marked SC dedifferentiation in these aged and badly damaged ears.


Asunto(s)
Sordera/patología , Células Laberínticas de Soporte/citología , Envejecimiento/patología , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Proteínas de Unión al Calcio/análisis , Proteínas de Unión al Calcio/biosíntesis , Diferenciación Celular , Sordera/inducido químicamente , Sordera/metabolismo , Diuréticos/administración & dosificación , Diuréticos/efectos adversos , Furosemida/administración & dosificación , Furosemida/efectos adversos , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/análisis , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Proteína Jagged-1 , Kanamicina/administración & dosificación , Kanamicina/efectos adversos , Células Laberínticas de Soporte/efectos de los fármacos , Células Laberínticas de Soporte/metabolismo , Proteínas de la Membrana/análisis , Proteínas de la Membrana/biosíntesis , Ratones , Inhibidores de la Síntesis de la Proteína/administración & dosificación , Inhibidores de la Síntesis de la Proteína/efectos adversos , Factores de Transcripción SOXB1/análisis , Factores de Transcripción SOXB1/biosíntesis , Proteínas Serrate-Jagged , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patología , Tubulina (Proteína)/análisis , Tubulina (Proteína)/biosíntesis
3.
Hear Res ; 79(1-2): 161-77, 1994 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-7806478

RESUMEN

The function of supporting cells was investigated by comparing their morphologic adaptations at six different places in the gerbil cochlea. The volume of Deiters cells and tectal (cover) cells increased whereas that of Boettcher and Claudius cells decreased from base to apex. Deiters cells in the basal region tuned between 40 and 20 kHz lacked the unique rosette complex seen in regions encoding frequencies at or below 10 kHz. Deiters cells in high frequency regions differed from those at lower frequency places in several other ways: they possessed more apical microtubules, a larger basal microtubule stalk, mitochondria in the basal compartment, apical mitochondria that were unassociated with plasmalemma and more symmetric, and a less elaborately folded apicomedial plasmalemma enveloping fewer nerves. The tectal cells covering the outer tunnel appeared unlike Hensen cells in location and structure and differed further in exhibiting more variability with position in the cochlea. These covering cells in regions encoding high frequencies (20 and 40 kHz) extended a thin process medially that formed the roof of the outer tunnel and connected with the phalanx of the third Deiters cell. The tectal cells exclusively in places at 10 kHz or below projected numerous fimbriae into the outer tunnel. Hensen cells lateral to the cover cells also differed with frequency in showing abundant apical microvilli and mitochondria and basal juxtaposition to Boettcher cells only in the 40 to 20 kHz region. The observed structural differences provide evidence for functional variability along the place-frequency map. They attest to greater ion resorption from the outer tunnel by Deiters and tectal cells in low to mid frequency regions, and for greater ion exchange between endolymph and perilymph by Hensen, Boettcher and outer sulcus cells in regions of the cochlea encoding high frequencies. Amplification of the Deiters cells' microtubule system in the base of the cochlea possibly imparts increased stiffness to these cells and enhances transmission of mechanical energy at high frequency.


Asunto(s)
Cóclea/citología , Células Ciliadas Auditivas Externas/citología , Células Laberínticas de Soporte/citología , Estimulación Acústica , Animales , Membrana Basal/citología , Membrana Basal/ultraestructura , Membrana Basilar/citología , Membrana Basilar/ultraestructura , Cóclea/ultraestructura , Gerbillinae , Transporte Iónico , Células Laberínticas de Soporte/ultraestructura , Microscopía Electrónica , Fijación del Tejido
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