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Cell Rep. 2019 Jul 9;28(2):312-324.e4. doi: 10.1016/j.celrep.2019.06.028.

Atoh1 Directs Regeneration and Functional Recovery of the Mature Mouse Vestibular System.

Author information

1
Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Special Education and Communication Disorders, College of Education and Human Sciences, University of Nebraska, Lincoln, NE 68583, USA.
3
Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: aglcheng@stanford.edu.

Abstract

Utricular hair cells (HCs) are mechanoreceptors required for vestibular function. After damage, regeneration of mammalian utricular HCs is limited and regenerated HCs appear immature. Thus, loss of vestibular function is presumed irreversible. Here, we found partial HC replacement and functional recovery in the mature mouse utricle, both enhanced by overexpressing the transcription factor Atoh1. Following damage, long-term fate mapping revealed that support cells non-mitotically and modestly regenerated HCs displaying no or immature bundles. By contrast, Atoh1 overexpression stimulated proliferation and widespread regeneration of HCs exhibiting elongated bundles, patent mechanotransduction channels, and synaptic connections. Finally, although damage without Atoh1 overexpression failed to initiate or sustain a spontaneous functional recovery, Atoh1 overexpression significantly enhanced both the degree and percentage of animals exhibiting sustained functional recovery. Therefore, the mature, damaged utricle has an Atoh1-responsive regenerative program leading to functional recovery, underscoring the potential of a reprogramming approach to sensory regeneration.

KEYWORDS:

Atoh1; hair cell; proliferation; regeneration; sensory; utricle; vestibular; vestibular evoked potential

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