Precise genetic control of ATOH1 enhances maturation of regenerated hair cells in the mature mouse utricle

Tian Wang, Tian Yang, Amanda Kedaigle, Gabriela Pregernig, Ryan McCarthy, Ben Holmes, Xudong Wu, Lars Becker, Ning Pan, Kathy So, Leon Chen, Jun He, Ahmad Mahmoudi, Soumya Negi, Monika Kowalczyk, Tyler Gibson, Noah Druckenbrod (), Alan G. Cheng () and Joseph Burns
Additional contact information
Tian Wang: Stanford University School of Medicine
Tian Yang: Decibel Therapeutics
Amanda Kedaigle: Decibel Therapeutics
Gabriela Pregernig: Decibel Therapeutics
Ryan McCarthy: Decibel Therapeutics
Ben Holmes: Decibel Therapeutics
Xudong Wu: Decibel Therapeutics
Lars Becker: Decibel Therapeutics
Ning Pan: Decibel Therapeutics
Kathy So: Decibel Therapeutics
Leon Chen: Stanford University School of Medicine
Jun He: Stanford University School of Medicine
Ahmad Mahmoudi: Stanford University School of Medicine
Soumya Negi: Decibel Therapeutics
Monika Kowalczyk: Decibel Therapeutics
Tyler Gibson: Decibel Therapeutics
Noah Druckenbrod: Decibel Therapeutics
Alan G. Cheng: Stanford University School of Medicine
Joseph Burns: Decibel Therapeutics

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases hair cell regeneration, however, these cells fail to fully mature. Here, we profiled mouse utricles at 14 time points, and defined transcriptomes of developing and mature vestibular hair cells. To mimic native hair cells which downregulate endogenous ATOH1 as they mature, we engineered viral vectors carrying the supporting cell promoters GFAP and RLBP1. In utricles damaged ex vivo, both CMV-ATOH1 and GFAP-ATOH1 increased regeneration more effectively than RLBP1-ATOH1, while GFAP-ATOH1 and RLBP1-ATOH1 induced hair cells with more mature transcriptomes. In utricles damaged in vivo, GFAP-ATOH1 induced regeneration of hair cells expressing genes indicative of maturing type II hair cells, and more hair cells with bundles and synapses than untreated organs. Together our results demonstrate the efficacy of spatiotemporal control of ATOH1 overexpression in inner ear hair cell regeneration.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-53153-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53153-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-53153-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().