Age-dependent mechanical stress underlies unexpected vestibular differentiation and regeneration patterns
- 1Tel Aviv University
Abstract
Loss of inner-ear sensory hair cells (HCs) is a major cause of hearing and balance disorders. Promoting HC regeneration offers a potential therapeutic strategy, but regenerative capacity is limited in adult mammals and declines rapidly during early postnatal development in mice. HCs can regenerate through trans-differentiation of neighboring supporting cells in a process controlled by Notch mediated lateral inhibition. However, the factors underlying the decrease in regeneration capacity are poorly understood. Here, we combine live imaging with single-HC ablation in mouse vestibular explants to track the dynamics of HC development and regeneration. We reveal unexpected age-dependent deviations from the classical lateral inhibition model, in which new HCs differentiate adjacent to existing HCs. We find that mechanical stress changes with age and that perturbing it alters the observed differentiation patterns. A mathematical model incorporating local mechanical regulation of Notch signaling captures both HC differentiation and regeneration patterns across ages. Together, these findings identify mechanical stress as a crucial regulator of HC differentiation and support an underlying mechanism in which the interplay between local mechanics and Notch signaling shapes regenerative responses. This coupling offers a framework for understanding the age-dependent decline in HC regeneration and motivates investigation of mechanical regulation as a potential therapeutic target.
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BibTeX
@misc{kasirer2026agedependent,
title = {{Age-dependent mechanical stress underlies unexpected vestibular differentiation and regeneration patterns}},
author = {S. Inbar Kasirer and M. Shraga and T. Dullweber and O. Loza and A. Erzberger and D. Sprinzak},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764569},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764569v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Age-dependent mechanical stress underlies unexpected vestibular differentiation and regeneration patterns
AU - S. Inbar Kasirer
AU - M. Shraga
AU - T. Dullweber
AU - O. Loza
AU - A. Erzberger
AU - D. Sprinzak
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764569
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764569v1
AB - Loss of inner-ear sensory hair cells (HCs) is a major cause of hearing and balance disorders. Promoting HC regeneration offers a potential therapeutic strategy, but regenerative capacity is limited in adult mammals and declines rapidly during early postnatal development in mice. HCs can regenerate through trans-differentiation of neighboring supporting cells in a process controlled by Notch mediated lateral inhibition. However, the factors underlying the decrease in regeneration capacity are poorly understood. Here, we combine live imaging with single-HC ablation in mouse vestibular explants to track the dynamics of HC development and regeneration. We reveal unexpected age-dependent deviations from the classical lateral inhibition model, in which new HCs differentiate adjacent to existing HCs. We find that mechanical stress changes with age and that perturbing it alters the observed differentiation patterns. A mathematical model incorporating local mechanical regulation of Notch signaling captures both HC differentiation and regeneration patterns across ages. Together, these findings identify mechanical stress as a crucial regulator of HC differentiation and support an underlying mechanism in which the interplay between local mechanics and Notch signaling shapes regenerative responses. This coupling offers a framework for understanding the age-dependent decline in HC regeneration and motivates investigation of mechanical regulation as a potential therapeutic target.
ER -