Abstract
ABSTRACTLack of sensory hair cell (HC) regeneration in mammalian adults is a major contributor to hearing loss. In contrast, the neonatal mouse cochlea retains a transient capacity for regeneration, and forced Wnt activation in neonatal stages promotes supporting cell (SC) proliferation and induction of ectopic HCs. We currently know little about the temporal pattern and underlying mechanism of this age-dependent regenerative response. Using an in vitro model, we show that Wnt activation promotes SC proliferation following birth, but prior to postnatal day (P) 5. This age-dependent decline in proliferation occurs despite evidence that the Wnt pathway is postnatally active and can be further enhanced by Wnt stimulators. Using an in vivo mouse model and RNA sequencing, we show that proliferation in the early neonatal cochlea is correlated with a unique transcriptional response that diminishes with age. Furthermore, we find that augmenting Wnt signaling through the neonatal stages extends the window for HC induction in response to Notch signaling inhibition. Our results suggest that the downstream transcriptional response to Wnt activation, in part, underlies the regenerative capacity of the mammalian cochlea.
Highlights
Noise-induced and age-related degeneration of sensory hair cells (HCs) is a leading cause of hearing deficits
Explants were immunolabeled for SOX2, BrdU and myosin VI (MYOVI) or myosin VIIA (MYOVIIA; HC markers)
We found that we could further extend this window for HC induction up to P8, as P0 cochlear explants cultured with CHIR and BrdU for 8 days in vitro (DIV), prior to treatment with DAPT for three additional days generated a statistically significant number of MYOVI+BrdU+ cells (Fig. 5E)
Summary
Noise-induced and age-related degeneration of sensory hair cells (HCs) is a leading cause of hearing deficits. Owing to a lack of regenerative capacity in the adult mammalian cochlea, damage to HCs is irreversible. Neonatal mice have a limited capacity to regenerate HCs (Bramhall et al, 2014; Chai et al, 2012; Shi et al, 2013, 2012; Yamamoto et al, 2006). There is considerable interest in defining the temporal pattern of this regenerative response and its underlying mechanisms in neonates.
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