The crosstalk between the Notch, Wnt, and SHH signaling pathways in regulating the proliferation and regeneration of sensory progenitor cells in the mouse cochlea

Abstract

Sensory hair cells (HCs) are highly susceptible to damage by noise, ototoxic drugs, and aging. Although HCs cannot be spontaneously regenerated in adult mammals, previous studies have shown that signaling pathways are involved in HC regeneration in the damaged mouse cochlea. Here, we used a Notch antagonist (DAPT), a Wnt agonist (QS11), and recombinant Sonic hedgehog (SHH) protein to investigate their concerted actions underlying HC regeneration in the mouse cochlea after neomycin-induced damage both in vivo and in vitro. With DAPT, the numbers of HCs increased, and supporting cell (SC) proliferation was seen in both the intact and damaged cochlear sensory epithelia, while these numbers were unchanged in the presence of QS11. When simultaneously treated with DAPT and QS11, the number of HCs increased dramatically, and much greater SC proliferation was seen in the cochlear epithelium. In transgenic mice with both Notch1 conditional knockout and β-catenin over-expression, cochlear SC proliferation and HC regeneration were more obvious than in either Notch1 knockout or β-catenin over-expressing mice separately. When cochleae were treated with DAPT, QS11, and SHH together, SC proliferation was even greater, and this proliferation was seen in both the HC region and the greater epithelial ridge. High-throughput RNA sequencing was used to identify the differentially expressed genes between all groups, and the results showed that the SHH and Wnt signaling pathways are involved in SC proliferation. Our study suggests that co-regulation of the Notch, Wnt, and SHH signaling pathways promotes extensive cell proliferation and regeneration in the mouse cochlea.

Crosstalk between glucose metabolism and morphogen signalling specifies tonotopic identity in developing hair cells

“…Given the crosstalk between Wnt and Shh signalling in regulating proliferation in sensory progenitors 70 , understanding their interrelationship with metabolism during this process has significant impact for HC regeneration. Untangling the interactions between components of the Shh, Bmp7 and glycolytic signalling networks will further our understanding of how hair cells might be morphologically specified for auditory coding during their formation.…”

Contribution of Notch/Wnt signaling modulation in reactive astrocyte reparative response after brain injury

“…Here we found a positive interaction of Wnt-Shh signaling in the Notch inhibitory profile. One group comprehensively studied the interaction between Notch-inhibition and Wnt-signaling activation in the regenerative response of mice hair cell progenitors of the inner ear (Li et al, 2015; Wu et al, 2016; Ni et al, 2016; Wu et al, 2021). Moreover, their most recent publication demonstrated the crosstalk between Notch, Wnt, and Shh signaling pathways in the reparative response of the cochlea after cytotoxic neomycin treatment.…”

“…Moreover, their most recent publication demonstrated the crosstalk between Notch, Wnt, and Shh signaling pathways in the reparative response of the cochlea after cytotoxic neomycin treatment. The study showed that Notch inhibition and SHH-Wnt treatment promoted progenitor proliferation and activation of a regenerative response (Wu et al, 2021). The study evaluated the combinatorial effects of the inhibitor DAPT, the Wnt agonist QS11, and recombinant Sonic Hedgehog (rmShh) in mice cochlea and their potential regenerative response after neomycin treatment.…”

Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions

“…Several studies using neonatal mammalian cochlear explants have shown that inhibition of Notch signaling by pharmacologic agents or gene therapy results in hair cell regeneration from supporting cells [17,150,[167][168][169][170][171]. Bai et al showed that in undamaged neonatal cochlear explants, inhibition of Notch generated increased OHC numbers.…”