Frizzled-9+ Supporting Cells Are Progenitors for the Generation of Hair Cells in the Postnatal Mouse Cochlea

Abstract

Lgr5+ cochlear supporting cells (SCs) have been reported to be hair cell (HC) progenitor cells that have the ability to regenerate HCs in the neonatal mouse cochlea, and these cells are regulated by Wnt signaling. Frizzled-9 (Fzd9), one of the Wnt receptors, has been reported to be used to mark neuronal stem cells in the brain together with other markers and mesenchymal stem cells from human placenta and bone marrow. Here we used Fzd9-CreER mice to lineage label and trace Fzd9+ cells in the postnatal cochlea in order to investigate the progenitor characteristic of Fzd9+ cells. Lineage labeling showed that inner phalangeal cells (IPhCs), inner border cells (IBCs), and third-row Deiters’ cells (DCs) were Fzd9+ cells, but not inner pillar cells (IPCs) or greater epithelial ridge (GER) cells at postnatal day (P)3, which suggests that Fzd9+ cells are a much smaller cell population than Lgr5+ progenitors. The expression of Fzd9 progressively decreased and was too low to allow lineage tracing after P14. Lineage tracing for 6 days in vivo showed that Fzd9+ cells could also generate similar numbers of new HCs compared to Lgr5+ progenitors. A sphere-forming assay showed that Fzd9+ cells could form spheres after sorting by flow cytometry, and when we compared the isolated Fzd9+ cells and Lgr5+ progenitors there were no significant differences in sphere number or sphere diameter. In a differentiation assay, the same number of Fzd9+ cells could produce similar amounts of Myo7a+ cells compared to Lgr5+ progenitors after 10 days of differentiation. All these data suggest that the Fzd9+ cells have a similar capacity for proliferation, differentiation, and HC generation as Lgr5+ progenitors and that Fzd9 can be used as a more restricted marker of HC progenitors.

Autophagy impairment as a key feature for acetaminophen-induced ototoxicity

“…In the inner ear of mammals, HCs are vulnerable to multiple types of damage, and these cells lack the ability to regenerate. Therefore, dead HCs cannot be spontaneously regenerated [51][52][53][54][55][56] , which serves as the major cause of the hearing loss induced by gene mutation, noise, ototoxic drugs, inflammation, and aging 15,[57][58][59][60] . In this study, we investigated the molecular mechanisms of APAP-induced ototoxicity using two in vitro models: HClike HEI-OC1 cells and whole-organ primary culture of the murine organ of Corti.…”

Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

“…HCs are sensitive to multiple stresses and injuries and are easy to damage. While a mammal's cochlea only has very limited HC regeneration ability, most of the HC damage is permanent and irreversible [28][29][30][31][32][33][34]. Genetic factor accounts for 50% of sensorineural hearing…”

Differences in Clinical Characteristics and Brain Activity between Patients with Low- and High-Frequency Tinnitus

“…In the mammal's inner ear, hair cells and spiral ganglion neurons are critical for hearing ability; hair cells convert the mechanical sound waves into neural signals, and spiral ganglion neuron transmits these signals to the auditory cortex for hearing [40][41][42]. In the mammal's inner ear, hair cells and spiral ganglion neurons are vulnerable for multiple damages, including gene mutation, noise, different ototoxic drugs, inflammation, or aging [43][44][45][46][47] while the mammals only have very limited hair cell and spiral ganglion neuron regeneration ability; most of the damaged hair cells and spiral ganglion neurons cannot be spontaneously regenerate [48][49][50][51][52][53][54][55]. Thus, most of the hearing loss is irreversible; and usually, tinnitus is always accompanied with hearing loss.…”