Wnt signaling enhances the capacity of cochlear Frizzled 10-positive glial cells as neural stem cells

Abstract The degeneration of cochlea spiral ganglion neurons (SGNs) results in irreversible sensorineural hearing loss due to the fact that SGNs lack regenerative ability. Cochlear glial cells (GCs) possess limited capacity for neural differentiation. However, the identity of these progenitor cells has been elusive. Here, we identified a distinct subpopulation of cochlear GCs that express Frizzled 10 (FZD10+), which may be the predominant type of GCs responsible for self-proliferation and neuronal differentiation in the neonatal and adult cochlea. Wnt signaling activation significantly promoted the capacity of FZD10 + GCs as neural stem cells, both in vitro and in vivo, and enhanced the neural excitability of the newly induced-neurons. Single-cell RNA sequencing analysis of the proliferated and differentiated FZD10 + GCs revealed that a cluster of neurogenesis-like cells possess characteristics of auditory neurons, suggesting they may be immature SGNs, with multiple signaling pathways, related regulatory genes, and three transcription factors (Pou3f4, Maf and Foxp1) highly expressed in them. Overall, this study identified FZD10 + GCs play a vital role in neurogenesis in the mouse cochlea, and demonstrated the essential function of the Wnt signaling in SGNs regeneration, as well as probed the underlying mechanisms that may be involved in this process.