Single cell RNA sequencing analysis of mouse cochlear supporting cell transcriptomes with activated ERBB2 receptor, a candidate mediator of hearing restoration mechanisms.

Abstract

Hearing loss caused by the death of cochlear hair cells (HCs) might be restored through regeneration from supporting cells (SCs) via dedifferentiation and proliferation, as observed in birds. We recently found that in mice, activation of ERBB2 in SCs promoted the differentiation of hair cell-like cells. Here we analyze transcriptomes of neonatal mouse cochlear SCs with activated ERBB2 using single-cell RNA sequencing. ERBB2 induction in vivo generated a new population of cells expressing de novo SIBLING (small integrin-binding ligand n-linked glycoproteins) proteins and their regulators, particularly Secreted Phosphoprotein 1 (SPP1). In other systems, SIBLINGs promote cell survival, proliferation, and differentiation. ERBB2 signaling induced after noise exposure in young adult mice also up-regulated the SPP1 receptor CD44, and drove formation of stem-like cell aggregates in the organ of Corti. Our results suggest that ectopic activation of ERBB2 signaling in cochlear supporting cells alters the microenvironment, promoting proliferation and cell rearrangements.