ERBB ERBB 2 signaling drives supporting cell proliferation in vitro and apparent supernumerary hair cell formation in vivo in the neonatal mouse cochlea

摘要

Abstract In mammals, cochlear hair cells are not regenerated once they are lost, leading to permanent hearing deficits. In other vertebrates, the adjacent supporting cells act as a stem cell compartment, in that they both proliferate and differentiate into de novo auditory hair cells. Although there is evidence that mammalian cochlear supporting cells can differentiate into new hair cells, the signals that regulate this process are poorly characterized. We hypothesize that signaling from the epidermal growth factor receptor (EGFR ) family may play a role in cochlear regeneration. We focus on one such member,ERBB 2, and report the effects of expressing a constitutively activeERBB 2 receptor in neonatal mouse cochlear supporting cells, using viruses and transgenic expression. Lineage tracing with fluorescent reporter proteins was used to determine the relationships between cells with activeERBB 2 signaling and cells that divided or differentiated into hair cells. In vitro, individual supporting cells harbouring a constitutively activeERBB 2 receptor appeared to signal to their neighbouring supporting cells, inducing them to downregulate a supporting cell marker and to proliferate. In vivo, we found supernumerary hair celllike cells near supporting cells that expressedERBB 2 receptors. Both supporting cell proliferation and hair cell differentiation were largely reproduced in vitro using small molecules that we show also activateERBB 2. Our data suggest that signaling from the receptor tyrosine kinaseERBB 2 can drive the activation of secondary signaling pathways to regulate regeneration, suggesting a new model where an interplay of cell signaling regulates regeneration by endogenous stemlike cells.