Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells

Abstract

SUMMARYPermanent hearing loss is caused by the irreversible damage of cochlear sensory hair cells and nonsensory supporting cells. In the postnatal cochlea, the sensory epithelium is terminally differentiated, whereas tympanic border cells (TBCs) beneath the sensory epithelium are proliferative. The functions of TBCs are poorly characterized. Using an Axin2 lacZ Wnt reporter mouse, we found transient but robust Wnt signaling and proliferation in TBCs during the first 3 postnatal weeks, when the number of TBCs decreases. In vivo lineage tracing shows that a subset of hair cells and supporting cells is derived postnatally from Axin2-expressing TBCs. In cochlear explants, Wnt agonists stimulated the proliferation of TBCs, whereas Wnt inhibitors suppressed it. In addition, purified Axin2 lacZ cells were clonogenic and self-renewing in culture in a Wnt-dependent manner, and were able to differentiate into hair celllike and supporting cell-like cells. Taken together, our data indicate that Axin2-positive TBCs are Wnt responsive and can act as precursors to sensory epithelial cells in the postnatal cochlea.

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

“…However, we found that other cells in the GER, targeted with GlastCreER T induced with tamoxifen at P0 and P1, are required for the replacement of at least a fraction of IBCs/IPhCs. Because the targeting of a significant number of GER cells in our studies did not completely abolished IBC/IPhC replacement at neonatal ages, we cannot rule out the possibility that other cell populations, such as tympanic border cells, also may contribute to this process (63). In contrast, when IBC/IPhC ablation was performed at P15 or P21, when the Sox2 + GER cell pool has receded completely, there was no regenerative response (Fig.…”

Sensory hair cell development and regeneration: similarities and differences

“…The subsequent determination of cell fate in the expanded Sox2 domain occurs as in the normal Sox2-expressing domain, indicating that Notch-mediated lateral inhibition takes place in these tissues (Jacques et al, 2012). By contrast, when cochlear explants from late embryonic or neonatal mice were treated with Wnt activators, a mitogenic response was only seen among a subset of supporting cells, and no ectopic hair cell formation was observed (Jacques et al, 2012;Jan et al, 2013). These observations indicate that the canonical Wnt pathway can regulate both the proliferative state and the fate of prosensory cells during cochlear development.…”

Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway

“…In the adult mammalian vestibular sensory epithelium, inner ear stem cells were isolated with the capacity to differentiate into HCs and other inner ear cell types (9). In contrast, only neonatal mammalian cochleae have limited HC regeneration capacity in vivo, and harbor stem cells or progenitor cells that could proliferate and regenerate new HCs (10)(11)(12); however, no spontaneous HC regeneration has been observed in the mature cochlea (13).…”

“…Recent studies reported that in neonatal mouse cochlea, Wntresponsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5 + ) cells are the progenitors with the capacity to regenerate HCs under certain condition (11,12,(14)(15)(16)(17). However, endogenous Lgr5…”