Nestin-expressing cells in the developing, mature and noise-exposed cochlear epithelium.

The auditory sensory epithelium in non-mammalian vertebrates can replace lost hair cells by transdifferentiation of supporting cells, but this regenerative ability is lost in the mammalian cochlea. Future cell-based treatment of hearing loss may depend on stem cell transplantation or on transdifferentiation of endogenous cells in the cochlea. For both approaches, identification of cells with stem cell features within the mature cochlea may be useful. Here we use a Nestin-ß-gal mouse to examine the presence of Nestin positive cells in the mature auditory epithelium, and determine how overstimulation of the ear impacts these cells. Nestin positive cells were found in the apical turn of the cochlea lateral to the outer hair cell area. This pattern of expression persisted into mature age. The area of Nestin positive cells was increased after the noise lesion. This increase in area coincided with an increase in expression of the Nestin mRNA. The data suggest that cells with potential stem cell features remain in the mature mammalian cochlea, restricted to the apical turn, and that an additional set of signals is necessary to trigger their contribution to cell replacement therapy in the ear. As such, this population of cells could serve to generate cochlear stem cells for research and potential therapy, and may be a target for treatments based on induced transdifferentiation of endogenous cochlear cells.

miR-410 controls adult SVZ neurogenesis by targeting neurogenic genes.

Over-expression of the early neural inducer, Noggin, in nestin positive subventricular zone (SVZ), neural stem cells (NSC) promotes proliferation and neuronal differentiation of neural progenitors and inhibits the expression of a CNS-enriched microRNA-410 (miR-410) (Morell et al., 2015). When expressed in neurospheres derived from the adult SVZ, miR-410 inhibits neuronal and oligodendrocyte differentiation, and promotes astrocyte differentiation. miR-410 also reverses the increase in neuronal differentiation and decreased astroglial differentiation caused by Noggin over-expression. Conversely, inhibition of miR-410 activity promotes neuronal and decreases astroglial differentiation of NSC. Using computer prediction algorithms and luciferase reporter assays we identified multiple neurogenic genes including Elavl4 as downstream targets of miR-410 via the canonical miRNA-3'UTR interaction. Over-expression of Elavl4 transcripts without the endogenous 3'UTR rescued the decrease in neuronal differentiation caused by miR-410 overexpression. Interestingly, we also observed that miR-410 affected neurite morphology; over-expression of miR-410 resulted in the formation of short, unbranched neurites. We conclude that miR-410 expression provides a new link between BMP signaling and the crucial lineage choice of adult neural stem cells via its ability to bind and control the expression of neurogenic gene transcripts.