Abstract
Cochlear supporting cells (SCs) have been shown to be a promising resource for hair cell (HC) regeneration in the neonatal mouse cochlea. Previous studies have reported that Lgr5+ SCs can regenerate HCs both in vitro and in vivo and thus are considered to be inner ear progenitor cells. Lgr5+ progenitors are able to regenerate more HCs than Lgr5- SCs, and it is important to understand the mechanism behind the proliferation and HC regeneration of these progenitors. Here, we isolated Lgr5+ progenitors and Lgr5- SCs from Lgr5-EGFP-CreERT2/Sox2-CreERT2/Rosa26-tdTomato mice via flow cytometry. As expected, we found that Lgr5+ progenitors had significantly higher proliferation and HC regeneration ability than Lgr5- SCs. Next, we performed RNA-Seq to determine the gene expression profiles of Lgr5+ progenitors and Lgr5- SCs. We analyzed the genes that were enriched and differentially expressed in Lgr5+ progenitors and Lgr5- SCs, and we found 8 cell cycle genes, 9 transcription factors, and 24 cell signaling pathway genes that were uniquely expressed in one population but not the other. Last, we made a protein–protein interaction network to further analyze the role of these differentially expressed genes. In conclusion, we present a set of genes that might regulate the proliferation and HC regeneration ability of Lgr5+ progenitors, and these might serve as potential new therapeutic targets for HC regeneration.
Highlights
Sensorineural hearing loss is a common sensory disorder caused by the loss of hair cells (HCs)
Several previous studies have noted that the apical turn of the cochlea has greater HC regeneration ability than the basal turn (Chai et al, 2012; Cox et al, 2014), so to avoid the gene expression differences between the apical and basal turns (Waqas et al, 2016a) we used the middle turn of the cochlea for all of the experiments and analyses
We found that each sphere that originated from Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)+ progenitors generated almost 8 times as many Myo7a+ HCs than spheres from the Lgr5− supporting cells (SCs) (Figures 2E–H), and the total spheres originating from Lgr5+ progenitors gave rise to significantly more total Myo7a+ HCs than those originating from the Lgr5− SCs (Figures 2I,J)
Summary
Sensorineural hearing loss is a common sensory disorder caused by the loss of hair cells (HCs). Previous studies have shown that some cochlear SCs in neonatal mammals are HC progenitors that possess a limited capacity to regenerate HCs (Chai et al, 2012; Shi et al, 2013; Bramhall et al, 2014; Cox et al, 2014; Wang et al, 2015) These SCs lose their intrinsic regenerative potential as the animal ages (Oesterle et al, 2008; Bermingham-McDonogh and Reh, 2011; Warchol, 2011; Cox et al, 2014), and as a result hearing loss tends to be permanent and incurable in mature mammals
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