6. Conclusions and Perspectives
The development of technologies that allow high throughput gene expression analysis at a relatively low cost has led to an increase of microarray and, now, RNA-seq studies related to the inner ear. These studies have resulted in massive amounts of gene expression data. In the publications resulting from these studies, authors only have space to focus on a few of the significantly regulated genes and/or cellular pathways. Fortunately, a requirement for publication of gene expression data in most journals today is the submission of all the data in a public database, such as the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI). Similar repositories are available for the submission of proteomics data. Unfortunately, because of differences in species, tissues, treatments and developmental stages (information that is submitted along with the gene expression data), it is not easy to compare gene expression patterns across multiple studies. Bioinformaticians are needed to help develop standards for performing meta-analyses with multiple gene expression datasets, so that the most conserved and important pathways related to hair cell regeneration can be focused upon.
In addition, it is clear that transcriptomics does not give a complete picture of the workings of the proteins in a cell, as it misses post-transcriptional and post-translational modifications. Future progress in understanding the processes of hair cell regeneration will rely on collaborations and integration between genomics, transcriptomics, miRNA analysis, proteomics and bioinformatics.
Hopefully, such collaborations will lead to the development of therapeutics that can prevent hair cell loss or promote hair cell regeneration in humans. Indeed, there is evidence that genes found to be regulated in the inner ear via microarray studies can lead to translational research. One example is a recent clinical trial using insulin growth factor-1 (IGF-1) following hearing loss. Growth hormone (GH) has been shown to be regulated in the inner ear of mice during development [42] and in zebrafish following trauma [25]. One of the main targets of GH is IGF-1, an insulin-like growth factor; binding proteins, IGFBP-2 and IBFBP-6, are expressed in the rat cochlea at greater levels than the central nervous system [58], and IGFBP-2 and IBFBP-5 are regulated during cochlear cell differentiation [40]. In addition, IGF-1 null mice have developmental abnormalities in the inner ear, suggesting that it plays a vital role in development [66]. Trials with noise-exposed guinea pigs showed that application of recombinant IGF-1 via a gelatin hydrogel applied to the round window membrane of the ear resulted in increased survival of outer hair cells and reduced hearing thresholds [95]. Use of gelatin hydrogels was a novel vehicle for delivering growth factors to the inner ear for clinical application. More recently, this same protocol has been applied in human clinical trials. Patients with sudden sensorineural hearing loss had gelatin hydrogels impregnated with IGF-1 applied to the middle ear. Forty-eight percent and 56% of the patients showed hearing improvement after 12 and 24 weeks, respectively [96]. Follow-up research examining mechanisms of the effects of this growth factor found that IGF-1 inhibits hair cell apoptosis and promotes cell proliferation in supporting cells in the mouse ear [97]. Although there was considerable variability in the results of the IGF-1 clinical trial, it demonstrates how high throughput molecular analyses can lead to testing in mammalian models followed by human clinical trials.