Zebrafish As a biomedical model for Stem Cells Research in Hearing impairment

Zebrafish is an excellent model for observing human genetic disorders. Hearing impairment is the most common genetic disorder including syndromic & non-syndromic hearing loss. Stem cells therapies are considered a new hope in case of hearing impairment. Stem cells are the master cells of the human body and having the capability to differentiate into any other form of cells more than 200 types of cells (regeneration). This review article describes zebrafish as a biomedical model for stem cell research in hearing impairment, which revolutionized the biomedical arena to compete for the challenges.


Introduction
Zebrafish (Danio rerio) is a small fish with big data belongs to family Cyprinidae. Zebrafish is an excellent model organism for the study and observation of human genetic diseases. The unique feature of zebrafish such as large fertility rates, transparency & optic clearance makes it remarkable biomedical model in stem cell research for genetic studies. Also, 70% of genome similarity of zebrafish with human make it a significant model for scientific research [1]. Hearing impairment is the most common genetic disorder caused by external & inner ear anomalies [2]. There is large no of genes which are involved in hereditary sensorineural hearing loss and the cellular signalling mechanism of the development of the ears [3]. Stem cell therapy considered a new hope in the restoring hearing balance & regenerative stem cells therapy of cell associated with the auditory function will make it possible to cure the hearing impairment [4].

Wnt & FGF pathway & its Role in the neuromast of zebrafish:
The zebrafish lateral line is an excellent model of the sensory network made up of mechanosensory hair cells called neuromast. These mechanosensory hair cells are similar in function & mechanism as the vertebrate hair cells of the inner ear. In this way, these are the excellent model system for observing the hair cells molecular mechanism related to hearing & balance to understand their genetic control. The unique properties of these hair cells of zebrafish in the lateral line are their regenerative capability, which makes them an excellent model for scientific research. Thus the molecular signalling pathway of these hair cells regeneration has great biomedical importance. Wnt and FGF pathway are crucial signalling pathway that is found in various organs and are   (Fig 2). The mutation of CX30 shows structural alteration in the inner ear. In the transgenic zebrafish, the mutation of CX30 is caused by decreased mechanosensory perception & instability in swimming. The CX26 & CX30 are homologous protein in term of subcellular location that affects the function of inner ear and development of inner ear by structural changes of the otolith. The mutation in CX26 & CX30 in transgenic zebrafish shows cellular anomalies that changed the anatomy of the inner ear [8].

The regeneration of hair cells in the zebrafish:
The genetics of zebrafish is helpful to study regeneration to find out genes involved in healing processes that lack in mammals. This large -scale genetic screen of neuromast development in zebrafish provides an essential platform for hair cells regeneration as well as in tissue regeneration. The authors analyzed the genetic screen involving 254 stable genetic mutations on hair cells regeneration. As a result, seven genes i-e hspd1, hspe1, hspa13, rnpc3, gem5, hspa13 & mgat5 are identified that are considered essential for hair cells regeneration. These seven regeneration genes are categorized in three functional groups: 1) heat shock protein (hspd1,hspe1,hspa13), 2) RNA splicing factor (rnpc3,gem5,hspa13) ,and 3) glycosylation enzyme (mgat5).These three functional group consists of one enhancer & six inhibitors of regeneration (Fig 3). The regenerative mechanism of theses 7 genes in the zebrafish   inner ear. It regulates p53 gene that regulates cells apoptosis, in this way miRNA-183 cluster plays an essential role in the stimulation of hair cells regeneration by regulating signal molecules that are involved in transdifferentiation of hair cells after ototoxic damage & helpful to develop a potential drug target for hearing impairment [17].

Stem cells research in the hearing impairment:
The stem cells therapies are considered a new hope in hearing impairments. Stems cells are the master cells of the body that can differentiate into more than 200 types of cells. The regenerative ability of stem cell gives direction to differentiate them in mechanosensory hair cells & nerves cells for the therapeutic approach of hearing impairment [18]. miRNA plays a crucial role in the development of hair cells & cochlea. It also participates in the proliferation of stem cells in the regeneration of hair cells of the inner ear to restore hearing loss [19]. Also, stem cells homing factor is an essential mechanism to utilize the mesenchymal stem cells for transplantation of cochlear tissue in the inner ear for recovery of hearing loss [20].

Conclusion:
It is concluded that zebrafish is the best biomedical model for stem cells research due to its transparent visualization of genetic screening. The mechanosensory hair cells in the neuromast of zebrafish & its regenerative capabilities make it best model animal for inner ear therapy. But still, there are gaps to reach the therapeutic goal of hearing impairment. The mechanism of the signalling pathway of gap junctions, FGF, SHP-2, SIX1 and SALL1 proteins are still questionable in the model organism to overcome the congenital hearing loss in human.