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 Table of Contents  
Year : 2017  |  Volume : 23  |  Issue : 4  |  Page : 217-221

The application of Mir-183 family and mesenchymal stem cells: A possibility for restoring hearing loss

1 Department of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
2 Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
3 Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord; Young Researchers and Elite Club, Islamic Azad University, Shahrekord Branch, Shahrekord, Iran

Date of Web Publication2-May-2018

Correspondence Address:
Majid Asadi-Samani
Shahrekord University of Medical Sciences, Rahmatiyeh, Shahrekord
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/indianjotol.INDIANJOTOL_105_17

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Hearing loss as one of the most common disabilities approximately over 5% of the world's population – 360 million people – has disabling hearing loss (328 million adults and 32 million children). Recent developments in stem cell technology provide new opportunities for the treatment of deafness. miRNAs are essential factors of an extensively conserved posttranscriptional process controlling gene expression at mRNA level. Various biological processes such as growth and differentiation are regulated by miRNAs. In this review paper we have discussed about the application of miR-183 family and mesenchymal stem cells as a possibility for restoring hearing loss. In this regards, the web of Science and PubMed databases were searched using the Endnote software for the publications about the application of miR-183 family and mesenchymal stem cells (MSCs) to study hearing loss published from 2000 to 2016. The miR-183 family (miR-183, miR-96, and miR-182) is expressed abundantly in sensory cells in inner ear. miR-183 family is significant for the development and persistence of auditory neurons and hair cell. These four genes, i.e. Sox2, Notch1, Jag1, and Hes1, are potentially the targets of miR-183 family. In studies on animal models such as mouse and zebrafish, the time of Atoh1 expression in the hair cells was found to be the E12/5-E14/5 day, and miR-183 family was reported to begin to express on the E14/5 day. Use of human MSCs in differentiating into hair cells has been investigated, demonstrating that MSCs have neuroregenerative capacity. Cell therapy-targeting regeneration of the auditory neurons and hair cell may therefore be a powerful strategy to cure hearing loss that cannot be reversed by current therapies. A combination of the MSCs, specific growth factors and miR-183 cluster (96-182-183) can increase the potential to differentiate into the auditory neurons and hair cell.

Keywords: Hearing loss, mesenchymal stem cells, miR-183, miRNA

How to cite this article:
Mahmoudian-Sani MR, Mehri-Ghahfarrokhi A, Poorshahbazi GR, Asadi-Samani M. The application of Mir-183 family and mesenchymal stem cells: A possibility for restoring hearing loss. Indian J Otol 2017;23:217-21

How to cite this URL:
Mahmoudian-Sani MR, Mehri-Ghahfarrokhi A, Poorshahbazi GR, Asadi-Samani M. The application of Mir-183 family and mesenchymal stem cells: A possibility for restoring hearing loss. Indian J Otol [serial online] 2017 [cited 2023 Feb 5];23:217-21. Available from: https://www.indianjotol.org/text.asp?2017/23/4/217/231638

  Introduction Top

The present review article was aimed to discuss the application of miR-183 family and mesenchymal stem cells as a possibility for restoring hearing loss. In this regards, the Web of Science and PubMed databases were searched for the publications about the application of miR-183 family and mesenchymal stem cells (MSCs) to study hearing loss between 2000 and 2016 using the EndNote software. The used search terms were miRNA-183 and deafness or hearing loss and mesenchymal stem cells in title/keywords/abstract. Each database was searched independently. The articles retrieved from both databases were analyzed once. Abstracts were reviewed based on predefined inclusion and exclusion criteria. When necessary, full texts were retrieved to assess study eligibility. The articles without English abstract and English available full texts were excluded from the study. Only the articles directly addressing the effect of miRNA-183 family in inner development and deafness were selected and analyzed. From the Web of Science, in this study, ninety articles were retrieved from the Web of Science and PubMed for first analysis. After reviewing the articles, we excluded 29 articles from the analysis as they did not meet the inclusion criteria 61 articles investigated the application of miR-183 family and mesenchymal stem cells to study hearing loss. Currently, cell-based therapy is considered a potential therapy approach to treat diseases and great efforts are being made to improve its efficacy. All cell-based therapy interventions are based on the stem cells potential to be implanted, proliferate, be differentiated, and survive in the tissue. These cells can serve as alternative or supplementary therapies for cell and tissue damage. Worldwide, there are over 250 million people with congenital deafness which is mainly due to damage to auditory sensory receptors (hair cells) and related nerves.[1],[2],[3] Definite treatment for hearing loss due to destruction of hair cells or upper nervous system is one of the main challenges ahead for decreasing of inner ear disorders which are likely to be partially repaired only through rehabilitation measures.[4] In other words, the cell components of inner ear that develop hearing sense and are our communication tool with the environment are vulnerable to many risk factors. Different types of congenital and acquired hearing loss are due to irrevocable destruction of hair cells or related neurons, which are not replaced in the same manner as other inner ear epithelial cells are divided or differentiated.[1] Therefore, developing new therapy interventions are highly important to treat deafness.[5],[6] Moreover, using and culturing stem cells to treat deafness and hearing loss is an important subject of study.[1] Theoretically, it can be argued that all types of the inner ear cells can be regenerated from the stem cells. Therefore, stem cell-based therapies are thought to be highly applicable to treat vestibular disorders and different types of hearing loss in the future and therefore are considered a great step to improving the most prevalent disability in the world.[7] Through identifying the genes involved in the auditory system of adults and embryos of rodents, poultry, and amphibian, the researchers can figure out the process of natural repair of hair cells.[8],[9] Particularly, study of rodents such as mice that have a hearing system similar to human has been helpful to answer many questions regarding the repair process of this disorder.[10]

  Mesenchymal Stem Cells Top

Preliminary investigations have found that MSCs can be differentiated into hair cells.[7] It is therefore particularly important to differentiate MSCs into hair cells, and to place and replace these differentiated cells in the organ of Corti in the inner ear. In this regard, the potential of human MSCs (hMSCs) to differentiate into auditory neurons and hair-like cells can be used in vitro.[11] Because in the hearing system, no stem/progenitor cell population exists after birth to regenerate hair cells and auditory neurons, it is necessary to transplant the effective cells that can differentiate into different types of destroyed sensory cells in the inner ear to effectively treat mild-to-severe hearing loss. Because auditory neurons and hair cells are derived from a single neuron progenitor,[12],[13],[14] and given the MSCs potential to differentiate into neurons,[15],[16] these cells are appropriate candidates for cell therapy-based neuroregeneration. MSCs are one of the most important stem cells that are currently being widely studied.[17] These cells that share many properties of the stem cells can differentiate into different mesenchymal lineage cells such as fat, cartilage, and muscle cells, and nonmesenchymal ones such as neurons.[18] Problems associated with the use of human embryonic stem cells (hESCs) and induced pluripotent stem (iPS) cells such as behavioral problems and tumor formation in receiving people have caused further attention to be paid to use of mesenchymal cells. Because these cells are isolated from the donor with his/her consent, they do not cause the problems associated with hESCs. Besides that, the patients can undergo a specific treatment much earlier compared to iPS. Easy isolation, high proliferation rate, and lack of stimulability of immunity system are some benefits of using these types of cells.[19] Naturally, MSCs are converted to adipocytes, osteocytes, and chondrocyte.[20] Recently, the use of hMSCs in differentiation into hair cells has been investigated, demonstrating that MSCs have neuroregenerative capacity. This finding increases the likelihood that these cells repair damaged auditory neurons in patients with auditory neuropathy.[15],[21],[22],[23],[24],[25] MSCs spontaneously express certain neuron-specific proteins such as nestin, tubulin III, and neurofilament, which can be a reason for selecting these cells to repair auditory neurons.[26] MSCs from mice are likely to differentiate into sensory neurons in the presence of specific growth factors,[27] and the MSCs that have already differentiated into sensory neurons are effective in auditory repair after being transplanted successfully in mouse with induced hearing loss.[28] However, there are wide differences between the data of mouse and human models, and scant evidence exists on differentiation of hMSCs into the hair cells and auditory neurons.[29],[30],[31] Currently, the first phase clinical trials are studying differentiation of hMSCs into otic precursors, and the subsequent studies will investigate differentiation into auditory neurons and hair cells.[32] Moreover, in the light of the MSCs' potential to differentiate into mesodermal cell lines, repairing fibrocytes in cochlear side wall and therefore reversing hearing loss are facilitated.[33] In addition, in the recent years, these cells have been demonstrated to differentiate into ectodermal cell lines (hair cells have an ectodermal origin).[21],[25],[34],[35]

  Mirnas Top

miRNAs are small RNAs that are derived from prefabrication with loop-stem structure [Figure 1],[36],[37] and contribute mainly to regulating gene expression through targeting and digesting mRNAs or inhibiting their expression. There are a wide spectrum of miRNAs in different cells and tissues of the body that plays very important part in many biological processes and cell differentiation such as neuroregeneration.[36],[37] According to bioinformatic predictions, approximately 1/3 of protein-coding genes in human genome are regulated by miRNA.[38] miRNAs are currently being investigated, in the second phase of clinical trials, for treatment of breast cancer, arthritic diseases, and hepatitis C.[39] Lack of cell lines related to inner ear and no convenient access to human ear tissue are the main challenges ahead for the studies on miRNAs role in the inner ear. Detecting miRNAs in the inner ear and their regulation-related targets is a therapy strategy to treat inner ear disorders. Ability to produce hair cell precursors is an effective strategy to study RNAs regulation by miRNAs in the inner ear.[39]
Figure 1: miRNA biogenesis is a multistep process. First, miRNA genes are transcribed by RNA polymerase II in the nucleus. The resulting primary transcript is cleaved by Drosha and DGCR8 to produce pre-miRNA. After exportin-5- and RanGTP-mediated transport to the cytoplasm, the pre-miRNA undergoes its final processing step, which consists of Dicer-dependent cleavage just below the stem loop to produce a duplex molecule. The duplex is then separated and usually one strand is selected as the mature miRNA and is directed to target-specific mRNAs. Adapted from Mahmoudian-Sani, et al. European thyroid journal. 2017;6(4):171-7.

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miRNA biogenesis is a multistep process. First, miRNA genes are transcribed by RNA polymerase II in the nucleus. The resulting primary transcript is cleaved by Drosha and DGCR8 to produce pre-miRNA. After exportin-5-and RanGTP-mediated transport to the cytoplasm, the pre-miRNA undergoes its final processing step, which consists of dicer-dependent cleavage just below the stem-loop to produce a duplex molecule. The duplex is then separated and usually one strand is selected as the mature miRNA and directed to target-specific mRNAs.[40]

  Mir-183 Family Top

miR-183 family consists of three homologous miRNA, miR-183, miR-192, and miR-92, expressed in sensory neurons and hair cells of vertebrates and sensory cells of all animal species.[41] In the vertebrates, members of miR-183 family are expressed in the olfactory epithelium, eye, neuromast, and ear.[42],[43] In the inner ear of mice, miRNAs are expressed in sensory neurons and hair cells of the Corti organ and vestibular end organs. miR-96, mir-182, and miR-183 comprise a fully preserved family of miRs and localize in intergenic loci of chromosome 7 long arm [Figure 2].[44],[45],[46] In vertebrates, the expression of miR-183 family may be limited to ciliated sensory epithelial cells and certain cranial and spiral ganglia. miR-182, alongside miR-183 and miR-96, are from a polycistronic miRNA cluster which localize in a 4 kb region on the chromosome 6 long arm.[47] They are expressed particularly in certain organs such as eye, nose, and inner ear.[48]
Figure 2: (a) Chromosomal locus of miR-183 cluster (b) seed sequences of the miR-96, -182, -183

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  Micrornas Role in Sensorineural Inner Ear Diseases Top

Study of the nervous system of different organisms has demonstrated the critical role of miRNA in evolution and function of the nervous system. We believe that, in the steps of MSCs differentiation into hair cells and auditory neurons, in addition to using growth factors, we can use the increased expression of the miRNA related to the differentiation step of interest, according to the evidence from bioinformatics studies and experimental data on mouse and other animal models. Relevantly, miR-183 family plays a fundamental role in differentiation into hair cells and auditory neurons.[39] In addition, regulatory dysfunction of miRNAs is seen in sensorineural damage and other ear diseases such as cholesteatomas and labyrinthitis. Because of lack of access to human inner ear, animal models, particularly mouse and bioinformatic research are used to study the miRNAs expression and function.

  Regulation of Atoh1 Activity Top

Atoh1 is the first and most important gene which has been detected so far in association with evolution of hair cells. Throughout evolution, expression of Atoh1 that codes a basic helix–loop–helix (bHLH) transcription factor is limited to the cells that differentiate into the hair cells.[49],[50] To induce ectopic differentiation, hair cell is needed.[51] In the light of significance of controlling and regulating the number and ratio of the cells that differentiate into the hair cells, the expression rate of this gene and the percentage of the cells at which it is expressed are likely to be controlled by several parallel mechanisms. To date, different factors have been detected in upregulating or downregulating Atoh1. The expression of Sox2, which occurs in all cells of the inner ear sensory region, is a prerequisite for the expression of Atoh1. However, it has been demonstrated that long-term expression of Sox2 leads to inhibiting Atoh1 ability to induce differentiation into the hair cells.[52] Inhibitors of differentiation (Id) genes are another family of Atoh1 regulators whose members are all antagonists of bHLH transcription factors.[53] In mammals, high levels of the factors Id1, Id2, and Id3 are expressed in the evolving cells of auditory system, but the expression of these factors in the cells that can differentiate into the hair cells decreases considerably such that the induced expression of Id3 has been reported to inhibit differentiation of the hair cells. These findings represent the role of Id factors in downregulating Atoh1.[54] Notch signaling is one of the signallng pathways whose role in regulation of Atoh1 expression and hair cells differentiation has been studied well.[55] Through notch signaling, pluripotent precursor cells can differentiate into different cells. Notch1 has been demonstrated to be expressed in epithelial cells, while two notch ligands, i.e. Delta-like1 and Jagged2, are exclusively expressed in the cells that are differentiating into hair cells.[56],[57] Besides that, several bHLH-inhibiting factors including Hes5 and Hes1 are exclusively expressed in the supporting cells,[58],[59] and elimination of Hes5 and Hes1 leads to increased number of the hair cells.[60] Regulating Atoh1 activity and the potential role of miRNA-183 family in regulating Atoh1 function bioinformatic studies to predict the targets of miR-183 family have demonstrated that these targets may include the factors that speed up evolution of prosensory cells. Moreover, the supporting cells and certain genes--Sox-2, Notch1, Jag1, and Hes1--that play a part in evolution of the supporting cells can be considered the targets of miRNA-183 family [Table 1]. Therefore, only if combined with miRNA-183 family, Atoh1 may direct differentiation from the partially differentiated cells toward hair cell-like ones.[61] The supporting cells exclusive expression of Sox2 occurs during evolution of inner ear, and Sox2 has been demonstrated to be Atoh1 antagonist.[52] Notch1 is the regulator of Hes1, which is the downregulator of Atoh1.[62] These four genes, i.e., Sox2, Notch1, Jag1, and Hes1, have the potential to be the targets of miR-183 family.[63] In the studies on animal models such as mouse and zebrafish, Atoh1 was expressed in the hair cells on E12/5-E14/5 day, and expression of miR-183 family was reported to begin on E14/5 day.[64] Differentiation of the hair cells in the cochlea begins between E14 and E15 in the mid-basal region. At the same time, when Hes1, Notch, and Sox2 downregulate differentiation of the hair cells, they are indeed directing differentiation toward the supporting cells. miR-183 is likely to play a vital, upregulatory role in differentiating into the hair cells and enables Atoh1 to perform its function.
Table 1: The target genes of miR-183 family[64]

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  Conclusion Top

miR-183 family (miR-96, -182, -183) contribute significantly to formation and survival of hair cells, removal of these microRNAs in the inner ear has led to hair cells death in mouse and zebrafish models. Also, the expression rate of miR-183 family was reduced by morpholino and locked nucleic acid, and miR-183 family was demonstrated to contribute to hair cell survival in vertebrate. The members of miR-183 family, in the future research studying regeneration of the hair cell from the stem cell, can be used to suppress regeneration of the supporting and prosensory cells to facilitate differentiation into the hair cells. A combination of the MSCs, specific growth factors and miR-183 cluster (96-182-183) can increase the potential of differentiation into the auditory neurons and hair cells.

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  [Figure 1], [Figure 2]

  [Table 1]


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