Loading

Journal of Ear, Nose and Throat Disorders

Factors Influencing the Proliferation and Differentiation of Inner Ear Stem Cells

Inaugural Article | Open Access | Volume 8 | Issue 1

  • 1. Department of Otorhinolaryngology, the Third Hospital of Jilin University, China
+ Show More - Show Less
Corresponding Authors
Xuewei Zhu, Department of Otorhinolaryngology, the Third Hospital of Jilin University, Changchun 130000, China
Abstract

Irreversible damage to cochlear hair cells is one of the main causes of sensorineural deafness. In recent years, it has been found that a class of cells with stem cell properties and the ability to differentiate into hair cells, which are called inner ear stem cells, and their proliferation and differentiation may be the ultimate solution of sensorineural deafness. Inner ear stem cells have the potential for self- renewal and multi-differentiation, and their proliferation and differentiation processes are affected by a variety of factors, ranging from growth factors and miRNAs to the extracellular microenvironment and related signaling pathways, etc. This paper focuses on the factors affecting the proliferation and differentiation of inner ear stem cells.

KEYWORDS
  • Inner Ear Stem Cells
  • Regeneration
  • Signaling Pathway
CITATION

Zhu X, Liu Y, Hao Y (2024) Factors Influencing the Proliferation and Differentiation of Inner Ear Stem Cells. J Ear Nose Throat Disord 8(1): 1057.

INTRODUCTION

Inner ear stem cells were initially isolated from the sensory epithelium of the elliptic bursa of adult mice by Li et al., in 2003 and were named inner ear stem cells [1]. Since then researchers have isolated such cells from the cochlear Corti apparatus, the large epithelial ridge, and the small epithelial ridge [2,3]. Inner ear stem cells have the potential for self-renewal and multidirectional differentiation, which have a greater potential to differentiate into cochlear hair cells than other types of transplanted stem cells. Cochlear hair cells are terminally differentiated cells, whose irreversible damage or absence is one of the main causes of sensorineural deafness. Many studies have attempted to fundamentally treat sensorineural deafness by culturing inner ear stem cells in vitro , inducing them to differentiate into hair cells or hair cell-like cells. A challenge with this approach is how to regulate cell proliferation and differentiation once the cells have been reprogrammed and undergone differentiation. The differentiation of inner ear stem cells into mature cochlear hair cells is closely related to the microenvironment in which they reside, as well as the exchange of material, signaling, and genetic regulatory.

MicroRNAs

During the differentiation of inner ear stem cells, cells begin to differentiate directionally when specific transcriptional programs of certain genes are activated. MicroRNAs (miRNAs) are a class of small non-coding RNAs processed from the transcripts of endogenous genes, which are involved in a wide range of physiological and pathological processes by regulating the expression of target messenger RNAs (mRNAs). To date, hundreds of miRNAs have been identified in cochlear progenitor cells in culture.

The miR-183 family (including miR-183, miR-96, miR-182) is thought to be essential in the development of the inner ear. They originate from a common primary transcript, and the initial pattern of expression is widely distributed, but as the embryo develops, miR-183 expression is progressively confined to sensory cells in the cochlea and vestibular end-organs, as well as in the spiral ganglion and vestibular ganglia, with the most abundant expression in hair cells [4]. It was found that overexpression of miR-183 in zebrafish induced additional and ectopic hair cells, while low expression reduced the number of hair cells [5]. MiR-183 regulates the behavior of inner ear stem cells by affecting different target genes and signaling pathways, it can target genes that affect the cell cycle to promote or inhibit the proliferation of inner ear stem cells [6,7]. In addition, miR-183 can affect the differentiation of inner ear stem cells to specific cell types such as hair cells by regulating differentiation related signaling pathways such as the Notch signaling pathway [8]. By establishing a gentamicin induced cochlear injury model in mice, Zhou W et al. found that gentamicin-induced hair cell injury activated the Notch signaling pathway and downregulated the expression of miR-183. Inhibition of this signaling upregulated miR-183 cluster expression and promoted hair cell regeneration, suggesting that miR-183 cluster may be involved in notch inhibition-induced hair cell regeneration in gentamicin-treated cochlea.

In recent years, the role of miR-21 in stem cell proliferation and differentiation has received increasing attention, and the regulation of miR-21 significantly affects the proliferative and differentiation capacity of these cells [9,10]. It has been shown that overexpression of miR-21 promotes the proliferation and differentiation of inner ear stem cells to hair cell-like cells, which is important for hair cell regeneration [11]. MiR-21 can also regulate the behavior of inner ear stem cells by targeting several signaling pathways. Among them, PTEN (phosphatidylinositol-3- kinase inhibitor 1) and Spry1 (spray delay protein 1) are known targets of miR-21, and by inhibiting the expression of these target genes, miR-21 can activate the AKT signaling pathway and ERK signaling pathway, which can promote the proliferation and differentiation of cells [12].

Similarly, miR-124 can affect the behavior of inner ear stem cells by binding to the mRNAs of target genes, which may be involved in cell cycle control, cell death, signaling pathways, and other important biological processes, by blocking their translation process or promoting their degradation. It has been shown that miR-124-3p negatively regulates the EYA1 gene by interacting with the 3 ‘ UTR target site of the EYA1 gene, which leads to inner ear dysplasia in zebrafish [13]. Jiang D et al., found that miR-124 was lowly expressed in undifferentiated inner ear neural stem cells, with a gradual increase in expression and a peak at day 14 of differentiation. miR-124 overexpression increased the percentage of neurons and axon length, suggesting that miR-124 plays an important role in neuronal differentiation of inner ear stem cells in vitro [14].

MiR-34 is an important downstream effector of the p53 signaling pathway. P53 participates in cellular response programs, including cell cycle arrest, apoptosis, and aging, by activating miR-34 expression. In inner ear stem cells, p53-activated miR- 34 expression may have an inhibitory effect on cell proliferation and differentiation [15]. The let-7 family is a group of highly conserved microRNAs that were first identified in Caenorhabditis elegans and subsequently characterized in a variety of organisms, including humans. Let-7 family members play important roles in different biological processes, especially in cell proliferation, differentiation, development, and the onset and progression of diseases. They play important roles in various biological processes, especially in cell proliferation, differentiation, development, and the onset and progression of disease. Let-7 is able to directly target and regulate key molecules that affect the cell cycle, such as Cyclin D and Cyclin E, as well as other proteins that promote the entry of cells into the proliferative state. By down-regulating the expression of these proteins, let-7 helps to maintain cells in a quiescent state or promote their exit from the proliferative cycle, which in turn affects the proliferative capacity of inner ear stem cells [16]. Let-7 promotes cell differentiation by targeting multiple transcription factors and signaling molecules associated with the undifferentiated state of cells, such as Hmga2, Myc and Lin28, and inhibiting their expression. In inner ear stem cells, this role of let-7 may help to drive the differentiation of stem cells to specific inner ear cell lines such as hair cells, which is critical for restoring or maintaining hearing function [17]. Let-7 is also involved in the regulation of multiple signaling pathways that are closely linked to cell fate decisions, including Wnt, Notch and TGF-β. By precisely regulating the expression of key molecules in these pathways, let-7 influences the function of inner ear stem cells [18] (Figure 1).

Figure 1 Factors influencing the proliferation and differentiation of inner ear stem cells. Growth factors, miRNA and extracellular microenvironment may affect the viability and proliferation of auditory stem cells.

Figure 1: Factors influencing the proliferation and differentiation of inner ear stem cells. Growth factors, miRNA and extracellular microenvironment may affect the viability and proliferation of auditory stem cells.

In addition, miR-9 [19], and miR-155 [20], can also target a series of key genes and pathways to regulate the proliferation, differentiation, and regeneration of inner ear stem cells. With the continuous progress of RNA detection technology, it is expected that more mRNAs will be found in the inner ear in the future, but so far, the exact mechanism by which miRNAs affect inner ear development is still not well understood. Therefore, an in- depth understanding of the specific mechanisms of action of these miRNAs in the proliferation and differentiation of inner ear stem cells will contribute to the development of new therapeutic strategies for hearing loss.

Atoh1 (Atonal homolog 1) is a transcription factor, a member of the bHLH (basic helix-loop-helix) family of proteins, which was first identified in Drosophila and subsequently in mammals, where its homologs are particularly critical for the development of the nervous system [21]. As a transcription factor, Atoh1 activates or represses the expression of a range of downstream genes by binding to specific sequences on DNA. These genes are involved in the regulation of cell growth, differentiation, and the determination of specific cell fates [22,26]. Currently, it has been found that transfection of small activating RNA targeting Atoh1 into inner ear progenitor cells induces differentiation of hair cell progenitors to hair cell-like cells [23].Thus, RNA activation technology has the potential to provide a new strategy for hair cell regeneration. Mcgovern MM et al., reprogrammed non- sensory cells in the vicinity of the organ of Corti with three hair cell transcription factors, Gfi1, Atoh1, and Pou4f3, and found that the non-sensory region of the cochlea produced a large number of hair-cell-like cells and that cells in the vicinity of the reprogrammed hair cells expressed markers for support cells, suggesting that transcription of non-sensory cochlear cells in adult animals factor reprogramming can generate chimeras like the sensory cells in the organ of Corti [24], this approach, if successful, will certainly provide a potential new strategy for treating certain types of hearing loss. Li X et al., converted non-sensory supporting cells from inner ear hair cell-impaired mice into inner hair cells by transiently expressing Atoh1 and permanently expressing Tbx2. The new inner hair cells had similar transcriptomic and electrophysiological properties as wild-type inner hair cells, and the formation efficiency and maturation were higher than those of previous studies. However, there was no significant improvement in hearing in mice with damaged inner hair cells, which may be related to the defective electromechanical transduction function of the newborn inner hair cells [25].

Classical signaling pathways

Wnt signaling pathway is an important cell signaling pathway involved in the regulation of a variety of biological processes, including embryonic development, tissue regeneration, cell proliferation and differentiation, etc. It mainly includes Wnt/β- catenin, Wnt/PCP and Wnt/calcium signaling pathways. In the inner ear, the Wnt signaling pathway also plays a critical role in influencing the proliferation and differentiation of inner ear stem cells. During early inner ear development in mammals, Wnt/β-catenin is involved in the differentiation of the inner ear auditory vesicle and auditory substrate [26], in addition, upregulation of Wnt signaling in cochlear sensory precursors and supporting cells also promotes hair cell differentiation [27]. Chai et al., found that activation of the Wnt/β-catenin signaling pathway promotes proliferation of Lgr5-positive stem cells [28,29], however, only a few of these proliferating stem cells transform into hair cells [30]. It suggests that activation of the Wnt pathway only promotes the regeneration of inner ear stem cells but fails to produce large numbers of new hair cells.

Notch signaling is a highly conserved signaling pathway whose activation depends on direct contact between neighboring cells and mechanical pulling of Notch receptors by Notch ligands [31]. Activation of Notch signaling inhibits the proliferation of inner ear precursor cells, maintaining these cells in an undifferentiated state. This inhibition is achieved by directly suppressing the expression of key regulators of cell cycle progression [32]. Cell division is inhibited, for example, by decreasing the activity of cyclin-dependent kinases to prevent cells from entering the S phase. In addition, the Notch signaling pathway inhibits cell differentiation by activating specific downstream target genes, such as the Hes family and the Hey family, and this inhibition is essential for maintaining the correct ratio of inner ear hair cells to supporting cells [33].

In addition, Math1 and Hesl are important regulators that promote hair cell differentiation. It was found that in mice, if Math1 was knocked out, embryonic mice did have cochlear and vestibular hair cells, and vice versa, regeneration of cochlear hair cells and differentiation of vestibular hair cells were observed [34,35]. Hesl, in contrast to Math1, is a negative regulator in cochlear development, and both play an important role in normal cochlear development [36,37].

Extracellular environmental

The extracellular microenvironment, including the extracellular matrix (ECM), surrounding cells, solubility factors (e.g., growth factors and cytokines), as well as physical and chemical conditions (e.g., oxygen concentration, stiffness, and pH), also have a profound effect on the proliferation and differentiation of inner ear cells [38].

The extracellular matrix is (ECM) a complex network of multiple proteins and polysaccharides that not only provides physical support for the cell, but is also involved in regulating cell behavior [39,40]. In the inner ear, components of the extracellular matrix (ECM) such as fibronectin, laminin and collagen can influence the adhesion, proliferation and differentiation of inner ear stem cells [41,42]. Laminin (LN) is a heterotrimer of α, β and γ-chains, which is located in the basement membrane and subbasement membrane surrounding the spiral ganglion of the mammalian cochlea. The dimeric glycoprotein fibronectin (FN) has also been found to be located in the cochlea [43], both of them grow alongside spiral ganglion dendrite-targeted hair cells during cochlear maturation and subsequently influence cochlear hair cell growth and differentiation. In 2005, Tomama et al., identified in the cochlea of perinatal mammals heterodimers of the integrin ECM receptor family, which was previously found to be expressed in the developing brain and consists of a heterodimeric transmembrane protein consisting of an α chain and a β chain, which binds to a variety of molecules in the ECM, linking them to the actin cytoskeleton and other intracellular effectors [42,44]. Specific ECM components can activate specific signaling pathways, such as FGF, Wnt/β-catenin, etc., which in turn affects the direction of cell differentiation.

Peripheral cells in the inner ear microenvironment are also important for the proliferation and differentiation of inner ear stem cells, and they can regulate each other through direct contact with specific receptors and ligands (intercellular adhesions) on the cell surface, or interact with each other through, for example, the secretion of solubility factors. Yushi et al. [45], found that cochlear support cells protect the survival and function of hair cells by inducing type I interferon after viral infection, in addition, damage or death of ciliated cells can activate surrounding support cells, inducing them to transform into stem cells and participate in repair and regeneration processes. The nerve cells of the cochlear, vestibular and spiral nerves in the inner ear can influence the neural differentiation of stem cells through direct contact or secretion of nerve growth factors, etc. Fibroblasts are the main synthesizing cells of the extracellular matrix (ECM), which can influence the attachment/ proliferation and differentiation of stem cells by regulating the composition of the extracellular matrix, and also influence the proliferation and transformation to specific types of cells by secretion of fibroblast growth factors. Proliferation and transformation of inner ear stem cells to specific cell types through the secretion of fibroblast growth factors [46]. In addition, fibroblasts are involved in local immune responses and inflammatory processes, which can affect the microenvironment of inner ear stem cells through the secretion of cytokines and chemokines, thereby influencing their value-added and differentiation [41,47].

Soluble factors in the extracellular matrix mainly include epidermal growth factor (EGF), fibroblast growth factor (FGF), nerve growth factor, transforming growth factor-β (TGF-β), insulin-like growth factor and estrogen (IGF-1), prostaglandin E2, retinol, tumor necrosis factor alpha (TNF-alpha), and interleukins (IL-1 and IL-6). They are all proteins or peptides produced by cells that have the ability to influence cell behavior. These molecules can affect cell proliferation, differentiation, migration, etc. by binding to specific cell surface receptors or specific signaling pathways. Campbell et al. [48], found that epidermal growth factor (EGF) and fibroblast growth factor (FGF), could promote the proliferation and differentiation of neonatal mouse neural stem cells. Lian M et al.[49], found through in vitro cellular experiments that nerve growth factor could promote the functional and neurotrophic effects of bone marrow mesenchymal stem cells, which improved the osteogenic capacity of bone repair cells. Chen G et al. [50], injected transforming growth factor-β-1-treated extracellular vesicles (T-EVS) into spinal cord-injured mice and found that it significantly enhanced the proliferation and anti-apoptotic capacity of neural stem cells in vitro, as well as increased the transition of reactive microglial cells from M1 to M2, which resulted in attenuation of neuroinflammation and enhancement of neuroprotective effects of residual cells in the acute phase. In neonatal mammals with different types of hair cell injury, insulin- like growth factor-1 (IGF-1) maintains the number of hair cells in the cochlea by activating two major pathways downstream of the IGF-1 signaling pathway, and in aminoglycoside-treated neonatal mouse cochlear explant cultures, the IGF-1-treated group promotes support for the cell cycle and inhibits apoptosis of capillary cells [51]. Poletti V et al. [52], found that prostaglandin E2 increased the transduction efficiency of hematopoietic stem cell progeny in vitro. Vitamin A (including retinol and its active form retinoic acid) plays an important role in the regulation of stem cell fate determination and cell lineage plasticity, and retinoic acid serves as an important signaling molecule that can directly regulate the transcription of target genes by binding to intracellular retinoic acid receptors. This mechanism allows vitamin A to precisely regulate the differentiation process of stem cells, including promoting the formation of certain cell types and inhibiting the formation of other [53].Tumor necrosis factor (TNF-α) is a cytokine that is produced mainly by immune cells and is widely involved in inflammatory responses, immune regulation, and apoptotic and survival processes. In the study of inner ear stem cells, the role of TNF-α has also attracted attention, especially its potential effects on the proliferation and differentiation of inner ear stem cells, which may be promoted or inhibited through the activation of signaling pathways such as NF-κB, or through the alteration of intracellular signaling networks and the regulation of the expression of specific genes. One study knocked out the tumor necrosis factor gene receptor from lung cancer mouse cells, resulting in a significant reduction in tumor size and weight in TNFR2 knockout mice compared to wild-type mice [54]. Interleukins (ILs) are an important class of cytokines widely involved in immune regulation, cell proliferation, differentiation, and inflammatory responses. One research found that the expression of interleukin 1β and insulin- like growth factor-1 was up-regulated in neurons and glial cells of the cochlear ventral nucleus in adult rats at 1, 7, and 15 days after bilateral cochlear surgery, reflecting the possible involvement of IL-1 in repairing the synaptic dynamic balance of the overall cellular environment of the cochlear nucleus [55]. IL-2, IL-4, IL-6, and IL-8 promote the proliferation and differentiation of certain inner ear cells by activating the JAK/STAT signaling pathway or nuclear factor-κB (NF-κB) pathway, etc., which promote the proliferation and differentiation of certain inner ear cells [56,57].

The proliferation and differentiation of inner ear stem cells are regulated by a combination of genetic, environmental and biochemical factors. A deeper understanding of these influencing factors will not only help us to reveal the repair mechanisms after inner ear injury, but will also provide a scientific basis for the development of new therapeutic strategies. Future studies need to explore in greater depth how these factors interact with each other and how to promote inner ear regeneration and repair by interfering with these factors, thus opening up new avenues for the treatment of hearing loss and balance dysfunction.

REFERENCES
  1. Li H, Liu H, Heller S. Pluripotent stem cells from the adult mouse inner ear. Nat Med. 2003; 9: 1293-1299.
  2. Oshima K, Grimm CM, Corrales CE, Senn P, Martinez Monedero R, Géléoc GS, et al. Differential distribution of stem cells in the auditory and vestibular organs of the inner ear. J Assoc Res Otolaryngol. 2007; 8: 18-31.
  3. Zhang Y, Zhai SQ, Shou J, Song W, Sun JH, Guo W, et al. Isolation, growth and differentiation of hair cell progenitors from the newborn rat cochlear greater epithelial ridge. J Neurosci Methods. 2007; 164: 271-279.
  4. Li H, Kloosterman W, Fekete DM. MicroRNA-183 family members regulate sensorineural fates in the inner ear. J Neurosci. 2010; 30: 3254-3263.
  5. Mahmoodian Sani MR, Hashemzadeh-Chaleshtori M, Saidijam M, Jami MS, Ghasemi-Dehkordi P. MicroRNA-183 Family in Inner Ear: Hair Cell Development and Deafness. J Audiol Otol. 2016; 20: 131-138.
  6. Lewis MA, Di Domenico F, Ingham NJ, Prosser HM, Steel KP. Hearing impairment due to Mir183/96/182 mutations suggests both loss and gain of function effects. Dis Model Mech. 2020; 14: dmm047225.
  7. Geng R, Furness DN, Muraleedharan CK, Zhang J, Dabdoub A, Lin V, et al. The microRNA-183/96/182 Cluster is Essential for Stereociliary Bundle Formation and Function of Cochlear Sensory Hair Cells. Sci Rep. 2018; 8: 18022.
  8. Zhou W, Du J, Jiang D, Wang X, Chen K, Tang H, et al. microRNA 183 is involved in the differentiation and regeneration of Notch signaling prohibited hair cells from mouse cochlea. Mol Med Rep. 2018; 18: 1253-1262.
  9. Niu Z, Goodyear SM, Rao S, Wu X, Tobias JW, Avarbock MR, et al. MicroRNA-21 regulates the self-renewal of mouse spermatogonial stem cells. Proc Natl Acad Sci USA. 2011; 108: 12740-12745.
  10. Hao F, Shan C, Zhang Y, Zhang Y, Jia Z. Exosomes Derived from microRNA-21 Overexpressing Neural Progenitor Cells Prevent Hearing Loss from Ischemia-Reperfusion Injury in Mice via Inhibiting the Inflammatory Process in the Cochlea. ACS Chem Neurosci. 2022; 13: 2464-2472.
  11. Chawra HS, Agarwal M, Mishra A, Chandel SS, Singh RP, Dubey G, et al. MicroRNA-21’s role in PTEN suppression and PI3K/AKT activation: Implications for cancer biology. Pathol Res Pract. 2024; 254: 155091.
  12. Zhang R, Sun Y, Zhang Q, Lin J, Zhang Y, Chen X, et al. Overexpression of miR-124-3p affects zebrafish inner ear development and hearing function via downregulation of EYA1 gene expression. Neurosci Lett. 2023; 802: 137172.
  13. Jiang D, Du J, Zhang X, Zhou W, Zong L, Dong C, et al. miR-124 promotes the neuronal differentiation of mouse inner ear neural stem cells. Int J Mol Med. 2016; 38: 1367-1376.
  14. Xiong H, Pang J, Yang H, Dai M, Liu Y, Ou Y, et al. Activation of miR- 34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss. Neurobiol Aging. 2015; 36: 1692-1701.
  15. Wang Y, Zhao J, Chen S, Li D, Yang J, Zhao X, et al. Let-7 as a Promising Target in Aging and Aging-Related Diseases: A Promise or a Pledge. Biomolecules. 2022; 12: 1070.
  16. Kuan II, Lee CC, Chen CH, Lu J, Kuo YS, Wu HC. The extracellular domain of epithelial cell adhesion molecule (EpCAM) enhances multipotency of mesenchymal stem cells through EGFR-LIN28-LET7 signaling. J Biol Chem. 2019; 294: 7769-7786.
  17. Ye Z, Su Z, Xie S, Liu Y, Wang Y, Xu X, et al. Yap-lin28a axis targets let7- Wnt pathway to restore progenitors for initiating regeneration. Elife. 2020; 9: e55771.
  18. Di Stadio A, Pegoraro V, Giaretta L, Dipietro L, Marozzo R, Angelini C. Hearing impairment in MELAS: new prospective in clinical use of microRNA, a systematic review. Orphanet J Rare Dis. 2018; 13: 35.
  19. Moutabian H, Radi UK, Saleman AY, Adil M, Zabibah RS, Chaitanya MNL, Saadh MJ, Jawad MJ, Hazrati E, Bagheri H, Pal RS, Akhavan-Sigari R. MicroRNA-155 and cancer metastasis: Regulation of invasion, migration, and epithelial-to-mesenchymal transition. Pathol Res Pract. 2023; 250: 154789.
  20. Hongmiao R, Wei L, Bing H, Xiong DD, Jihao R. Atoh1: landscape for inner ear cell regeneration. Curr Gene Ther. 2014; 14: 101-111.
  21. Choi SW, Abitbol JM, Cheng AG. Hair Cell Regeneration: From Animals to Humans. Clin Exp Otorhinolaryngol. 2024; 17: 1-14.
  22. Zhang YL, Kang M, Wu JC, Xie MY, Xue RY, Tang Q, et al. Small activating RNA activation of ATOH1 promotes regeneration of human inner ear hair cells. Bioengineered. 2022; 13: 6729-6739.
  23. McGovern MM, Hosamani IV, Niu Y, Nguyen KY, Zong C, Groves AK. Expression of Atoh1, Gfi1, and Pou4f3 in the mature cochlea reprograms nonsensory cells into hair cells. Proc Natl Acad Sci U S A. 2024; 121: e2304680121.
  24. Li X, Ren M, Gu Y, Zhu T, Zhang Y, Li J, et al. In situ regeneration of inner hair cells in the damaged cochlea by temporally regulated co- expression of Atoh1 and Tbx2. Development. 2023; 150: dev201888.
  25. Ohyama T, Mohamed OA, Taketo MM, Dufort D, Groves AK. Wnt signals mediate a fate decision between otic placode and epidermis. Development. 2006; 133: 865-875.
  26. Hosseini V, Dani C, Geranmayeh MH, Mohammadzadeh F, Nazari Soltan Ahmad S, Darabi M. Wnt lipidation: Roles in trafficking, modulation, and function. J Cell Physiol. 2019; 234: 8040-8054.
  27. Shi F, Hu L, Jacques BE, Mulvaney JF, Dabdoub A, Edge AS. β-Catenin is required for hair-cell differentiation in the cochlea. J Neurosci. 2014; 34: 6470-6479.
  28. Chai R, Kuo B, Wang T, Liaw EJ, Xia A, Jan TA, et al. Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea. Proc Natl Acad Sci U S A. 2012; 109: 8167-8172.
  29. Kuo BR, Baldwin EM, Layman WS, Taketo MM, Zuo J. In Vivo Cochlear Hair Cell Generation and Survival by Coactivation of β-Catenin and Atoh1. J Neurosci. 2015; 35: 10786-98.
  30. Gozlan O, Sprinzak D. Notch signaling in development and homeostasis. Development. 2023; 150: dev201138.
  31. Shu Y, Li W, Huang M, Quan YZ, Scheffer D, Tian C, et al. Renewed proliferation in adult mouse cochlea and regeneration of hair cells. Nat Commun. 2019; 10: 5530.
  32. Brown R, Groves AK. Hear, Hear for Notch: Control of Cell Fates in the Inner Ear by Notch Signaling. Biomolecules. 2020; 10: 370.
  33. Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, Eatock RA, et al. Math1: an essential gene for the generation of inner ear hair cells. Science. 1999; 284: 1837-1841.
  34. Li S, Qian W, Jiang G, Ma Y. Transcription factors in the development of inner ear hair cells. Front Biosci (Landmark Ed). 2016; 21: 1118- 1125.
  35. Zine A, Aubert A, Qiu J, Therianos S, Guillemot F, Kageyama R, et al. Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear. J Neurosci. 2001; 21: 4712- 4720.
  36. You D, Ni W, Huang Y, Zhou Q, Zhang Y, Jiang T, et al. The proper timing of Atoh1 expression is pivotal for hair cell subtype differentiation and the establishment of inner ear function. Cell Mol Life Sci. 2023; 80: 349.
  37. Pressé MT, Malgrange B, Delacroix L. The cochlear matrisome: Importance in hearing and deafness. Matrix Biol. 2024; 125: 40-58.
  38. Goh SK, Halfter W, Richardson T, Bertera S, Vaidya V, Candiello J, et al. Organ-specific ECM arrays for investigating cell-ECM interactions during stem cell differentiation. Biofabrication. 2020; 13.
  39. Chaudhuri O, Cooper-White J, Janmey PA, Mooney DJ, Shenoy VB. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature. 2020; 584: 535-546.
  40. Zhang J, Liu L, Li Y, Wu J, Lou X. Mouse Embryonic Fibroblasts-Derived Extracellular Matrix Facilitates Expansion of Inner Ear-Derived Cells. Cell J. 2023; 25: 447-454.
  41. Evans AR, Euteneuer S, Chavez E, Mullen LM, Hui EE, Bhatia SN, et al. Laminin and fibronectin modulate inner ear spiral ganglion neurite outgrowth in an in vitro alternate choice assay. Dev Neurobiol. 2007; 67: 1721-1730.
  42. Cosgrove D, Rodgers KD. Expression of the major basement membrane-associated proteins during postnatal development in the murine cochlea. Hear Res. 1997; 105: 159-170.
  43. Johnson Chacko L, Lahlou H, Steinacher C, Assou S, Messat Y, Dudás J, et al. Transcriptome-Wide Analysis Reveals a Role for Extracellular Matrix and Integrin Receptor Genes in Otic Neurosensory Differentiation from Human iPSCs. Int J Mol Sci. 2021; 22: 10849.
  44. Hayashi Y. Signaling pathways regulating the immune function of cochlear supporting cells and their involvement in cochlear pathophysiology. Glia. 2024; 72: 665-676.
  45. Yang Q, Shi H, Quan Y, Chen Q, Li W, Wang L, et al. Stepwise Induction of Inner Ear Hair Cells From Mouse Embryonic Fibroblasts via Mesenchymal to Epithelial Transition and Formation of Otic Epithelial Cells. Front Cell Dev Biol. 2021; 9: 672406.
  46. Cumpata AJ, Labusca L, Radulescu LM. Stem Cell-Based Therapies for Auditory Hair Cell Regeneration in the Treatment of Hearing Loss. Tissue Eng Part B Rev. 2024; 30: 15-28.
  47. Campbell CE, Webber K, Bard JE, Chaves LD, Osinski JM, Gronostajski RM. Nuclear Factor I A and Nuclear Factor I B Are Jointly Required for Mouse Postnatal Neural Stem Cell Self-Renewal. Stem Cells Dev. 2024; 33: 153-167.
  48. Lian M, Qiao Z, Qiao S, Zhang X, Lin J, Xu R, et al. Nerve Growth Factor-Preconditioned Mesenchymal Stem Cell-Derived Exosome- Functionalized 3D-Printed Hierarchical Porous Scaffolds with Neuro- Promotive Properties for Enhancing Innervated Bone Regeneration. ACS Nano. 2024; 18: 7504-7520.
  49. Chen G, Tong K, Li S, Huang Z, Liu S, Zhu H, et al. Extracellular vesicles released by transforming growth factor-beta 1-preconditional mesenchymal stem cells promote recovery in mice with spinal cord injury. Bioact Mater. 2024; 35: 135-149.
  50. Yamamoto N, Nakagawa T, Ito J. Application of insulin-like growth factor-1 in the treatment of inner ear disorders. Front Pharmacol. 2014; 5: 208.
  51. Poletti V, Montepeloso A, Pellin D, Biffi A. Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells. Mol Ther Methods Clin Dev. 2023; 31: 101131.
  52. Tierney MT, Polak L, Yang Y, Abdusselamoglu MD, Baek I, Stewart KS, Fuchs E. Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices. Science. 2024; 383: eadi7342.
  53. Yeo IJ, Yu JE, Kim SH, Kim DH, Jo M, Son DJ, et al. TNF receptor 2 knockout mouse had reduced lung cancer growth and schizophrenia- like behavior through a decrease in TrkB-dependent BDNF level. Arch Pharm Res. 2024; 47: 341-359.
  54. Fuentes-Santamaría V, Alvarado JC, Gabaldón-Ull MC, Manuel Juiz J. Upregulation of insulin-like growth factor and interleukin 1β occurs in neurons but not in glial cells in the cochlear nucleus following cochlear ablation. J Comp Neurol. 2013; 521: 3478-3499.
  55. Kubo T, Anniko M, Stenqvist M, Hsu W. Interleukin-2 affects cochlear function gradually but reversibly. ORL J Otorhinolaryngol Relat Spec. 1998; 60: 272-277.
  56. Tan CQ, Gao X, Guo L, Huang H. Exogenous IL-4-expressing bone marrow mesenchymal stem cells for the treatment of autoimmune sensorineural hearing loss in a guinea pig model. Biomed Res Int. 2014; 2014: 856019.
  57. Iguchi H, Anniko M. Interleukin 8 can affect inner ear function. ORL J Otorhinolaryngol Relat Spec. 1998; 60: 181-189.

Zhu X, Liu Y, Hao Y (2024) Factors Influencing the Proliferation and Differentiation of Inner Ear Stem Cells. J Ear Nose Throat Disord 8(1): 1057.

Received : 07 Jul 2024
Accepted : 01 Aug 2024
Published : 01 Aug 2024
Journals
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X